Vaccines 54 - Edit PDF

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()

()

1 :
1

2

3

4

5

6

7

8

2:
9

10

11

12

2
10
19
30
40
61
67
76
100
109
117
126
13

14

15 -

16

17

18

19

20

21

22

23

24

25

26

27

136
153
164
173
184
194
207
212
221
238
249
268
279
294
317
28

29

30

31

32

33

34

3 :
35

36

37

38

39

40

41

42

332
342
352
365
377
383
393
406
421
432
442
483
499
506
567
43

44

45

46

47

48

49

50

51

52

53

54
gene-based vectors

55

573
580
594
605
615
629
642
651
662
673
681
687
695
4 :
56 714

57 729
HIV-exposed babies

58
737

59
742

60
750

61 767

62 Community Immunity
775

63 786

5 :
64
794

65
812

66

67

68

69
820
833
841
851
869

10
(smallpox)

(variolation)

.. 2264
Lady Mary Wortley Montagu

Lady Mary Wortley Montagu

Cotton Mather
Onesimus
.. 2337 Edward Jenner

Jenner
(cowpox)
Jenner
Sarah Nelmes
8 James
Phipps 14 .. 2339
..James Phipps

..James Phipps
2 Jenner
..James
Phipps ..James Phipps
Jenner

Jenner
Royal Society of London

Jenner
An Inquiry into the Causes
and Effects of the Variolae Vaccine 75

Jenner
4
Jenner .. 2264 Lady Mary Wortley Montagu variolation

Jenner
Jenner

Jenner .. 2343 Jenner
vaccine
vacca
vaccination
.. 2420 Louis Pasteur

(attenuation)
Joseph Lister antiseptic

diphtheria, tetanus diphtheria
antitoxin, tetanus antitoxin
diphtheria tetanus

immunization
Paul Ehrich
active passive immunization
antiserum
..2469 Alexander Glenny alum
(adjuvant)
adjuvant
Glenny secondary immune response

primary immune response

protein, polysaccharide
(recombinant technology)

11-3

.. 2378

2
.. 2378 (Dr. Dan Beach Bradley)

200 400

9
variolation
variolation

1

1 5
1
Live, Attenuated
Smallpox (1798)
Rabies (1885)
BCG (1927)
Yellow fever (1935)
OPV
Measles
Mumps
Rubella
Adenovirus
Typhoid (Ty21a)
Varicella
Rotavirus
Cholera
Cold-Adapted Influenza (2003)
Rotavirus
(new reassortants) (2006)
Zoster (2006)
Killed Whole Organism Protein or Polysaccharide
Genetically Engineered
Typhoid (1896)
Cholera (1896)
Plaque (1897)
Pertussis (1926)
Diphtheria toxoid (1923)
Influenza (1936)
Typhus (1938)
Tetanus toxoid (1926)
IPV
Pneumococcal polysaccharide
Rabies (cell culture)
Meningococcal polysaccharide
JE
Hib polysaccharide
Tick-borne encephalitis Meningococcal conjugate
HAV
Hib conjugate
HBV
Typhoid (Vi)
Acellular pertussis
Anthrax
PCV (2000)
Meningococcal quadrivalent
conjugates (2005)

.. 2385

2
()
HBV
Lyme OspA
Cholera
HPV (2006)
(.. )
2

.. 2444
.. 2446

..
2453

.. 2456
1 .. 2445

.. 2456
( 1)4
.. 2454

26 .. 2456
.

.. 2460

(Louis Pasteur)

24 .. 2463

4
46 3 71
258,000

( 2)

1 7

7 .. 2465

GMP (Good manufacturing practice)

ISO/IEC 17025
ilac MRA DMSc

WHO Collaborating Center for Research
on Rabies Pathogenesis and Prevention WHO
Collaborating Center for Venomous Snake Toxicology
and Research5
.. 2520
(Expanded Program on Immunization,
EPI)

(Compulsory vaccines)
10

6
(Optional vaccines)

Hemophilus influenzae type b

Acellular Pertussis Vaccine, Inactivated Poliomyelitis
Vaccine (IPV), Pneumococcal Conjugate Vaccine
(PCV), Influenza Vaccine, Rotavirus Vaccine, Human
Papillomavirus Vaccine Live attenuated Japanese
Encephalitis Vaccine Optional vaccine

Optional vaccine
(Vaccine for
special situation) Rabies Vaccine, Meningococcal
8
Vaccine

6 DPT, IPV, Hib, HBV

anaphylaxis hypotonichyporesponsive episode

1:1000 1: 1,000,000
207,8

..
2520

(herd immunity)
1. Plotkin SA, Orestein WA, Offit PA, Editors.

Vaccines.5th ed. China: Saunders Elsevier Inc., 2008.
2. . .
: , . .
: ; 2519. . 13-25.
3. Ada GL. Vaccines. In: Roitt MR, Delves
PJ, editors. Encyclopedia of immunology. London:
Academic press; 1992. p.1540-4.
4. .
(-)
. http://www.nham.or.th/content/
detail/print/88/
1 9
5. . http://www.
saovabha.com/th/aboutus.asp
6. .. :
, , . Leadership in Medicine 2010. :
; 2553. . 184-90.
7. Tantawichien T, Thisyakorn U. Vaccines for
everyone. In: Joint TPAA-Chula International Medical
Congress 2011. Safety and quality in health-care practice; 2011 Feb 7-8; Bangkok: Chulalongkorn University
Press; 2011. p. 27.
8. Centers for Disease Control and
Prevention(CDC). Ten great public health achievements-- United States, 1900-1999. MMWR Morb
Mortal Wkly Rep.1999;48:241-3.
11
2
innate immune response adaptive immune
response
adaptive immune response

lymphocyte T cell B cell
(specificity) (memory)

innate immune response

2
innate immune response adaptive immune
response
1. Innate immune response

adaptive immune response
innate (specificity)
(memory)
innate
innate immune system

macrophage, dentritic cell, neutrophils, eosinophils
monocytes 3

pathogenassociated molecular pattern (PAMPs)1
pattern-recognition receptor (PRR)

PRR PRR Toll-like
receptor (TLR)
2
TLR 11, 3 TLR 1, 2, 4,
5, 6
TLR 3, 7, 8, 9
mutation
innate
PRR
4
12
1 Toll-like receptor
Toll-like receptors
TLR1
TLR2
TLR3
TLR4
TLR5
TLR6
TLR7
TLR8
TLR9
TLR10
Ligands
Lipoproteins, lipoteichoic acid
Lipoproteins
Peptidoglycan, lipoteichoic acid
Zymosan
Lipoarabinomannan
Double-stranded RNA
Endotoxin
Viral coat proteins
Flagellin
Lipoproteins, lipoteichoic acid
Single-stranded RNA
Single-stranded RNA
Unmethylated CpG DNA
Unknown
Microbial sources
Gram-positive bacteria, mycoplasma
Bacterial cell walls, mycoplasma
Gram-positive bacteria cell walls
Fungi
Mycobacteria cell walls
Viral RNA
Gram-negative bacteria cell walls
Respiratory syncytial virus
Bacteria
Gram-positive bacteria, mycoplasma
Viral RNA
Viral RNA
Bacterial and viral DNA
Unknown
( 1, 3)
T cell B cell clone

innate adaptive
(diversity) T cell B cell
gene rearrangement
2. Adaptive immune response
(random) T cell B cell
adaptive T cell gene rearrangement
B cell V(D)J recombination combination
receptor T cell B cell receptor
(antigen specific receptor)
gene rearrangement
(diversity) (specificity) diversity
innate (memory)
multiple mutation
adaptive somatic hypermutation

(Antibodies)
plasma cell
(antigen recognition)
B cell 11 Y
adaptive heavy chain light chain
(specificity) 2 5
(diversity)
antigen-binding sites
(specific) receptor heavy chain
2 13
1 Y
heavy chain light chain disulfide bonds
(1)
heavy chain
class isotype
isotype
21,6-8
Humoral immune response
2 T-cell
independent T-cell dependent
2 31
T cell independent response
B cell
plasma cell

T-cell independent
response affinity
IgM (memory)
secondary immune response
T-dependent pathway
T cell dependent response
T cell B cell T cell
B cell germinal center

memory B cell
secondary immune response
affinity
isotype switching IgM IgG IgA
effectors B
lymphocyte T lymphocyte

B cell T cell
B cell
T-independent9,10 T-cell
protein, toxoid
inactivated live attenuated virus vaccine
B cell T-dependent
immune memory
affinity T-independent
live attenuated vaccine
CD8 cytotoxic T cell
CD8 cytotoxic T cell

14
2 isotype
Item
IgM
IgD
IgG1
IgG2
IgG3
IgG4
Subunit form
5
1
1
1
1
1
Molecular weight (kd) 950
175
150
150
150
150
Concentration in
2
0.03
10
4
1
0.5
serum (mg/dL)
Complement activation ++/-/+
++/+
+/+
++/+
-/+
a
(C/A)
Macrophage
+
++
++
++
FcR binding
Mast cell sensitizing
Placental transport
++
+
++
+/Mucosal transport
c
ADCC
+
+
+
+
Half-life (days)
5
3
23
23
8-9
23
Function
1 immune Lymphocyte
2 immune response
response surface
Major form of circulating antibodies
Lymphocyte
surface
a: C=complement pathway, A= alternative pathway
b: Dimer only
c: ADCC= antibody-dependent cell-mediated cytotoxicity
(1, 6-8)
2 T-cell independent B cell activation

( 1)
IgA1
IgA2
IgE
1, 2
1, 2
1
160, 400 160, 400 190
2
0.5
0.003
-/+
-/+
-/-
++
++
+++
b
b
+++
+++
+
6
6
2
Mucosal immunity Immediate
Secretory Ig
allergic
reactions
2 15
3 T cell dependent B cell activation

( 1)
1. Antibody

(extracellular pathogen)

1.1
(inactive)
1.2
1.3 opsonization
macrophage neutrophil
1.4 complement complement
2. CD4 T cell
cytokine B cell
CD8 T cell macrophage
3. CD8 T cell
intracellular pathogen

T cell

16
antigen presenting cell dendritic cell (DC) DC
immature mature
DC
Tcell B cell

danger signals
/ (adjuvants)
inflammation 10
(DC, monocyte
neutrophil) receptor
self antigen pathogen- associated molecular pattern (PAMPs)1
(danger signal)
receptor
TLR
inflammation inflammation
maturation DC T cell
B cell
live virus vaccine
viral RNA TLR
target tissue
DC
T B cell live vaccine
immunogenicity non-live vaccine

immunogenicity
10
Non-live vaccine pathogen recognition
patterns danger signal
live vaccine non-live
vaccine
live vaccine

(intradermal injection)
DC
(dermis) DC

DC
(intramuscular)
(subcutaneous)11
1.
live vaccine
non live vaccine live vaccine
12

T-dependent pathway

T-independent pathway
T- dependent antigen
memory B cell 13
2.
3

primary response
14
primary booster dose
4
affinity maturation memory B cell
secondary response 14
2 17
T cell B cell immunogenicity

adaptive
system (adjuvant)
innate immune response
maturation dendritic cell
1. Moser M, Leo O. Key concepts in

immunology. Vaccine. 2010;28(Suppl 3):C2-13.
2. Akira S, Uematsu S, Takeuchi O. Pathogen
recognition and innate immunity. Cell. 2006;124:783801.
3. Liu AH, Zasloff MA, Johnston RB. Innate
Immunity. In: Adkinson NF, Bochner BS, Busse
WW, Holgate ST, Lemanske RF, Simon FER,
editors. Middletons Allergy: Principles&Practice.
7 t h e d. Philadelphia: Elsevier; 2009.
p. 19-35.
4. Bowie AG, Unterholzner L. Viral evasion and
subversion of pattern-recognition receptor signalling.

Nat Rev Immunol. 2008;8:911-22.
5. Amzel LM, Poljak RJ. Three-dimensional
structure of immunoglobulins. Annu Rev Biochem.
1979;48:961-97.
6. Torres RM, Imboden J, Schroeder HW.
Antigen receptor genes, gene products, and
co-receptors. In: Rich RR, Fleisher TA, Shearer
WT, Schroeder HW, Frew AJ, Weyand CM, editors.
Clinical Immunology: Principles and Practice. 3rd ed.
Philadelphia: Elsevier; 2008. p. 53-77.
7. Bankers-Fulbright JL, Li JT. Immunoglobulin structure and function. In: Adkinson NF, Bochner
BS, Busse WW, Holgate ST, Lemanske RF, Simon
FER, editors. Middletons Allergy: Principles&Practice.
7th ed. Philadelphia: Elsevier; 2009. p. 73-87.
8. Chaplin DD. Overview of the immune
response. J Allergy Clin Immunol. 2010;125
(2 Suppl 2):S3-23.
9. Lee CJ, Lee LH, Lu CS, Wu A. Bacterial
polysaccharides as vaccines--immunity and chemical
characterization. Adv Exp Med Biol. 2001;491:453-71.
10. Weintraub A. Immunology of bacterial
polysaccharide antigens. Carbohydr Res.
2003;338:2539-47.
11. de Lalla F, Rinaldi E, Santoro D, Pravettoni
G. Immune response to hepatitis B vaccine given at
different injection sites and by different routes:
a controlled randomized study. Eur J Epidemiol.
1988;4:256-8.
12. Manz RA, Hauser AE, Hiepe F, Radbruch
A. Maintenance of serum antibody levels. Annu Rev
Immunol. 2005;23:367-86.
13. Southern J, Deane S, Ashton L, Borrow
R, Goldblatt D, Andrews N, et al. Effects of prior
polysaccharide vaccination on magnitude, duration,
18
and quality of immune responses to and safety
profile of a meningococcal serogroup C tetanus toxoid
conjugate vaccination in adults. Clin Diagn Lab
Immunol. 2004;11:1100-4.
14. Siegrist CA. Vaccine immunology.
In: Plotkin SA, Orenstein WA, Offit PA, editors. Vacines.
5th ed. Philadelphia: Elsevier; 2008.
19
, ,

(Expanded Programme
on Immunization: EPI)
.. 1974

adjuvant

potency
potency

(Adverse Events Following Immunization:
AEFI)
1-3
1-4
adjuvant

20
1.

2.
0 o.
potency

( 1)
3.

BCG, Measles, Rubella MMR
1.2

ice pack
1.3

1.4

1.5
1-7

1.

1.1

3 21
2.
2.1
2.1.1

10
1
1) -15
o
-25 .
2) 2
8 o.
3) 2
2
4) ice pack

5)
3
6
6)

1:1
7)

8) 5
.
9)
10)
2.1.2 ( 2)
1)
2)
3)

4)
5) Lyophilized vaccines
2 - 8 o. 6 BCG
2 (HB, DTP, dT)
2 - 8 o. 8
22
2.2
2.2.1

3-4 ( 3)

1-1 ( 4)
2.2.2
1) ice pack
4
ice pack
2)
10-15
2 - 8 o.
3)
ice pack
4)
ice pack
5) ice pack
2 - 8 o.
2.3
2.3.1 Vaccine Vial Monitor (VVM)

VVM

( 5)
2.3.2 Freeze Watch (FW)

FW
0 o. 1

3 23
5 Vaccine Vial Monitor (VVM)
6 Freeze Watch
HB, DTP-HB, DTP, dT

TT ( 6)
2.3.3 Data Logger

Sensor -40
+85 o.
//
/
( 7)
2.3.4 Vaccine Cold Chain Monitor (VCCM)
( 8)

(indicator)
A, B C
10 o. D
34 o. VCCM

1) A, B, C D

10 o.
2) A
B, C D 3
10 o.
1
3) A
24
7 Data Logger
8 Vaccine Cold Chain Monitor
B, C D 3

10 o. 3 OPV
VVM VVM 3

4) A
B
C D 2
10 o.
5 OPV VVM
VVM 3

5) A B
C
D 2
10 o. 8
OPV VVM
VVM M,
YF, MMR R 3
6) A B
C
D
10 o.
10 OPV VVM
VVM
3 25
M, YF, MMR R
DTP BCG 3
dT TT
7) A, B C
D
10 o.
12 OPV VVM
VVM
M, YF, MMR R
DTP BCG 3
dT TT
8) A, B, C D

10 o. 14
34 o. 2 OPV
VVM VVM

3.

( 9)

4.1
breaker
4.2
4.3

4.

/
9
26
1. BCG
Live bacteria
2. HBV
Recombinant viral antigen
3. DTwP, DTap, DT, Td, Tdap, TT Toxoids and inactivated bacterial
component
4. OPV
Live virus
5. IPV
Inactivated virus
6. MMR, M, MMRV
Live-attenuated viruses
7. JE
Inactivated virus
8. JE
9. Hib
10. PCV
11. PS23
12. RV (ROTA)
13. Var
Live-attenuated virus
Polysaccharide-protein conjugate
Polysaccharide-protein conjugate
Polysaccharide
Live-attenuated viruses
14.
15.
16.
17.
18.
19.
20.
Inactivated viral antigen

Inactivated viral component
Recombinant viral antigens
Inactivated virus
Polysaccharide
Polysaccharide
HAV
Influenza
HPV
Rabies
Ty
MPSV
Yellow fever
2-8 o.
2
2-8 o.
2-8 o.
2-8 o.
2-8 o.
2-8 o.
6
2-8 o.
()
2-8 o.
2-8 o.
2-8 o.
2-8 o.
2-8 o.
2-8 o.
30
2-8 o.
2-8 o.
2-8 o.
2-8 o.
2-8 o.
2-8 o.
2-8 o.
: 1. 2-8 o.
2.

3. (-15 o. +20 o.)

2-8 o.
4.
3 27
OPV
BCG
Measles
MMR
MR
Yellow fever
Hib lyophilized
Meningitis
JE
Hepatitis B
DTP-HB
DTP-HB-Hib
liquid
DTP
DT/TT/dT
Pneumococcal
Rotavirus
()
6-12
3
1-3
-15 o. -25 o.
OPV
lyophilized vaccines +2 o. +8 o.

-15 o. -25 o.
o
+2 . +8 o.
+2 o. +8 o.
+2 o. +8 o.
5.

(stability data)

( 10)
5.1
5.2 / , Lot
no.,
5.3 VVM

6. Shake Test ( 11)
Shake Test

HB, DTP, DTP-HB, dT TT

6.1 1
28
10
11 Shake Test
Lot no.
(control)
10 -10 o.

6.2
6.3
2 10-15
6.4 2
6.5 2

Thailand Chapter
of International Society of Tropical Pediatrics

1. Plotkin SA, Orestein WA, Offit PA, Editors.

Vaccines. 5th ed. China: Saunders Elsevier Inc.; 2008.

2.
.
3 29
.. 2539.:
;
2539.
3.
.
.. 2547. :
; 2547.
4. Department of Immunization, Vaccines and
Other Biologicals, World Health Organization. Temperature monitors for vaccines and the cold chain. Geneva:
WHO; 1999.
5. Department of Immunization, Vaccines
and Other Biologicals, World Health Organization.
Cold chain, vaccines and safe-injection equipment
management. Geneva: WHO; 2008.
6. , ,
, ,
, .
2010-2011. :
; 2553.
7. . . :
, , . Leadership in Medicine 2010. :
; 2553. .184-90.
31
20

(disease burden)

(pathophysiology of infection), vaccine immunology

live cowpox virus inoculation

(antibody generator)

(immunogen)
basic immunology,
pathogen and host interaction, immune response to infection
molecular technique and genetic engineering technique

purified antigen
(new adjuvants),
(new delivery systems)

intradermal route, mucosal route
vaccine antigen
live attenuated pathogen

pathogen toxin whole killed pathogen
inactivate pathogen

(high reactogenicity)

(specific immunogen from pathogen
to specific receptor) split antigen, subunit
antigen, recombinant protein vaccine
antigen vaccine antigen
1

( )
Human Papillomavirus
recombinant
protein (L1 protein) vaccine
antigen
32
1 vaccine antigen
1 Highly purified antigens
naked pathogen-derived DNA

vaccine antigen
(DNA vaccine) target
antigen circular plasmid expression vector
vector host cell activate gene
expression
humural immunity (HMI) cell
mediated immunity (CMI)
DNA vaccine

live vector attenuated live intracellular

organism target antigen
live vector uptake host cell

purified antigen

pathogen toxin
1
4 33
1,2
1.
(tetanus toxin, diphtheria toxin)
Hib vaccine,
conjugated pneumococcal vaccine
2. Immunologic structure
virus-like particle (VLP)
VLP HPV vaccine L1 protein
VLP
3. (adjuvant)

aluminium salt (aluminium hydroxide,
aluminium sulfate) 80

2 3 MF-59 influenza vaccine
combination adjuvant (ASO)
2,3
(DNA)

purified antigen
(immunogenicity)
immunogenicity aluminium
salt
2.

ASO3

3.
avian influenza H5N1 vaccine
pandemic influenza
influenza H5N1 vaccine
1

(adjuvants)
4.
(adjuvants)

(mucosal immunity)

cell-mediated immunity (CMI) T lymphocyte

1

( 2)2-5
3 3-5
1.
1.

34
4 35
(persistence of antigen) aluminium salt emulsion-based adjuvant
2.
(antigen presenting cell, APC)

APC
T lymphocyte
(direct activation of innate immune cells)
MF59
APC dendritic cell macrophage
3. innate immunity
adaptive immunity

cytokines
cytokines Th1 (type 1)
Th2 (type 2)
cytokines IFN-gamma delayed-type hypersensitivity (DTH)
Th1 cellmediated immunity cytotoxic-T lymphocyte
IgG1 subtype
cytokines
IL-2, IFN-gamma, GM-CSF, IL-12
bacterial toxins cholera toxin, pertussis toxin
Th2
Aluminium salt
80 aluminium salt
aluminium hydroxide
pertussis, diphtheria and tetanus vaccines,
aluminium phosphate hepatitis A (HAV) and
B (HBV) virus vaccines, aluminium hydroxyphosphate
sulphate quadrivalant human papillomavirus
(HPV) vaccine aluminium salt
(depot mechanism)
APC macrophage

aluminium T lymphocyte, cell-mediated immunity
intracellular
infection 6
Liposome virosome artificial vesicles
lipid layers lipid
membrane liposome virosome
APC B cell
3-5,7
Emulsion ( oil in water water in oil
) aluminium salt
APC
oil in water
MF59 oil in water
APC
innate immunity
squalene pandemic influenza
H1N1 vaccine3-5,7
Bacterial product
Toll-like receptor
(TLR) APC T lymphocyte
microbial products
( 2, 3) DNA CpG motifs,
36
2
Types of adjuvants
Mineral salt : Aluminum salt adjuvants :
Aluminum hydroxide adjuvant
Aluminum phosphate adjuvant
Alum adjuvant
Mechanisms : depot mechanism
promote uptake of Ag by APC
inflammation at injection site
Oil-emulsion/surfactant based adjuvants :
MF-59, Virus-Like Particle
Microbial products/TLR agonist :
Monophosphoryl lipid A (MPL), AGP, CpG,
CT, LT (heat-labile toxin)
Saponin (QS21)
Cytokines : IL-2, IL-12,.
3
Adjuvant
Aluminium salts
Vaccine
DTaP (paediatric diphtheria, tetanus and acellular pertussis)

DTaP, polio and Haemophilus influenza type b
DTaP, polio, Haemophilus influenza type b and hepatitis B
Hepatitis A
Hepatitis B
Human papillomavirus-6/11/16/18
Influenza (H5N1)
Pneumococcus (conjugated)
Virosomes
Hepatitis A
Influenza (seasonal)
Oil-in-water emulsion (MF59) Influenza (H5N1, H1N1)
Influenza (seasonal)
Adjuvant System AS04
Hepatitis B
Human papillomavirus-16/18
Adjuvant System AS03
Influenza (H5N1, H1N1)
Thermo-reversible
Influenza (H1N1)
oil-in-water emulsion
4 37
endotoxin monophosphoryl lipid A (MPL) modified derivative of lipopolysaccharide (LPS) endotoxin

Salmonella spp. (detoxified LPS)
innate immune system MPL
toll-like receptot-4 (TLR4) endotoxin
APC cytokines
adaptive immunity Th-1 response
humoral and cellular immune responses
MPL HPV
vaccine, malaria vaccine, herpes virus vaccine
exotoxins
cholera toxin, E.coli heat-labile toxin, pertussis toxin
muramyl dipeptide (MDP)8,9
Cytokine
IL-2

aluminium salt system

ASO3, ASO4

1

( 2 MPL
aluminium salt)
10,11 3, 4
AS04
aluminium salts MPL

HPV, HBV, HSV, H5N1
AS04

seroprotection rates
aluminium salt
AS04-adjuvanted
HPV 16/18 vaccine VLP HPV
16 HPV 18 20 AS04
aluminium hydroxide 0.5
MPL 50 AS04
HPV 16/18 vaccine

memory B lymphocyte 11,12
38

(delivery)

(intradermal injection)

cold-adapted trivalent influenza
vaccine (CAIV-T)
1,2
(adverse reaction)
aluminium salt
(
)

MF-59, virosome

ASO4
3,548 AS04
13
ASO4-HPV vaccine

autoimmune diseases
1.Bae KD, Choi JY, Jang YS, Ahn SJ, Hu BK.
Innovative vaccine production technologies: the evolution and value of vaccine production technologies.
Arch Pharm Res. 2009;32:465-80.
2.Vogel FR, Hem SL. Immunologic adjuvants.
In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 5th ed. New York: Elsevier; 2008. p. 5971.
3.Marciani DJ. Vaccine adjuvants: role and
mechanisms of action in vaccine immunogenicity. Drug
DiscoveryToday. 2003;20:934-43.
4.Reed SG, Bertholet S, Coler RN, Friede M. New
horizons in adjuvants for vaccine development. Trends
Immunol. 2008;30:23-32.
5.Schmidt CS, Morrow WJW, Sheiks NA.
Smart adjuvants. Expert Rev Vac. 2007;6:391-400.
6.Noe SM, Green MA, Esch MH, Hem SL. Mechanism of immunopotentiation by aluminum-containing
adjuvants elucidated by the relationship between antigen retention at the inoculation site and the immune
response. Vaccine. 2010;28:3588-94.
7.Garcon N, Goldman M. Boosting vaccine
power. Sci Am. 2009;301:72-9.
8.Mata-Haro V,Cekic C,Martin M,Chilton PM,
Casella CR, Mitchell TC. The vaccine adjuvant monophosphoryl Lipid A as a TRIF-biased agonist of TLR4.
Science. 2007;316:1628-32.
9.DidierlaurentAM,MorelS,LockmanL. AS04,an
aluminum salt- and TLR4 agonist-based adjuvant system,
induces a transient localized innate immune response
leading to enhanced adaptive immunity. J Immonol.
2009;183:618697.
10.Garcon N. Change and necessity. Human
Vac 2008;4:173-5.
11.Schwarz TF, Leo O. Immune response to
human papillomavirus after prophylactic vaccination
with AS04-adjuvanted HPV-16/18 vaccine: Improv-
4 39
ing upon nature. Gynecol Oncol. 2008;110(3 Suppl

1):S1-10.
12.Schwarz TF. Clinical update of the AS04adjuvanted human papillomavirus-16/18 cervical cancer vaccine, Cervarix. Adv Ther. 2009;26:983-98.
13.Verstraetena T, Descampsa D, Davida PM,
et al. Analysis of adverse events of potential autoimmune aetiology in a large integrated safety database of
AS04 adjuvanted vaccines. Vaccine. 2008;26:6630-8.
41

(passive immunization)

(active immunization)
1
3
1. (toxoid)
2. (killed vaccine)

(genetic engineering)

3. (live vaccine)

--

4
1. (compulsory vaccines)

- -
-
2. (optional
vaccines)

3. (vaccines in special
circumstances)

42

4.
(investigational vaccines)

1-4

-
- -
--

lot number

lot number

70%

5
1. (oral route)

2.

3. (intradermal)
27

(cellmediated immune response)

5 43
Bacillus Calmette Guerin

Diphtheria, tetanus pertussis
(DTwP, DTaP, DT, Td, Tdap, TT)
Haemophilus influenza type b
Hepatitis A (HepA)
Hepatitis B (HepB)
HepA-HepB
Human papillomavirus
Influenza, inactivated
Influenza, live attenuated
Japanese Encephalitis(JE),
inactivated
JE, live attenuated
Measles, mumps, rubella
(MMR, M)
Measles, mumps, rubella,
varicella (MMRV)
Meningococcal conjugate
Meningococcal Polysaccharide
Pneumococcal conjugate
Pneumococcal Polysaccharide
Polio, inactivated
Polio, live attenuate
Rabies
Rotavirus
Typhoid
Varicella
Yellow fever
Herpes Zoster
2-8O.
2-8O.
2-8O.
2-8O.
2-8O.
2-8O.
2-8O.
2-8O.
2-8O.
2-8O.
2-8O.
()
2-8O.
2-8O.
2-8O.
(
2-8O.)
2-30O.
2-25O.
< -15O.
2-25O.
2-8O.
2-8O.
2-8O.
2-8O.
2-8O.
2-8O.
2-8O.
2-8O.
2-8O.
2-8O.
RV1 20-25O.
RV5
2-25O.
2-8O.
2-25O.
2-8O.
2-8O. ()
2-8O.
< -15O.
6 .
: RV1= monovalent rotavirus; RV5 = pentavalent rotavirus

( 4)
44
4. (subcutaneous)

adjuvant --
26G
45

5. (intramuscular)

()
()

24
3

lidocane
5-7

6,8 lidocane
1 met
hemoglobin methemoglobinemia 9

(18 )
*
1-12
1-2
3-18
(19 )
,
<60 .
,
6070 .
, 70118 .
, 7090 .
, >118 .
, >90 .
5/8 (16 .)
1 (25 .)
111/4 (2532 .)
5/81 (1625 .)
5/81 (1625 .)
111/4 (2532 .)
26
25
24-25
24-25
24-25
24-25
(Deltoid)
(Deltoid)
1 (25 .)
23-25
1 (25 .)
23-25
111/2 (2538 .)
23-25
23-25
23-25
23-25
11/2 (38 .)
* 28

5/8 <60 .
( 4)
(Deltoid)
5 45
Bacillus Calmette Guerin

Live bacteria
Diphtheria, tetanus, pertussis Toxoids and
(DTwP, DTaP, DT, Td, Tdap, TT) inactivated bacterial
component
Haemophilus influenza type b Polysaccharide protein
conjugate
Hepatitis A (HepA)
Inactivated viral antigen
0.05 0.1 .*
0.5 .
ID
IM
0.5 .
IM
1-18 : 0.5 .
19 : 0.5-1 .
: 0.5 .**
: 1.0 .
18 : 1.
IM
Hepatitis B (HepB)
Recombinant viral antigen
HepA - HepB
Inactivated HepA antigen

and recombinant HepB antigen
Recombinant viral antigens 0.5 .
Inactivated viral component 6-35 : 0.25 .
3 : 0.5 .
0.2 . 0.1.
Inactivated virus
< 3 : 0.5./0.25 .
3 : 1.0 ./ 0.5 .
0.5 .
0.5 .
Human papillomavirus
Influenza, inactivated
Influenza, live attenuated
Japanese Encephalitis(JE),
inactivated
JE, live attenuated
Measles, mumps, rubella
(MMR, M)
Measles, mumps, rubella,
Varicella (MMRV)
Meningococcal conjugate
IM
IM
IM
IM
Intranasal spray
SC
SC
SC
SC
0.5 .
SC
Polysaccharide
protein conjugated
Polysaccharide
0.5 .
IM
0.5 .
SC
Polysaccharide
protein conjugated
Pneumococcal Polysaccharide Polysaccharide
Polio, inactivated
Inactivated virus
Polio, live attenuate
Live virus2-3
Rabies
Inactivated virus
0.5 .
IM
Meningococcal
Polysaccharide
Pneumococcal conjugate
0.5 .
IM
0.5 .
IM
Oral
0.5-1 .
IM
0.1 .
ID
Rotavirus
RV1: 1.
Oral
RV5 : 2 .
Typhoid
polysaccharide
0.5 .
IM
Varicella
0.5 .
SC
Yellow fever
0.5 .
SC
Herpes Zoster
0.65 .
SC
: IM = intramuscular, ID = intradermal, Sc = subcutaneous
RV1= monovalent rotavirus; RV5 = pentavalent rotavirus
*
** 11-15 1.0 . 2 0 4-6
46
10
6
11,12

2-3

< 4
4
> 5

4
2
6
() 4

28
9 13 1 11 2
1
12-15 4
14

1

1 15,16

17

5-7
4

5 47
4 1
(vaccine&dose no.)
BCG
HepB-1
HepB-22
HepB-33
DTwP, DTaP -1
DTwP, DTaP -2
DTwP, DTaP -34
DTwP, DTaP -4
DTwP, DTaP -5
Tdap5
Td
OPV, IPV -1
OPV, IPV -2
OPV, IPV -3
OPV, IPV -46
OPV, IPV -5
MMR-1
MMR-27
Inacitvated JE-1
Inacitvated JE-2
Inacitvated JE-3
Live JE -1
Live JE-2
Hib-18
Hib-2
Hib-3
Hib-49
PCV-18
PCV-2
PCV-310
PCV-4
PPSV-1
PPSV-2
RV-111
RV-2
RV-3
( pentavalent)
Var-1
Var-212
HepA-1
HepA-2
TIV
LAIV
(recommended age)
(minimum age)
1-2
6-18
2
4
6
15-18
4-6
11
11-12
2
4
6
15-18
4-6
9-12
4-6
12-18
13-19
24-30
12
12-24
2
4
6
12-15
2
4
6
12-15
2
4
6
4
24
6
10
14
12
4
10
7
6
10
14
12 3
4
9
12
12
12
24
9
12
6
10
14
12
6
10
14
12
2
5
6
10
14
12-18
4-6
12-23
18-41
6 - 18
2-49
12
15
12
18
6
2
(recommended interval) (minimum interval)

1-4
4
2-17
8
2
4
2
4
6-12
6
3
6
10
5
2
4
2
4
6-12
6
6
3-5
4
4
1
11
3
3-12
3
2
4
2
4
6-9
8
2
4
2
4
6
8
5
3
2
4
2
4
3-5
6-12
1 13
1
12
6
4
4
48
(vaccine&dose no.)
MCV4-1
MCV4-2
MPSV4-1
MPSV4-2
HPV-1
HPV-2
HPV-3
Herpes zoster
(recommended age)
(minimum age)
11-12
11-12 (+1-2 )
11-12 (+6 )
> 60
2
11 +8
2
7
9
109
114
60
(recommended interval) (minimum interval)

5
8
5
5
1-2
4
4-5
12
-
: BCG= Bacillus Calmette Guerin Vaccine; DTwP= Diphtheria and Tetanus toxoids, and whole cell Pertussis; DTaP =
Diphtheria and Tetanus toxoids and acellular pertussis; HepA = hepatitis A; HepB = hepatitis B; Hib = Haemophilus influenzae
type b; HPV = human papillomavirus; IPV = inactivated poliovirus; JE=Japanese Encephalitis Vaccine; LAIV = live, attenuated
influenza vaccine; MCV4 = quadrivalent meningococcal conjugate vaccine; MMR = measles, mumps, and rubella; MPSV4
= quadrivalent meningococcal polysaccharide vaccine; OPV=Oral Poliomyelitis Vaccine; PCV = pneumococcal conjugate
vaccine; PPSV = pneumococcal polysaccharide vaccine; RV= rotavirus; Td = Tetanus and diphtheria toxoids; TIV = trivalent
inactiated influenza vaccine; Tdap = Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis; Var = varicella vaccine.
1

2
HBsAg HBIG HBV 1
3
DTP+HBV HBV 4 24
4
DTwP DTaP 3 4 6 DTwP DTaP
4 DTwP, DTaP-3 4
5
Tdap dT 1 DTP 4-6
6
IPV 4 4
7
MMRV
8
Hib PCV 7
9
Hib-4
10
PCV-3 ( 2+1)
11
RV 15 8
12
Varicella vaccine 1-12 1-2 2 4-6
4 3 > 13 2 4
13
Influenza vaccine 9 2 1
( 1)
( 4)
5 49
6
1
2
+,#
2 +
+

# 7
( 4)
7
+

/
Tetanus IG
Hepatitis A IG
-
-
Hepatitis B IG
Rabies prophylaxis (HRIG)
Varicella IG
Measles prophylaxis IG
- ()
- ()
- Red blood cells (RBCs),washed

- RBCs adenine-saline added
- Packed RBCs (Hct 65%)
- Whole blood (Hct 35-50%)
- Plasma/platelet products
Replacement therapy for immune deficiencies (IVIG)
Respiratory syncytial virus prophylaxis
Immune thrombocytopenic purpura (IVIG)
Kawazaki desease (IVIG)
(. IgG/.)
250 (10 . IgG/.) IM
()
3
0.02 ./. (3.3 . IgG/.) IM

0.06 ./. (10 . IgG/.) IM
0.06 ./. (10 . IgG/.) IM
20 IU/. (22 . IgG/.) IM
125 /10 . (20-40 . IgG/.)
IM ( 625 )
3
3
3
4
5
0.25 ./. (40 . IgG/.) IM

0.50 ./. (80 . IgG/.) IM
5
6
10 ./. ( IgG ) IV
10 ./. (10 . IgG/.) IV
10 ./. (60 . IgG/.) IV
10 ./. (80-100 . IgG/.) IV
10 ./. (160 . IgG/.) IV
300-400 ./. IV
750 ./. IV ( RSV-IGIV)
400 ./. IV
1,000 ./. IV
2 /. IV
0
3
5
6
7
8
9
8
10
11
: IG = immune globulin; IgG = immune globulin G; IVIG = intravenous immune globulin; IM = intramuscular; IV =
intravenous

( 1, 4)
50

7

18,19

20,21

22,23-27
20,21
3
2 Trivalent
inactivated influenza vaccine Live-attenuated
influenza vaccine
2

28

2 9-31
1.
2.
3.

T cell

outer membrane protein Neisseria meningitidis

30,32
5 51

delayed-type
anaphylaxis
8
48,49

4. Thimerosal
.. 1930 preservative
systemic .. 1999
anaphylaxis thimerosal
anaphylaxis
-- - 50
33

anaphylaxis
34,35 51-53

-- 54-56
36-39
angioedema
40,41
2 1
( HBIG )
1. 3 2
Anaphylaxis 1-2 2 3
42-44 1-2 6
2 desensitization 4

fibroblast
anaphylaxis skin test 57-59
45-47
30 2
2. Latex
latex
60
latex
3.

52
1. Bacillus Calmette
Guerin (BCG)
2. Hepatitis B
1. local reation:
osteitis
2. disseminated fatal infection
severe
combined immune deficiency syndrome
1. local reaction:
2. systemic reaction:
3. allergic reaction: anaphylaxis
3. Diphtheria, tetanus 1. local reaction: ,
pertussis (DTP)

(sterile abscess)
2. systemic reaction :
encephalopathy, hypotonic
hyporesponsive episode
3. allergic reaction: anaphylaxis
4. Polio, live attenuate Vaccine-associated paralytic poliomyelitis
(OPV)
(VAPP)
5. Polio, inactivated
(IPV)
6. Measles, mumps,
rubella (MMR)
7. Japanese
Encephalitis(JE),
inactivated
- BCG
3-4
- BCG
INH
2-3
3 .
sudden infant
death syndrome demyelinating disease
multiple sclerosis
acellular
whole cell
- VAPP
- streptomycin, neomycin polymyxin
B

-
Inflammatory bowel disease
-
MMR
skin test
30
1. systemic reaction: 5-12

transient thrombocytopenia
encephalitis
encephalopathy
2. allergic reaction:

neomycin
1. local reaction:
2
20
10
3. allergic reaction: angioedema
0.2-0.6 2
5 53
8. JE, live attenuate
9. Haemophilus
influenza type b
10. Pneumococcal
conjugate
11. Pneumococcal
polysaccharide
12. Rotavirus
13. Varicella
14. Hepatitis A
15. Influenza,
inactivated (TIV)
16. Human
papillomavirus
1. local reaction:
9.3 6.7
hypersensitivity
1. local reaction:
25
24
1. local reaction:
2. systemic reaction: 1-2
1. local reaction:

3. allergic reaction: arthus-like

2

1. local reaction:
(maculopapular rash vesicle)
1. local reaction:
1. local reaction:
13 6-24 .
Guillain-Barre
syndrome 1
anaphylaxis
1. local reaction:

30
54
17. Rabies
1. local reaction:
15-25

10-20
3. allergic reaction: immune complex like
reaction HDCV
2-21
angioedema
18. Typhoid
1. local reaction:
(Vi capsular
7
polysaccharide vaccine) 2. systemic reaction:
1.5-3 0-1
48
19. Meningococcal

1-2
20. Yellow fever
1. local reaction:
2 - 5 5 - 10

25

6
anaphylaxis serum
sickness
1
21.Zoster

( 1)
-
-
- 10
2 3

5 55
-
-

14,61

1

4
14,62
1,2
1.

2.

3.

4.

5.
6.
7.
1
8.

9.
2,000
2,000 1-2
10.

11.

12.

13.
-

14.

56
15.

16.

17.

18.

19.

1
vention (CDC). General recommendations on immunization: recommendations of the Advisory Committee

on Immunization Practices (ACIP). MMWR Recomm
Rep. 2006;55:1-48.
4. National Center for Immunization and
Respiratory Diseases. General Recommendations on
Immunization --- Recommendations of the Advisory
Committee on Immunization Practices (ACIP). MMWR
Recomm Rep. 2011;60:1-64.
5. Taddio A, Nulman I, Goldbach M, Ipp M,
Koren G. HYPERLINK http://www.ncbi.nlm.nih.gov/
pubmed/8151485 Use of lidocaine-prilocaine cream
for vaccination pain in infants. J Pediatr. 1994;124:6438.
6. Halperin SA, McGrath P, Smith B, Houston T. Lidocaine-prilocaine patch decreases the
pain associated with the subcutaneous administration of measles-mumps-rubella vaccine but does not
adversely affect the antibody response. J Pediatr.
2000;136:789-94.
7. Uhari M. A eutectic mixture of lidocaine and
prilocaine for alleviating vaccination pain in infants.
Pediatrics. 1993;92:719-21.
8. Halperin BA, Halperin SA, McGrath P, Smith
B, Houston T. Use of lidocaine-prilocaine patch to de
crease intramuscular injection pain does not adversely
1. , , affect the antibody response to diphtheria-tetanus , , acellular pertussis-inactivated poliovirus-Haemophilus
, . 2010-2011. influenzae type b conjugate and hepatitis B vaccines in
2553. infants from birth to six months of age. Pediatr Infect
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9. Frayling IM, Addison GM, Chattergee K,
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3. Kroger AT, Atkinson WL, Marcuse EK, with prilocaine-lignocaine cream. BMJ. 1990;301:153Pickering LK; Advisory Committee on Immunization 4.
10. Allen KD, White DD, Walburn JN. Sucrose
Practices (ACIP) Centers for Disease Control and Pre-
5 57
as an analgesic agent for infants during immunization

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11. French GM, Painter EC, Coury DL. Blowing away shot pain: a technique for pain management
during immunization. Pediatrics. 1994;93:384-8.
12. Fowler-Kerry S, Lander JR. Management
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15. Halsey N, Galazka A. HYPERLINK http://
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16. Wilkins J, Chan LS, Wehrle PF. Age and
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17. Siber GR, Werner BG, Halsey NA, Reid
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18. Kaplan JE, Nelson DB, Schonberger LB,
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19. Harpaz R, Ortega-Sanchez IR, Seward
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MMWR Recomm Rep. 2008;57:1-30.
20. Pertussis vaccination: use of acellular
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Recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Recomm Rep.
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21. Use of diphtheria toxoid-tetanus toxoidacellular pertussis vaccine as a five-dose series.
Supplemental recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR
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22. Bush LM, Moonsammy GI, Boscia JA.
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23. Chan CY, Lee SD, Tsai YT, Lo KJ. Booster
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24. Greenberg DP, Lieberman JM, Marcy SM,
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25. Anderson EL, Decker MD, Englund JA,
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26. Piazza M, Abrescia N, Picciotto L, Orlando
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27. Bryan JP, Henry CH, Hoffman AG, South-
58
Paul JE, Smith JA, Cruess D, et al. Randomized,
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28. Pichichero ME. Impact of a birth dose of
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29. Prevention of pneumococcal disease:
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1997;46.1-24.
30. Broder KR, Cortese MM, Iskander JK, Kretsinger K, Slade BA, Brown KH, et al; Advisory Committee on Immunization Practices (ACIP). Preventing
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use of tetanus toxoid, reduced diphtheria toxoid and
acellular pertussis vaccines: recommendations of
the Advisory Committee on Immunization Practices
(ACIP). MMWR Recomm Rep. 2006;55.1-34.
31. Kretsinger K, Broder KR, Cortese MM,
Joyce MP, Ortega-Sanchez I, Lee GM, et al. Preventing tetanus, diphtheria, and pertussis among adults:
acellular pertussis vaccine recommendations of the
Advisory Committee on Immunization Practices
(ACIP) and recommendation of ACIP, supported by
the Healthcare Infection Control Practices Advisory
Committee (HICPAC), for use of Tdap among healthcare personnel.MMWR Recomm Rep. 2006;55.1-37.
32. Bilukha OO, Rosenstein N; National Center
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meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recomm Rep. 2005;54.1-21.

33. Zaloga GP, Chernow B. Life-threatening
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34. Matuhasi T, Ikegami H. Elevation of levels
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35. Nagel J, Svec D, Waters T, Fireman P.
IgE synthesis in man. I. Development of specific IgE
antibodies after immunization with tetanus-diphtheria
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36. Bronstein DE, Cotliar J, Votava-Smith JK,
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37. Wise RP, Iskander J, Pratt RD, Campbell
S, Ball R, Pless RP, et al. Postlicensure safety surveillance for 7-valent pneumococcal conjugate vaccine.
JAMA. 2004;292:1702-10.
38. Greenberg RN, Schosser RH, Plummer
EA, Roberts SE, Caldwell MA, Hargis DL, et al. Urticaria, exanthems, and other benign dermatologic
reactions to smallpox vaccination in adults. Clin Infect
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39. Patja A, Mkinen-Kiljunen S, Davidkin I,
Paunio M, Peltola H. Allergic reactions to measlesmumps-rubella vaccination. Pediatrics. 2001;107:E27.
40. Andersen MM, Rnne T. Side-effects with
Japanese encephalitis vaccine. Lancet. 1991;337:1044.
41. Ruff TA, Eisen D, Fuller A, Kass R. Adverse
reactions to Japanese encephalitis vaccine. Lancet.
1991;338:881-2.
42. Fiore AE, Shay DK, Haber P, Iskander JK,
Uyeki TM, Mootrey G,et al. Prevention and control of
influenza. Recommendations of the Advisory Commit-
5 59
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Recomm Rep. 2007;56:1-54.
43. Yamane N, Uemura H. Serological examination of IgE- and IgG-specific antibodies to egg
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44. Bierman CW, Shapiro GG, Pierson WE,
Taylor JW, Foy HM, Fox JP. Safety of influenza vaccination in allergic children. J Infect Dis. 1977;136:S6525.
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protein. Am J Dis Child. 1990;144:33-5.
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Sampson HA. Safe administration of the measles
vaccine to children allergic to eggs. N Engl J Med.
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MMR vaccine and neomycin allergy. Am J Dis Child.
1993;147:128-9.
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defense system and its relationship to routine immu-
nizations. Clin Perinatol. 1984;11:73-84.

53. Wara DW, Barrett DJ. Cell-mediated immunity in the newborn: clinical aspects. Pediatrics.
1979;64:822-8.
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55. Whitelaw A, Parkin J. Development of
immunity. Br Med Bull. 1988;44:1037-51.
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of alpha-1 fetoprotein, IgG globulin, and albumin in
newborn infants. J Pediatr. 1973;82:430-7.
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gov/pubmed/3263614 Response of preterm infants
to diphtheria-tetanus-pertussis vaccine. Pediatr Infect
Dis J. 1988;7:704-11.
58. DAngio CT, Maniscalco WM, Pichichero
ME. Immunologic response of extremely premature
infants to tetanus, Haemophilus influenzae, and polio
immunizations. Pediatrics. 1995;96:18-22.
59. Pullan CR, Hull D. Routine immunisation
of preterm infants. Arch Dis Child. 1989;64:1438-41.
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Committee on Infectious Diseases. 28th ed. Elk Grove
Village, IL: American Academy of Pediatrics; 2009.
p.9-55.
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RG, Cordero JF, Slater E. HYPERLINK http://www.
ncbi.nlm.nih.gov/pubmed/11430950 Varicella vaccine
exposure during pregnancy: data from the first 5 years
of the pregnancy registry. Obstet Gynecol. 2001;98:149.
60
62. Marin M, Gris D, Chaves SS, Schmid
S, Seward JF; Advisory Committee on Immunization
Practices, Centers for Disease Control and Prevention
(CDC). Prevention of varicella: recommendations of
(ACIP). MMWR Recomm Rep. 2007;56:1-40.
61

(Vaccine reaction)

(Programmatic error)
(Injection reaction)
(Coincidental events)
(Unknown)

1. (Vaccine reactions)
(Immune system)

(Adverse Events Following Immu- (systemic reaction)
nization : AEFI) Surveillance of adverse events
following immunization : Field Guide for Managers of
Immunization Programmes, WHO Geneva 1997 (antibiotic) (adjuvant)
An adverse events following immunization is a (preservative)
medical incident that takes place after an immunization
and is believed to be caused by the immunization.

1.1 (Mild, common vaccine

reactions)
1

(systemic reaction)
62
BCG
Hib
Hepatitis B
Measles/MMR
Oral Polio Vaccine (OPV)
Tetanus/DT
DTP
( )
90-95 %
5 - 15 %
30 %
5 %
10 %
10 % *
50 %
2 - 10 %
1-6%
5-15 %
<1 %
10 %
50 %
5
<1
25
55
* 50 - 85 Tetanus/DT
( 2)
2
1 2

measles/MMR 5 - 12
10
DTP (whole
cell)
50 ( 1)
1.2 (More serious, rare vaccine
reactions)

(Thrombocytopaenia)
/ (Hypotonic Hyporesponsive Episodes)
(Persistent screaming) ( 2)
2.

(cluster)

(Bacterial abscess)
sepsis
toxic shock syndrome

(sterile
abscess) ( 3)
3.
(Injection reactions)
6 63
BCG
Hib
Hepatitis B
Measles/MMR/MR
Oral Polio (OPV)

Tetanus
Tetanus-diphtheria
DTP
Suppurative Lymphadenitis
BCG Osteitis
Disseminated BCG-infection
None known
Anaphylaxis
Febrile Seizures
Thrombocytopaenia
Anaphylactoid (severe allergic reaction)
Anaphylaxis
Encephalopathy
Vaccine-Associated Paralytic Poliomyelitis (VAPP)
Brachial Neuritis
Anaphylaxis
Tetanus vaccine
Persistent (>3 hours) inconsolable screaming
Seizures
Hypotonic Hyporesponsive Episode (HHE)
Anaphylaxis
Encephalopathy ()
2-6
1-12
1-12
100-1,000
0.01-300
0.19-1.56
0-1
6-12
15-35
0-2
0-1
6-12
4-30
2-28
0-1
1-2
330
30
~10
~1
<1
~0.4
5-10
0.4-10
0-24
0-2
0-24
0-1
0-2
1,000-60,000
80-570
30-990
20
0-1
( 3)
(Adverse event expected)
BCG
DTP/DT/TT

toxic shock syndrome

( 2)

sciatic nerve
64

5

Hyperventilation

1. (Local Adverse Events)

1.1 (Bacterial Abscess)

Neutrophil ( 50)
5
1.2 (Sterile Abscess)

5
1.3 (Lymphadenitis;
Includes Suppurative Lymphadenitis)
4. (Coincidental events)
1.5
.
2 - 6
(
)
.. 2539 (National
1.4 (Severe
Immunization Days) Local Reaction)
OPV

wild polio virus 3
wild polio virus 5
OPV

(coincidental event)
2.
(Central Nervous System Adverse Events)
5. (Unknown)
2.1 Vaccine-Associated Paralytic Poliomyelitis
(VAPP)

6 65
4 - 30 OPV
4 - 75
OPV 60

2.2 Guillain-Barr Syndrome (GBS)

6
2.3 (Encephalopathy)

1 72
measles/MMR
7-12
2.4 (Encephalitis)

30
2.5 (Meningitis)

30
2.6 Febrile Seizures

38.5 .
() 15
2.7 Afebrile Seizures

15
2.8 Brachial (Brachial

Neuritis)

2
2-28
3. (Other Adverse Events)
3.1 (Fever)

1-2 measles MMR
5-12
3.2 (Allergic Reaction)

24
3.3 Anaphylactoid Reaction (Acute Hypersensitivity Reaction)

(wheezing)
Stridor

2
3.4 Anaphylaxis (Anaphylactic Shock)

(wheezing) Stridor
66
3.5 (Arthralgia)

10 8
3.6 Disseminated BCG-itis

1 - 12
Mycobacterium
bovis
3.7 / (HypotensiveHyporesponsive Episode : Shock Collapse)
48

3.8 (Osteitis/
Osteomyelitis)

8 - 16
Mycobacterium bovis
3.9 (Persistent Screaming)

3
24
3.10 (Sepsis)

5
3.11 Toxic Shock Syndrome

2 - 3
3.12 (Thrombocytopaenia)
50,000 /
..

8
1.Information for health-care workers managing adverse events [Internet]. Available from: http://
www.who.int/immunization_safety/aefi/managing_AEFIs
2.Immunization Safety Surveillance: Part 2:
Adverse events following immunization (AEFIs). WHO
Regional Office for the Western Pacific; 2009.
3.Supplementary information on vaccine safety: Part 2: Background rate of adverse event following
immunization. Geneva: World Health Organization;
2000.
67

1
1.

2.

68
7 69

1.

--

4
5 6

---

5

4 1.
2.
3.

(
)6

70

( 2
4 )
8 5
1
2-3

8
3 7-valent,
10-valent 13-valent 7-valent
10-valent 13-valent

7-valent
10-valent
10

13-valent

2009 (H1N1)

H1N1

H1N1

H1N1 1 3
7 71

9
2. 1
1-10

( )

1-2 ( 3 )
(
3-5 )

5 5

3-12
72

75-80

90-95 1
2
( )
3.
10-12
--

-- (Tdap)
10-12
- (Td)
10
-- (Tdap)
Td

Tdap

--
7 73
10

11
80

5
4.

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77
1
(allergens) (antigens) (vaccines)
(hormones) (cytokines)
(enzymes) (stem cells)
(tissues)
(human whole blood and plasma derivatives) (immune sera)
(immunoglobulins)
(monoclonal antibodies)
(fermentation
or recombinant DNA)

1.
(eukaryotic cells)
2.
(extraction of substances from Biological
tissues including human, animal and plant tissue (allergen)
3. (recombinant DNA
or rDNA techniques)
4. (hybridoma technique)
5.
(propagation of microorganisms in embryo or animals)
6.
()
(antigens)
(adjuvants) (preservatives)
(suspending fluid)

(vaccine)2
vaccin-us vacca cow
(.. 2339)
(cowpox)
(smallpox)
(cowpox)
(cowpox)
(smallpox)

(EPI NIP)

78

(cold chain)
3

5

()
(MMR)
(OPV)
3. (Toxoid vaccines)
(toxin)
(toxoid)

(Diphtheria) (Tetanus)
1. (Inactivated vaccines)

4. (Subunit vaccines)

(Pertussis) (whole cell)

2. (Live-attenuated vaccines)

8 79
5. (Conjugated vaccines)
(subunit)

(polysaccharide capsule)
(Haemophilus influenzae type b)

(DTP)
(MMR)

(Immunization)
100 100
(NRA)

2

1.

(Pre-clinical phase)
(fully functional system

+ 6 regulatory functions)

UN Prequalified

Technical Report Series (TRS)
WHO Good Manufacturing Practices

(GMP)
2. (Clinical preclinical clinical
phase)

United Nation (UN
1, 2, 3 Tender)
80

complex mixtures of proteins, lipids, and
biological materials
(pathogenic)
(transmissible microorganisms)
aseptic process

(Building
Quality into the Products)

unidirectional airflow (UDAF) systems
environmental monitoring
(EM)

(Risk management)

GMP
()
4
1 (
)

2 (
)

3 (
4 (
(AEFI) )
Lot
release

(Laboratory
assessed)
8 81

( )
( )5
(
H.influenzae type b)
(recombinant)

(ultrafiltration)
(column chromatography)

Staphylococcus
6,7

(pathogen-associated molecular pattern)8

(Good Manufacturing
Practice GMP) PIC/S (Pharmaceutical
International Convention/Scheme)

(Good manufacturing practices, GMP)
82
(manufactures protocols)
2.

3.

NCL
4. NCL
(Pharmacopoeia)

5. NCL
1.

6.
1.1 (potency)
(safety) (NRA)

7.
In vitro In vivo test
8.
1.2
preclinical potency (
1.3 antibody responses
1.4 immunity
) sterility, innocuity, pyrogen2. unfinished bulk icity stability test
9.
materials

(NCL)
strain (origin) master and

(NCL) Lot release working seeds batches

1.

(Validation)
(Quality Assurance)

(Good manufacturing practice GMP)

(Good Laboratory
Practice)
8 83
(certificate of analysis)

(validation) strain

(Clinical phase) GCP

(Good Clinical Practice)
pharmacokinetic, pharmacodynamic, clinical safety
efficacy

1.

2.

master formula

84

Lint-free
(Air lock)
(Air lock) 2

(Double HEPA Filter)

Waste
(Killed
tank) 132 .
(Spore)

(U-shape)

(Curve)

8 85
(lint-free)

(Validation)
(Hot Air
or Steam Sterilizer) 2 (Double Doors)

Quarantine Area

(Batch production record)

(Intermediate products)

(Fumigation)

86

Endotoxin

(identification) (seed)
9
(EM)
LF (Classification
and environmental monitoring (EM) of clean rooms
and laminar flow work Stations) ISO
14644-1
(in operation) (at rest)
4
Grade A:
laminar air flow
work station 0.36-0.54 /

Grade B: larminar air flow
grade A aseptic preparation
Grade C and D:
(validation)
8 87
1 EN ISO 14644-1
(Maximum permitted airborne particulate concentration per air grade)1

Grade
A
B
C
D
At rest
Max. permitted particles /m3
0.5 m
5.0 m
3,520
20
3,520
29
352,000
2,900
3,520,000
29,000

HVAC

(validation) 12
A B 6
ISO 14644-1 (clean room
routine environmental monitoring according
ISO 14644-1)
(out of trend = OOT)
(validation)

In operation
0.5 m
5.0 m
3,520
20
352,000
2,900
3,520,000
29,000
Not defined
Not defined
88
2
(Commended limits for microbiological monitoring of clean areas during operation)
Grade
A
B
C
D
Recommended limits for microbial contamination (a)

Air sample
Settle plates
Contact plates
cfu/m3
(diam. 90 mm),
(diam. 55 mm),
cfu/4 hours (b)
cfu/plate
<1
10
100
200
<1
5
50
100
<1
5
25
50
Glove print
5 ngers
cfu/glove
<1
5
-
: (a) These are average values

(b) Individual settle plates may be exposed for less than 4 hours
3
(Recommended clean room grades for general activities in the manufacture of prequalified vaccines)2
8 89
90
8 91
4 (Vaccine - specifie production

activities)
92
8 93
:
(1)
UDAF in C or D or UNC (unclassified) refers to the situation where a unidirectional airflow system may not be classified as
Grade A (due to the lack of a Grade B surrounding) but can provide significant additional protection to operations.

campaign basis

(seed lot)
(cell bank)

Bacillus
anthracis, Clostridium botulinum Clostridium
tetani

campaign basis
(biological substances)

94

(air extraction)

(aerosol)

(bioburden)

(positive pressure)

(negative pressure)
(containment requirements)
(air-handling units)
(processing area)

3 4

(airvent filter) (hydrophobic)

(inoculation room)
(postmortem room)

8 95

Revised Requirements for Biological
Substances No.7

..
2510

25(3) .. 2510

(preservatives)
(additives)

96

(Batch
packaging records)

1
(Follow-up-stability study)
monitor

Quarantine
(Lot Release)

1.

.. 2549.
2. Stern AM, Markel H. The history of vaccines
and immunization: familiar patterns, new challenges.
Health Aff (Millwood). 2005;24:61121.
3. Good manufacturing practices for sterile
pharmaceutical preparations in: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth Report, Geneva, World Health
Organization, 2010, Annex 4 (WHO Technical Report
Series 957). Available from: http://whqlibdoc.who.int/
trs/WHO_TRS_957_eng.pdf
4. Guided by Experts Committee on Standardization of Biological (ECBS) recommendations on
safety, efficacy issued in WHO Technical.
8 97
5. The Washington Post [Internet]: Three ways

to make a vaccine. Available from: http://www.washingtonpost.com/wp-dyn/content/graphic/2009/11/24/
GR2009112401834.html
6. Thimerosal in vaccines. Center for Biologics Evaluation and Research, U.S. Food and Drug
Administration; 2007.
7. Muzumdar JM, Cline RR. Vaccine supply,
demand, and policy: a primer. J Am Pharm Assoc.
2009;49:e8799.
8. Bae K, Choi J, Jang Y, Ahn S, Hur B.
Innovative vaccine production technologies: the
evolution and value of vaccine production technologies.
Arch Pharm Res. 2009;32:46580.
9. WHO [Internet]. Environmental monitoring
of clean rooms in vaccine manufacturing facilities;
2011. Available from: http://www.who.int/immunization_
standards/vaccine_quality/env_monitoring_
cleanrooms_draft.pdf
8 79
5. (Conjugated vaccines)
(subunit)

(polysaccharide capsule)
(Haemophilus influenzae type b)

(DTP)
(MMR)

(Immunization)
100 100
(NRA)

2

1.

(Pre-clinical phase)
(fully functional system

+ 6 regulatory functions)

UN Prequalified

Technical Report Series (TRS)
WHO Good Manufacturing Practices

(GMP)
2. (Clinical preclinical clinical
phase)

United Nation (UN
1, 2, 3 Tender)
80

complex mixtures of proteins, lipids, and
biological materials
(pathogenic)
(transmissible microorganisms)
aseptic process

(Building
Quality into the Products)

unidirectional airflow (UDAF) systems
environmental monitoring
(EM)

(Risk management)

GMP
()
4
1 (
)

2 (
)

3 (
4 (
(AEFI) )
Lot
release

(Laboratory
assessed)
8 81

( )
( )5
(
H.influenzae type b)
(recombinant)

(ultrafiltration)
(column chromatography)

Staphylococcus
6,7

(pathogen-associated molecular pattern)8

(Good Manufacturing
Practice GMP) PIC/S (Pharmaceutical
International Convention/Scheme)

(Good manufacturing practices, GMP)
82
2.

3.

NCL
4. NCL
(Pharmacopoeia)

5. NCL
1.

6.
1.1 (potency)
(safety) (NRA)

7.
In vitro In vivo test
8.
1.2
preclinical potency (
1.3 antibody responses
1.4 immunity
) sterility, innocuity, pyrogen2. unfinished bulk icity stability test
9.
materials

(NCL)
strain (origin) master and

(NCL) Lot release working seeds batches

1.

(Validation)
(Quality Assurance)

(Good manufacturing practice GMP)

(Good Laboratory
Practice)
8 83
(certificate of analysis)

(validation) strain

(Clinical phase) GCP

(Good Clinical Practice)
pharmacokinetic, pharmacodynamic, clinical safety
efficacy

1.

2.

master formula

84

Lint-free
(Air lock)
(Air lock) 2

(Double HEPA Filter)

Waste
(Killed
tank) 132 .
(Spore)

(U-shape)

(Curve)

8 85
(lint-free)

(Validation)
(Hot Air
or Steam Sterilizer) 2 (Double Doors)

Quarantine Area

(Batch production record)

(Intermediate products)

(Fumigation)

86

Endotoxin

(identification) (seed)
9
(EM)
LF (Classification
and environmental monitoring (EM) of clean rooms
and laminar flow work Stations) ISO
14644-1
(in operation) (at rest)
4
Grade A:
laminar air flow
work station 0.36-0.54 /

Grade B: larminar air flow
grade A aseptic preparation
Grade C and D:
(validation)
8 87
1 EN ISO 14644-1
(Maximum permitted airborne particulate concentration per air grade)1

Grade
A
B
C
D
At rest
0.5 m
5.0 m
3,520
20
3,520
29
352,000
2,900
3,520,000
29,000

HVAC

(validation) 12
A B 6
ISO 14644-1 (clean room
routine environmental monitoring according
ISO 14644-1)
(out of trend = OOT)
(validation)

In operation
0.5 m
5.0 m
3,520
20
352,000
2,900
3,520,000
29,000
Not defined
Not defined
88
2
(Commended limits for microbiological monitoring of clean areas during operation)
Grade
A
B
C
D
Recommended limits for microbial contamination (a)

Air sample
Settle plates
Contact plates
cfu/m3
(diam. 90 mm),
(diam. 55 mm),
cfu/4 hours (b)
cfu/plate
<1
10
100
200
<1
5
50
100
<1
5
25
50
Glove print
5 ngers
cfu/glove
<1
5
-
: (a) These are average values

(b) Individual settle plates may be exposed for less than 4 hours
3
(Recommended clean room grades for general activities in the manufacture of prequalified vaccines)2
8 89
90
8 91
4 (Vaccine - specifie production

activities)
92
8 93
:
(1)
UDAF in C or D or UNC (unclassified) refers to the situation where a unidirectional airflow system may not be classified as
Grade A (due to the lack of a Grade B surrounding) but can provide significant additional protection to operations.

campaign basis

(seed lot)
(cell bank)

Bacillus
anthracis, Clostridium botulinum Clostridium
tetani

campaign basis
(biological substances)

94

(air extraction)

(aerosol)

(bioburden)

(positive pressure)

(negative pressure)
(containment requirements)
(air-handling units)
(processing area)

3 4

(airvent filter) (hydrophobic)

(inoculation room)
(postmortem room)

8 95

Revised Requirements for Biological
Substances No.7

..
2510

25(3) .. 2510

(preservatives)
(additives)

96

(Batch
packaging records)

1
(Follow-up-stability study)
monitor

Quarantine
(Lot Release)

1.

.. 2549.
2. Stern AM, Markel H. The history of vaccines
and immunization: familiar patterns, new challenges.
Health Aff (Millwood). 2005;24:61121.
3. Good manufacturing practices for sterile
pharmaceutical preparations in: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fourth Report, Geneva, World Health
Organization, 2010, Annex 4 (WHO Technical Report
Series 957). Available from: http://whqlibdoc.who.int/
trs/WHO_TRS_957_eng.pdf
4. Guided by Experts Committee on Standardization of Biological (ECBS) recommendations on
safety, efficacy issued in WHO Technical.
8 97
5. The Washington Post [Internet]: Three ways

to make a vaccine. Available from: http://www.washingtonpost.com/wp-dyn/content/graphic/2009/11/24/
GR2009112401834.html
6. Thimerosal in vaccines. Center for Biologics Evaluation and Research, U.S. Food and Drug
Administration; 2007.
7. Muzumdar JM, Cline RR. Vaccine supply,
demand, and policy: a primer. J Am Pharm Assoc.
2009;49:e8799.
8. Bae K, Choi J, Jang Y, Ahn S, Hur B.
Innovative vaccine production technologies: the
evolution and value of vaccine production technologies.
Arch Pharm Res. 2009;32:46580.
9. WHO [Internet]. Environmental monitoring
of clean rooms in vaccine manufacturing facilities;
2011. Available from: http://www.who.int/immunization_
standards/vaccine_quality/env_monitoring_
cleanrooms_draft.pdf
101
Enterobacteriaceae Yersinia
3 Y. pestis, Y. enterocolitica
Y. pseudotuberculosis

Y. pestis1
Y. pestis 3 biovars (orientalis,
mediaevalis antigua) 3 biovars
2
Yersinia pestis .. 2437
Yersin & Hitasato

3
6

24 50
2 14
The Black Death ()
25
3
(Plague) .. 2439
Yersinia pestis bi-
polar staining safety pin
Congo red agar 26-28 . .. 2443-2444
(bull-eye) 60,000
.. 2453-2454 10,000
48 Y. pestis
102

- .. 2552

3
9

. 2447

.. 2495

3,4

pneumonic plague
3
1. (Bubonic plaque)

50-60
2. (Pneumonic plaque)

95-100
5
3. (Septicemic plaque)
1-7

bubonic
plague

6-9

(Septicemic plague) Y. pestis
bipolar-staining coccobaccilli
9 103
safety-pin
Haemagglutination inhibition test
Fluorescent antibody
polymerase chain reaction immunohistochemical staining
10-16
streptomycin 30
././ gentamicin, tetracycline,
doxycycline, chloramphenicol, trimethoprimsulfamethoxazole ciprofloxacin
chloramphenicol

cell vaccines; KWC)

195/P Y. pestis17
United States Pharmacopoeia (USP)
..1999
KWC Commonwealth Serum Laboratories (CSL, Australia)
195/P
3 x 109/.
0.5 . 1-4
6
1
Live attenuated vaccines
.. 1908
EV76 Y. pestis18

Sub-unit vaccines
sub-unit

recombinant proteins
recombinant F1 V proteins alhydrogel adjuvanted19-22
phase I 145

sub-unit
( 2 )

KWC23
..
1946

sub-unit
phase 1

Pre-exposure prophylaxis

Y. pestis

Killed whole-cell vaccines
(Killed whole-
104
1
(Killed whole-cell vaccine)
6 - 2
3-6
7-11
> 12
0.1 .
0.2 .
0.3 .
0.5 .
0.1 .a
0.2 .a
0.3 .a
0.5 .a
0.1 .a
0.2 .a
0.3 .a
-
0.1 .b
0.2 .b
0.3 .b
0.3 .c
1-4
6
c
6 0.1 . (intradermal)

24

bubonic form
Post-exposure prophylaxis
KWC

sub-unit

Y. pestis
KWC
passive
F1
1:128 27,28

F1 V

F1 V
subunit recombinant F1 V proteins phase I

32
( 21
) 1 F1 29

KWC
6
subunit recombinant F1 V proteins
8-12 30

KWC
F1
25
F1 26 .. 1961-1971
9 105
(333
/106 person-year of exposure)

KWC
(1 /106 person-year of exposure) 24,31

KWC

32
EV76
KWC 33
sub-unit recombinant
F1 V proteins

25,34

35
KWC

1036,37
EV76
20 38
33,38
sub-unit recombinant F1 V
proteins
39

18

KWC

sub-unit
KWC
subunit Y. pestis

KWC

sub-unit

Yersinia secretory protein
F
39
106
1. Brubaker RR. Factors promoting acute and

chronic diseases caused by yersiniae. Clin Microbiol
Rev. 1991;4:309-24.
2. Perry RD, Fetherston JD. Yersinia
pestis--etiologic agent of plague. Clin Microbiol Rev.
1997;10:35-66.
3. Prentice, MB, Rahalison, L. Plague. Lancet. 2007; 369:1196-207.
4. ,

.
. 2552;40:497-50.
5. Ratsitorahina, M, Chanteau, S, Rahalison,
L, Ratsifasoamanana L, Boisier P. Epidemiological
and diagnostic aspects of the outbreak of pneumonic
plague in Madagascar. Lancet. 2000;355:111-3.
6. Crook, LD, Tempest, B. Plague. A clinical
review of 27 cases. Arch Intern Med. 1992; 152:1253-6.
7. Centers for Disease Control and Prevention (CDC). Human plague--United States, 1993-1994.
MMWR Morb Mortal Wkly Rep. 1994;43:242-6.
8. Weniger, BG, Warren, AJ, Forseth, V,
Shipps GW, Creelman T, Gorton J, et al. Human bubonic plague transmitted by a domestic cat scratch.
JAMA. 1984;251:927-8.
9. Butler, T. Yersinia infections: centennial
of the discovery of the plague bacillus. Clin Infect Dis.
1994;19:655-61.
10. Anisimov AP, Amoako KK. Treatment of
plague: promising alternatives to antibiotics. J Med
Microbiol. 2006;55:1461-75.
11. Meyer KF. Modern therapy of plague. J
Am Med Assoc. 1950;144:982-5.
12. Koirala J. Plague: disease, management,

and recognition of act of terrorism. Infect Dis Clin North
Am. 2006;20:273-87.
13. Mwengee W, Butler T, Mgema S, Mhina G,
Almasi Y, Bradley C, et al. Treatment of plague with
gentamicin or doxycycline in a randomized clinical trial
in Tanzania. Clin Infect Dis. 2006;42:614-21.
14. Mccrumb FR, Mercier S, Robic J, Bouillat
M, Smadel JE, Woodward TE, et al. Chloramphenicol
and terramycin in the treatment of pneumonic plague.
Am J Med. 1953; 14:284-93.
15. Boulanger LL, Ettestad P, Fogarty JD,
Dennis DT, Romig D, Mertz G. Gentamicin and tetracyclines for the treatment of human plague: review of
75 cases in new Mexico, 1985-1999. Clin Infect Dis.
2004;38:663-9.
16. Nguyen-Van-Ai, Nguyen-Duc-Hanh,
Pham-Van-Dien, Nguyen-Van-Le. Letter: Co-trimoxazole in bubonic plague. Br Med J. 1973;4:108-9.
17. Williams JE, Altieri PL, Berman S, Lowenthal JP, Cavanaugh DC. Potency of killed plague
vaccines prepared from avirulent Yersinia pestis. Bull
World Health Organ. 1980;58:753-6.
18. Meyer KF, Smith G, Foster LE, Marshall
JD Jr, Cavanaugh DC. Plague immunization. IV. Clinical reactions and serologic response to inoculations
of Haffkine and freeze-dried plague vaccine. J Infect
Dis. 1974;129(Suppl):S30-6.
19. Leary SE, Williamson ED, Griffin KF, Russell P, Eley SM, Titball RW. Active immunization with
recombinant V antigen from Yersinia pestis protects
mice against plague. Infect Immun. 1995;63:2854-8.
20. Simpson WJ, Thomas RE, Schwan TG.
Recombinant capsular antigen (fraction 1) from Yer
sinia pestis induces a protective antibody response in
9 107
BALB/c mice. Am J Trop Med Hyg. 1990;43:389-96.

21. Miller J, Williamson ED, Lakey JH, Pearce
MJ, Jones SM, Titball RW. Macromolecular organisation of recombinant Yersinia pestis F1 antigen and the
effect of structure on immunogenicity. FEMS Immunol
Med Microbiol. 1998;21:213-21.
22. Carr S, Miller J, Leary SE, Bennett AM, Ho
A, Williamson ED. Expression of a recombinant form of
the V antigen of Yersinia pestis, using three different
expression systems. Vaccine. 1999;18:153-9.
23. Heath DG, Anderson GW Jr, Mauro JM,
Welkos SL, Andrews GP, Adamovicz J, et al. Protection against experimental bubonic and pneumonic
plague by a recombinant capsular F1-V antigen fusion
protein vaccine. Vaccine. 1998;16:1131-7.
24. Prevention of plague: recommendations
of the Advisory Committee on Immunization Practices
25. Williamson ED, Eley SM, Griffin KF, Green
M, Russell P, Leary SE, et al. A new improved subunit vaccine for plague: the basis of protection. FEMS
Immunol Med Microbiol. 1995 ;12:223-30.
26. Williams JE, Cavanaugh DC. Measuring the efficacy of vaccination in affording protection
against plague. Bull World Health Organ. 1979;57:30913.
27. Meyer KF. Effectiveness of live or killed
plague vaccines in man. Bull World Health Organ.
1970;42:653-66.
28. Marshall JD Jr, Cavanaugh DC, Bartelloni PJ, Meyer KF. Plague immunization. 3. Serologic
response to multiple inoculations of vaccine. J Infect
Dis. 1974;129:(Suppl):S26-9.
29. Williamson ED, Flick-Smith HC, Lebutt
C, Rowland CA, Jones SM, Waters EL, et al. Hu-
man immune response to a plague vaccine comprising recombinant F1 and V antigens. Infect Immun.
2005;73:3598-608.
30. Williamson ED, Vesey PM, Gillhespy KJ,
Eley SM, Green M, Titball RW. An IgG1 titre to the
F1 and V antigens correlates with protection against
plague in the mouse model. Clin Exp Immunol. 1999
;116:107-14.
31. Cavanaugh DC, Elisberg BL, Llewellyn CH,
Marshall JD Jr, Rust JH Jr, Williams JE, et al. Plague
immunization. V. Indirect evidence for the efficacy of
plague vaccine. J Infect Dis. 1974 ;129(Suppl):S37-40.
32. Cohen RJ, Stockard JL. Pneumonic
plague in an untreated plague-vaccinated individual.
JAMA. 1967;202:365-6.
33. Russell P, Eley SM, Hibbs SE, Manchee
RJ, Stagg AJ, Titball RW. A comparison of Plague
vaccine, USP and EV76 vaccine induced protection
against Yersinia pestis in a murine model. Vaccine.
1995;13:1551-6.
34. Williamson ED, Eley SM, Stagg AJ, Green
M, Russell P, Titball RW. A sub-unit vaccine elicits IgG
in serum, spleen cell cultures and bronchial washings
and protects immunized animals against pneumonic
plague. Vaccine. 1997;15:1079-84.
35. Jones SM, Griffin KF, Hodgson I, Williamson ED. Protective efficacy of a fully recombinant plague vaccine in the guinea pig. Vaccine.
2003;21:3912-8.
36. Reisman RE. Allergic reactions due to
plague vaccine. J Allergy. 1970;46:49-55.
37. Marshall JD Jr, Bartelloni PJ, Cavanaugh
DC, Kadull PJ, Meyer KF. Plague immunization.
II. Relation of adverse clinical reactions to multiple immunizations with killed vaccine. J Infect Dis.
108
1974;129(Suppl):S19-25.
38. Meyer KF, Cavanaugh DC, Bartelloni
PJ, Marshall JD Jr.Plague immunization. I. Past and
present trends. J Infect Dis. 1974;129(Suppl):S13-8.
39. Matson JS, Durick KA, Bradley DS, Nilles
ML. Immunization of mice with YscF provides protection from Yersinia pestis infections. BMC Microbiol.
2005;5:38.
109

Variolation

(Mode of Infection)

1 Lady Mary Wortley Montagu

( )
10

.. 2264 Lady Mary Wortley
Montagu

Dr. Zabdiel Boylston
Cotton Mather
Variolation 23

(Rinderpest,
) (sheep pox)

110
.. 2339
Edward Jenner Berkeley, Gloucestershire

(Cow pox)

(Vaccine) Vacca
2
75
An Inquiry into the Causes and Effects of the Variolae Vaccinae, A Disease Discovered in Some of the
Western Countries of England, Particularly Gloucestershire and Know by the Name of the Cowpox

(cow-to-human)

(Human-to-Human arm-to-arm)
6

arm-to-arm

(Humanized Vaccinia Virus)

Vaccinia virus
(original cowpox virus)
Variolation
.. 2383 Variolation

(crossimmunization)
Vaccinia virus

neurovirulence
(post-vaccinal encephalitis)

(generalized vaccinia)
(eczema vaccinatum)

1.
2.
3.
4.
1.

(chorioallantoic
membrane)

avian leukosis virus

10 111
11.5
0.03

(jet injector) (scar)

(killed vaccine) (live vaccine)
Ehrengut
(primary vaccination)

108 pock forming unit pfu

1 .
4 .
3 - 6

(freeze-dried lyophilization in vacuo)

(Lister Institue, Estree)

45 . 6
2.

.. 2517
5

1. 3.
2.

3.

4. chorioallan-
toic membrane 12 48
35 . (pock)
112

Thomas Rivers

The first revived strain
CV1
3 The second revived strain CV2

Modified Vaccinia Ankara Virus
MVA
(.. 2553)

1. (Primary vaccination)

Primary take
Papule 5
(Vesicle) 7 - 10

(multilocular)
0.5 1.5 .
Jennerian vesicle
Pustule

major reaction

1

crust
3

foveation smallpox
vaccination scar
pox mark

8
2. (Revaccination)

10 113

pox mark
2.1 (Successful revaccination) major reaction 1

(vesicle)
(pustule) (induration)
(congestion)
( vaccinoid
reaction accelerated reaction
major reaction)
2.2 (Equivocal reaction)

2 - 3

(allergic reaction)
( Reaction of
immune Immediate reaction Allergic reaction)

(non-endemic area)
1-2
(Post vaccinal
encephalitis, PVE)
1 2-10

2-3
6

/
Dysgamma globulinemia
Blood dyscrasia
Eczema dermatitis

(Immunosuppressive agents)

114

vaccinia immune
gamma globulin

(Live attenuated virus vaccine)
2.

dermatotropism

2.1 Generalized vaccinia

1.
6

2. 6-9
2.2 Eczema vaccinatum

5

3.
3
2.3 Vaccinia gangrenosa

1.

() vaccinia
immune gamma globulin

( 70%

3. Post Vaccinal Encephalitis (PVE)
)
PVE
8-15

Clostridium tetani, Escherichia 10 1
coli, hemolytic Streptococci Bacillus anthracis Vaccinia gamma
(non-pathogenic globulin
bacteria) 500 1 .
10 115
4. Post vaccinal myocarditis

ed needle) (
)

5.

3
(Bifurcated needle)
4
(Hagedorn needle)

1. Multiple pressure method

Hagedorn needle 6
6-10 10 .
(
50 )
7
2. Scratch method
Hagedorn needle
6.5 . 40 Glycerin M/30 dil. Mc Ilvaine buffer, pH 7.6

1. , .
3. Multiple puncture method
.
(Bifurcat- . 2464;4:75.
116
2. Brown CM. Smallpox immunization. The
practitioner. 1959;183:253-7.
3. Kempe CM. Studies on smallpox and
complication of smallpox vaccination. Pediatrics. 1960;26:
176-89.
4. Cox CR. WHO expert committee on smallpox.
First report. World Health Organ Tech Rep Ser. 1964;283:
1-37.
5. Kaplan C. Smallpox vaccine:present status,
suggested use, desirable development. lbid. 144.
6. . .
. 2517;2:342.
7. Ehrengut W, Weise HJ. Am Ende der
Pockenimpfpflicht. Kongress-dienst Bayer. 1975;36:1.
117
(Tick-borne
encephalitis, TBE)

Tick borne encephalitisvirus
(TBE virus)
3 TBE

Langat virus (LGTV)
TBE LGTV

.. 1956 1

2

(hard tick)

accidental host

11

1,2

.. 1937

Russian Spring and Summer
encephalitis (RSSE)

.. 1974 2003
4
2,755 ( .. 1973) 8,755
( .. 1996 10,298 )

3
.. 1980
118

10 1,3

15
10,000-12,000
TBEV family
Flaviviridae, genus Flavivirus

50
structural protein prM E protein
capsid protein
RNA 1
11
structural nonstructural protein (NS1-5)
4
genus Flavivirus
(Ixodes spp.)

TBE

3 (subtype) Far Eastern (FE-TBE),
Siberian (S-TBE) Western European (W-TBE)
Flavivirus
TBEV
Louping ill virus (LIV), Langat virus (LGTV), Powassan
(POWV), Omsk hemorrhagic fever virus (OHFV),
Kyasamur Forest disease virus (KFDV), Kadan virus

TBE
(
80)
TBE
LIV

TBE FE-TBE
S-TBE W-TBE 1,2
TBE
3
larva nymph adult

nymph

Ixodes persulcatus
FE-TBE
Ixodes ovatus Ixodes ricinus

TBE 0.1-0.52 TBE

5

1,2
TBE
Langerhans cells
(Regional
lymph node)
T lymphocyte, B lymphocyte
11 119
mediator
TBE

blood brain barrier

(ataxia)
(paresis, paralysis)

gray matter lymphocyte
glial cell

2,5
7-10 (4-28) 5
2-7
( 38-39o .)

(fasciculation)

1-2
2-10

1-2 o .
Febrile form 1/3

1-5

Meningeal form

febrile form

7-14
Meningoencephalitis form

(coma)

30

60
Poliomyelitic form

2

(wrist drop) (hanged head)
2-3

Polyradiculoneuritic form

(biphasic) 3-7

1-2

120
Chronic form Siberia

Far East
subtype Siberian

(Kozshevnikovs epilepsy) ,
Parkinson syndrome

severe dementia

Siberia S-TBE febrile form
80 paralytic form
7-8 chronic form 4-5
7
Far East
meningoencephalitis

601,2

10-20 ()

75 C-reactive protein
80 ESR 90

mononuclear cell

60 /.. 31
100 /..

1,000 /.. neutrophil
mononuclear cell

ELISA IgG IgM

IgG

cross reaction
flavivirus neutralization test
6
RNA RT-PCR
systemic infection 1/3 2,7
11 121

(secondary prophylaxis) 96
60
antibody dependent enchancement3

10

TBE S-TBE
FE-TBE W-TBE
( W-TBE)
W-TBE

FSME-immun

active antigen

TBE

far-eastern 205
Sofjin 1
(inactivated)
.. 1940
TBE

TBE

FSME-immun (TicoVac) Encepur

96-99
3

TBE
3
60
FSME-immun

2 FSME-immun
Encepur
122
- FSME-immun
.. 1970
Neudoerfl
- Encephur TBE
.. 1994
Novartis ( Chiron)
K53
Karlsruhe

master seed virus embryonic
fibroblast cell inactivated formaldehyde
ultracentrifugation
sucrose gradient
adjuvant (aluminium hydroxide)

2,8-10
12
(Encepur-adults)/ 16 FSME-immun-adults)
1.5 (Encepur-adults)
2.4 (FSME-adults) 0.5 .
12 (Encepur-children)/ 16
(FSME-immun-junior)
0.25 .2
1
2-8o .
1 inactivated TBE vaccine

Vaccine
Encepur adult
Encepur children
FSME-immun adult
FSME-immun junior
Type of vaccine
Inactivated vaccine
Manufacturer
Novartis, Germany
Baxter AG, Austria
Composition
Antigen details
Strain
K-23
K-23
Neudoerfl
Neudoerfl
Amount of
1.5
0.75
2.4
1.2
antigen (g)
Excipients
Adjuvant
Al(OH)3
Stabilizer
sucrose
Human serum albumin
Adjusted (mL)
0.5
0.25
0.5
0.25
Vaccine Schedule
Age limit (years)
>12
<12
>16
<16
nd
Standard vaccine
0, 1-3 month, 5-12 months after 2 dose
schedule (Booster)
(every 5 years for adults and every 3 years for children/elders)
Rapid vaccine
0, D7, D21 (12-18 month*)
0, WK2 (5-12 month after 2nd dose*)
schedule
(* for long term protection)
Route
IM
( 2, 7)
11 123

3 0, 1-3
5-12
1

5 16-50
(FSME-immun-adult) 12-50 (Encepuradult) 3

FSME-immun
Encepur 2
FSME-immun 8

FSME-immun 0, 2
5-12
Encepur
0, 7 21 12-18
2
99
7-9,11

35-45

FSME-immun-adults
Encepur-adults

38o .
15, 5 2-5 1-2 , 3-11
12

15
7,8
.. 1997-1998
Encepur-children

Polygeline stabilizer
aluminum hydroxide
2
(seroconversion) 90-100 encepur .. 2001 stabilizer

( 85-95)

stabilizer10

TBE

124
1

category C

12

.. 1970
Langat virus (LGTV) Elantcev15-20/3
TBE
LGTV flavivirus
TBE
12-18
6

10
20

100 1

1 : 10,0001 LGTV
TBE

0.9 : 1,000

1 : 10,000

7
(Future vaccine)

Live attenuated vaccine
11 125

viral like particle recombinant
subviral particles, DNA vaccine,
non structural protein subunit
DEN-4
TBE 13,14
immunogenicity of the modified adult tick-borne encephalitis vaccine FSME-IMMUN: results of two large
phase 3 clinical studies. Vaccine. 2006;24:5256-63.
9. Pllabauer EM, Pavlova BG, Lw-Baselli A,
Fritsch S, Prymula R, Angermayr R, et al. Comparison
of immunogenicity and safety between two paediatric
TBE vaccines. Vaccine. 2010;28:4680-5.
10. Zent O, Hennig R, Banzhoff A, Brker
M.Protection against tick-borne encephalitis with a new
vaccine formulation free of protein-derived stabilizers.
J Travel Med. 2005;12:85-93.
11. Demicheli V, Debalini MG, Rivetti A.

1. Gritsun TS, Lashkevich VA, Gould EA. Vaccines for preventing tick-borne encephalitis.
Tick-borne encephalitis. Antiviral Res. 2003;57:129-46. Cochrane Database Syst Rev. 2009;(1):CD000977.
2. Kaiser R.Tick-borne encephalitis.Infect.
12. Dumpis U, Crook D, Oksi J.Tick-borne
Dis Clin North Am. 2008;22:561-75.
encephalitis. Clin Infect Dis. 1999;28:882-90.
3. Mansfield KL, Johnson N, Phipps LP,
13. Pletnev AG, Bray M, Hanley KA, Speicher
Stephenson JR, Fooks AR, Solomon T.Tick-borne J, Elkins R. Tick-borne Langat/mosquito-borne denencephalitis virus - a review of an emerging zoonosis. gue flavivirus chimera, a candidate live attenuated
vaccine for protection against disease caused by
J Gen Virol. 2009;90:1781-94.
4. Gould EA, Solomon T.Pathogenic members of the tick-borne encephalitis virus complex:
evaluation in rhesus monkeys and in mosquitoes.
flaviviruses. Lancet. 2008;371:500-9.
5. Haglund M, G nther G. Tick-borne J Virol. 2001;75:8259-67.
encephalitis--pathogenesis, clinical course and
14. Pripuzova NS, Tereshkina NV, Gmyl LV,
long-term follow-up. Vaccine. 2003;21(Suppl 1):S11-8. Dzhivanyan TI, Rumyantsev AA, Romanova LIu,et
6. Holzmann H. Diagnosis of tick-borne al. Safety evaluation of chimeric Langat/Dengue 4
encephalitis. Vaccine. 2003;21(Suppl 1):S36-40.
flavivirus, a live vaccine candidate against tick-borne
7. . encephalitis. J Med Virol. 2009;81:1777-85.
Tick-Borne Encephalitis. :
, , ,
, , . Travel and
adult immunization.:;
2552. .210-3.
8. Loew-Baselli A, Konior R, Pavlova BG,
Fritsch S, Poellabauer E, Maritsch F, et al. Safety and
76
127

Japanese encephalitis (JE)
arbovirus family Flaviviridae, genus
Flavivirus Culex tritaeniorhynchus

10-35
30-501-3
18

.. 2468
19

Culex

.. 2512

12
2,000

4-6 .. 2552

543 0.86
106
( 19.52) 0.17

15 0-4
1.1
5-9 15 10-14
0.3, 0.09 0.08
7
1 : 300 1 : 1000

5-15 1-3
128
8,9

(inapparent infection) aseptic meningitis
(encephalitis) 3
1. Prodromal stage

1-6
2. Acute encephalitic stage

pyramidal tract signs, flaccid
paralysis deep tendon reflex
10
1 2
2
3. Late stage and sequele

antidiuretic hormone (SIADH)

4,9

10-1,000 / ..

9

(viral isolation)
10
1. JE virus-specific IgM antibody
7
.. 2522
(AFRIMS)
anti-JE IgM IgG
ELISA
anti-JE IgM 80
5 11
2. JE virus antigens
immunohistochemistry
3. JE vius genome

12 129
reverse transcriptase polymerase chain reaction

(PCR)
4.

5. 4 JE
virus-specific IgG antibody
hemagglutination inhibition (HI) plaque reduction
neutralization assay (PRNT)
14 (acute convalescent sera)
cross reactivity
Flavivirus

mannitol
10 dexamethasone

12
controlled clinical
trials Neutralizing murine monoclonal
antibodies

13
interferon

uncontrolled series
14 recombinant
interferon-alpha 13 14,15
randomized double-blind
placebo-controlled trial

interferon alpha 2a 16
ribavirin salicylates

10
17

1.
2. amplifying host
3.
4.
(JEV)
.. 2473

.. 2495

10

130

SA14-14-2

vero cell Intercell

IXIARO

2.
(Live-attenuated vaccine)
1. (Inactivated vaccine)
2.1
1.1 (Inactivated
mouse brain JEV)
SA14-14-2 primary hamster kidney cells
(PHK) Biogenetech
CD.JE VAX
2.2
Nakayama Acambis
Cosma medical 0.5 ./ PrM E SA14 3 1 ./ 3 14-2 PrM E
17D structural protein
DS Japanese Encephalitis vaccine
Beijing non-structural
0.25 ./ 3 protein
0.5 ./ 3 Flavivirus
Chimeri Vax
JE (Beijing)-GPO vaccine
1.2 (Inactivated IMOJEV
cell culture-derived JEV)

SA14-14-2 1
hamster kidney cell
Nakayama Beijing
DS JEV (Nakayama)
JEV-GPO (Beijing)
SA14-14-2
CD.JE VAX
12 131
Inactivated mouse brain JEV

Inactivated mouse brain JEV 2
2-8o . 9419
(lyophilized) -10o . 80-9120,21

90-100 22,23
Live-attenuated JEV 2-8o . Nakayama Beijing
20,21
Live-attenuated JEV
2
150 seroconversion 89.3
Live-attenuated JEV Inactivated 95.0 30 90
mouse brain JEV
100 2
Inactivated mouse brain JEV 9922
Live-attenuated JEV

3
99.3 96.5 12-15 5
*
12-18
2 1-4
1
Beijing 0.5 .
Nakayama 1 .
3
9-12
3-12
0.5 .
:
* 1. 1 ( 4) 3 3-5
5
2. Nakayama Beijing
3 Live-attenuated JEV
Inactivated JEV

1
2-3
4
( 18)
Live-attenuated JEV
2 3-12
2 3-12
1 1
132
1 23,24 95-100
2 25
IXIARO Inactivated cell

culture-derived JEV
0, 28 1
phase III
83, 53 48
6 1 2

100

9 6
11
99

11
26
ChimerivaxJE (IMOJEV)

1

99.1
3 ( 95.1)

93.6
14
1
27,28
1 28
1

23
13
angioedema 2
0.2-0.6
29,30

1:5075,000 1: 1
Live-attenuated JEV
9.3 6.7
hypersensitivity
18
1. 12-18

2. 1

1
10
Inactivated mouse
brain JEV 3 0, 7 30
0, 7 1431
12 133
1.
2.
3.
4. Live-attenuated JEV
5.
1
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4. .
. : , , .
. : ; 2536.
.89-97.
5. , ,
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. 2527;15:573-6.
6. , .
Japanese Encephalitis Virus .

12. 2541;9:65-71.
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. Situation of encephalitis and Japanese B
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, ,
, . 2010-2011.
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24. Tandan JB, Ohee H, Sohn YM, Yoksan
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76
137

influenza virus
1-3

5-7
2
4-6
(Antigenic drift)

(Seasonal influenza)
(Antigenic shift)
(Pandemic influenza)
10 - 40
.. 2552 A (H1N1)
2009
7,8

13
(Influenza)
(Influenza virus) RNA

Orthomyxoviridae matrix
protein (M) internal antigen
7-8 influenza virus 3 A,
B C influenza A B 8
influenza C 7 (surface antigen) haemagglutinin (HA) neuraminidase (NA)
haemagglutinin
A
B
C
A
subtype surface antigen haemagglutinin neuraminidase haemagglutinin
16 subtype (H1-H16) neuraminidase
9 subtype (N1-N9) haemagglutinin
neuraminidase A
A
haemagglutinin H1-H3 neuraminidase
N1 N2 subtype

H1N1, H2N2 H3N2
A surface antigen H1
138
H16 N1-N9

H5N19

A B
.
A/New Calidonia/20/99/ [H1N1]
A New Calidonia
20 . 1999
H1N1
30
10

900,000
36,000
300 11 .. 2552
120,400
189.73
.. 2552 3 - 5
A(H1N1) 2009 231

0.36
0.1912
2-3
20
(..-..)
.. 2461 (1918) H1N1
.. 2500 (1957) H2N2
.. 2511 (1968) H3N2
.. 2520 (1977) H1N1
Spanish flu
Asian flu
Hong Kong flu
Russian flu
.. 2552-2553

A H1N1
H1N1/09 (pandemic H1N1/09 virus)
H1N1 2009

(reassortment)
13 H1N1 2009
14
1

columnar

3-4
1-4 2

13 139

26-29
Influenza virus
Influenza-like illness

3
nasal swab nasopharyngeal aspirate throat swab
viral culture, rapid diagnostic (antigen) testing,
reverse transcription polymerase chain reaction (RTPCR) immunofluorescence assays30

10-14

(influenza rapid diagnostic

2 test kit)
65 21-25
immunochromatography
15- 30 influenza A
influenza B

90
20-70

RT (encephalitis) PCR viral culture31-35 rapid diagnostic
(encephalopathy) test 36
Guillain-Barr (Reye
syndrome) A (H1N1)
2009 rapid diagnostic test
A (H1N1) 2009 62.7

99.2 < 2
76.737
40

90

6,7
.. 2461, 2500 255215-20

3

140

38-45
(oseltamivir)
(zanamivir)
46

48

2-49
3
Influenza A 2 H1N1
H3N2 Influenza B 1

antigenic drift
shift

.. 2010
(- ..
2553) 2010-11
( .. 2553-
.. 2554) 2011
(-
.. 2554)
2011-12 ( ..
.. 1940 2554- .. 2555)
inactivated whole virus
vaccine 47,48
.. 1970
-A/California/7/2009 (H1N1)-like virus
split vaccine subunit vaccine
-A/Perth/16/2009 (H3N2)-like virus

-B/Brisbane/60/2008-like virus
haemagglutinin circulating antibody
A B
.. 2010-2012
circulating antibody

2
13 141
1. (Live-attenu-
ated influenza vaccine; LAIV)

2. (Trivalent
inactivated influenza vaccine; TIV)
Live-attenuated influenza vaccine (LAIV)

LAIV

TIV (mucosal immunity)
(humoral immunity) LAIV
cytotoxic T cell interferon
4-6
LAIV 1-2 secre cold-adapted virus tory IgA 30

15-71

3 TIV
94 89 2
(local IgA) 1 49,50
( 1 ) 49,51
2 49
12- 36
(
Flumist) 72.9
live-attenuated vaccine 70.152

LAIV TIV LAIV

TIV

Live-attenuated influenza vaccine TIV53-57
2-8o .

58-64
2-49 2
0.1 . wheezing < 24
142
63
5. Guillian-Barr syndrome (GBS)

6.

7. anaphylaxis
65
LAIV
Trivalent inactivated influenza vaccine (TIV)

2-49

1. Inactivated whole virus vaccine

2. Split vaccine surface antigen

internal antigen VaxigripTM, FluzoneTM, Flu
arixTM BegrivacTM
1. 2
3. Subunit vaccine purified surface 50
antigen internal antigen Agrippal S1TM
2. reactive air- InfluvacTM adjuvant MF59
way disease FluadTM
virosome
3. 2-4 wheezing adjuvant Inflexal VTM
1
1
4. 6 - 18
Begrivac
Fluarix
Fluzone
Vaxigrip
Agrippal S1
Influva
Inflexal V
Novartis Vaccines/ Biogenetech

GlaxoSmithKline
sanofi pasteur
sanofi pasteur
Abbott
Crucell/DKSH
6
6
6
6
6
6
6
Fluad
65
( 97)
Split
Split
Split
Split
Subunit
Subunit
Virosome,
Subunit
MF59
adjuvant
Subunit
Northern or southern strains

Northern strain
13 143
TIV 2-8o .
Split vaccine subunit vaccine

6 whole virus vaccine 12

2
9 2 1
9
1 (intramuscular) (deep subcutaneous)
LAIV TIV 3
70-9066,67
antigenic drift

antigenic shift68

1
3 6769
TIV
H3N2 H1N1 92
100 2 H1N1
( ) 68
270
71,72
6
.. 2552-2553
H1N1 2009 monovalent H1N1 (2009)
1 6-35
20 2
80-9573-75
6 - 8
2

2 76-78

2 79

62
2
4 8280

81,82

83

60
84
6-35
3-8
9
(.)
0.25
0.5
0.5
1-2
1-2
1
144
3 LAIV TIV
TIV
3 (2 influenza A, 1 influenza B)
4-6
antigenic drift
> 6
2-4
wheezing 1

< 4

< 4
LAIV
3 (2 influenza A, 1 influenza B)
*
12-24
3 influenza A
2-49
2-49
* 9 1

( 98)
influenza-like illness (ILI) 48

adjusted risk ratio 1.9 (95% CI: 1.25-2.95)

85-89

90,91

1-2 92,93 split vaccine subunit vaccine
whole virus vaccine subunit vaccine
13 145
GBS > 50
1 94,95
GBS 96
1.

2. (anaphylaxis)
6
3.

4. GBS
6
97,98
5.
1.
6.
2. hemodynamic
3
3. 1,000 ..
99
4. hemoglobinopathy
5.
Reye syndrome

6.

7. chronic metabolic disease
8. (BMI >35)
9. 2-3
10.

11.

1-8
6 -18
< 5

146
2-49
LAIV TIV LAIV

2
49

100
1. Monto AS, Kioumehr F. The Tecumseh

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153

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(International Certificates of Vaccination; yellow book)

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02-535-4245
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02-249-4418
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053-200-647
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- . 038-401-112
- . 074-331-206, 074-332-641
- . 076-212-108
.. 2008

17DD

15
.. 2010
inactivate betapropiolactone adjuvant (aluminum hydroxide)

2,15
Contraindication
Age <6 months
Thymus disease or history of thymus disease
Immunosuppression
Precautions
Age 6-12 months
Age 60 years for first dose vaccine
Pregnancy
Lactation
Asymptomatic HIV infection with laboratory verification of adequate immune system function
Hypersensitivity to eggs
Hypersensitivity to gelatin
( 10)
14 161
Country
2 *
Africa
Angola
Benin
Burkina Faso
Burundi
Cameroon
Central African Republic
Chad
Congo (Democratic
Republic of Kinshasa)
Congo (Republic of
the Brazzaville)
Cte dIvoire (Ivory Coast)
Equatorial Guinea
Ethiopia
French Guiana
Gabon
Gambia
Ghana
Guinea
Guinea-Bissau
Kenya
Liberia
Mali
Mauritania
Niger
Nigeria
Rwanda
So Tom and Prncipe
Senegal
Sierra Leone
Somalia
Sudan
Tanzania
Togo
Uganda
US CDC Yellow Fever Vaccine Recommendations
For all travelers 9 months of age

For all travelers 9 months of age traveling to areas south of the Sahara Desert
For all travelers 9 months of age. The cities of Nairobi and Mombasa have lower
risk of transmission than rural areas.
For all travelers 9 months of age traveling to areas south of the Sahara Desert,
EXCLUDING the city of Khartoum
For all travelers 9 months of age. The city of Dar es Salaam has a lower risk of
transmission than rural areas.
162
2 * ()
Country
South America
Argentina
Bolivia
Brazil
Colombia
Ecuador, including
the Galpagos Islands
Guyana
Panama
Paraguay
Peru
Suriname
Trinidad and Tobago
Venezuela
US CDC Yellow Fever Vaccine Recommendations
For all travelers 9 months of age traveling to the northern and northeastern forested
areas of Argentina, including Iguassu Falls and all areas bordering Paraguay and Brazil.
For all travelers 9 months of age traveling to areas east of the Andes Mountains.
Vaccination is NOT recommended for travel only to the cities of La Paz or Sucre.
For all travelers 9 months of age traveling to areas at risk for yellow fever transmission.
For all travelers 9 months of age. Travelers whose itinerary is limited to the cities of
Bogot, Cali, or Medelln are at lower risk and may consider foregoing vaccination.
For all travelers 9 months of age traveling to the following provinces in the Amazon
Basin: Morona-Santiago, Napo, Orellana, Pastaza, Sucumbos, and Zamora-Chinchipe,
and all other areas in the eastern part of the Andes Mountains, NOT including the cities
of Quito and Guayaquil or the Galpagos Islands.
For all travelers 9 months of age traveling to the provinces of Darien, Kuna Yala
(old San Blas), Comarca Ember, and Panama east of the Canal Zone, EXCLUDING
the Canal Zone, Panama City, and San Blas Islands
For all travelers 9 months of age traveling to the areas east of the Andes Mountains and
for those who intend to visit any jungle areas of the country <2,300 m (<7,546 ft).
Travelers who are limiting travel to the cities of Cuzco and Machu Picchu do NOT need
vaccination.
For all travelers 9 months of age whose itinerary includes Trinidad. Port of Spain has
lower risk of transmission than rural or forested areas. Cruise ship passengers who do
not disembark from the ship or travelers visiting only the urban area of Port of Spain (in
cluding passengers in-transit only) may consider foregoing vaccination. Vaccination is
NOT recommended for those visiting only Tobago.
For all travelers 9 months of age traveling to Venezuela, EXCEPT the northern coastal
area 3. The cities of Caracas and Valencia are NOT in the endemic zone.
(16)
*
14 163
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2010;28:3827-40.
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history. Yale J Biol Med. 2010;83:77-85.
4.Staples JE, Monath TP. Yellow fever: 100
years of discovery. JAMA. 2008;300:960-2.
5.Gould EA, Solomon T. Pathogenic flaviviruses. Lancet. 2008;371:500-9.
6. ,
. : ,
, , ,
, . Travel and adult
immunization.:;2552.
.202-9.
7.Staples JE, Gershman M, Fischer M. Centers for Disease Control and Prevention (CDC).Yellow
fever vaccine: recommendations of the Advisory
Recomm Rep. 2010;59:1-27.
8.Monath TP. Treatment of yellow fever. Antiviral Res. 2008;78:116-24.
9.Lang J, Zuckerman J, Clarke P, Barrett P,
Kirkpatrick C, Blondeau C. Comparison of the immunogenicity and safety of two 17D yellow fever vaccines.
Am J Trop Med Hyg. 1999;60:1045-50.
10.Monath TP, Cetron MS. Prevention of yellow fever in persons traveling to the tropics. Clin Infect
Dis. 2002;34:1369-78.
11.Poland JD, Calisher CH, Monath TP, Downs

WG, Murphy K. Persistence of neutralizing antibody
30-35 years after immunization with 17D yellow fever
vaccine. Bull World Health Organ. 1981;59:895-900.
12.Hayes EB. Acute viscerotropic disease
following vaccination against yellow fever. Trans R Soc
Trop Med Hyg. 2007;101:967-71.
13.Kitchener S. Viscerotropic and neurotropic
disease following vaccination with the 17D yellow fever
vaccine, ARILVAX. Vaccine. 2004;22:2103-5.
14.Lindsey NP, Schroeder BA, Miller ER,
Braun MM, Hinckley AF, Marano N. Adverse event
reports following yellow fever vaccination. Vaccine.
2008;26:6077-82.
15.Hayes EB. Is it time for a new yellow fever
vaccine?. Vaccine. 2010;28:8073-6.
16.Yellow Book [Internet]. Atlanta: US CDC.
[update July 27, 2009; cited 2011 April 5] Available
from: http://wwwnc.cdc.gov/travel/yellowbook/2010/
chapter-2/yellow-fever-vaccine-requirements-andrecommendations.aspx
76
165
Corynbacterium
diphtheria

diphtheria
toxin

antitoxin

2-6

pseudomembrane

(congestive heart failure)

(myocarditis)
C. diphtheria
cutaneous diphtheria

C. diphtheria
15
(nontoxigenic strain)

pseudomembrane Tinsdale medium
C. diphtheria1

diphtheria toxin
C. diphtheria
Elek test (in vivo
neutralization assay)
polymerase chain reaction (PCR) (tox gene)
diphtheria antitoxin erythromycin
penicillin G 14
2,3

5
0.1
3
90 4,5

166

.. 2553
78 10 0.12
14 0.02

5 ( 21.05) 5-9 ( 14.47)
10-14 ( 11.84 ) 97.4
1.3 1.3
70 (6.95 )

6
Clostridium tetani

tetanus toxin tetanospasmin

(spastic paralysis)
3-21

generalized tetanus

Localized tetanus
Cephalic tetanus
Neonatal tetanus (Tetanus
neonatorum) generalized tetanus

7,8
10

.. 2553 168
0.26 0.01
65
55 - 64
45 - 54
0.01
0.17 6
Bordetella pertussis

90
6-20 ( 7-10 )
Catarrhal
stage 1-2
Paroxysmal stage
2-6

Convalescent stage 4-6

(encephalopathy)
15 -- 167
(apnea)

(nasopharyngeal aspirate)
(nasopharyngeal wash) BordetGengou (BG) agar
B. pertussis
PCR
DNA probe
9,10
macrolides
catarrhal stage

11

1

(Cocoon strategy)12
.. 2552

16,858 12 13
..2549 60
( 83.3 )
..2553 0.01
5
6
--
- -
(DTP) purified diphtheria toxoid,
purified tetanus toxoid Inactivated B. pertussis

1
1 DTP Tdap
Acelluvax
Tripacel/Actacel/
Pediacel
Tetraxim/
Pentaxim/
Hexavac
Adacel/Adacel polio
Infanrix/
Infanrix-IPV-Hib/
Infanrix-Hexa
Boostrix/ Boostrix polio
FHA
PT
Pn
Fim 2&3
Biocine 2.5 g 5 g 2.5 g SP
5 g 10 g 3 g 5 g
SP
26 g
25 g
SP
GSK
5 g
25 g
2.5 g 3 g
25 g 8 g
GSK
8 g
8 g
5 g
-
2.5 g -
DTaP
DTaP / DTaP +Hib/
DTaP +IPV+Hib
DTaP+IPV/
DTaP+IPV+Hib/
DTaP+IPV+Hib+HB
Tdap/Tdap-IPV
DTaP/
DTaP+IPV+Hib/
DTaP+IPV+Hib+HB
Tdap/Tdap-IPV
168
1. Tetanus toxoid (TT)
2. Diphtheria-tetanus toxoid (DT)
DT Td
3. Diphtheria-tetanus-pertussis vaccine
(DTP) whole cell pertussis
vaccine (DTwP)
acellular pertussis vaccine (DTaP)

Pertussis toxin (PT), Filamentous
hemagglutinin (FHA), Pertactin (Pn) Fimbria
(Fm) DTaP
HBV, Hib IPV
4. Diphtheria-tetanus-pertussis vaccine
(Tdap)

2-8 .

18

DTwP, DTaP Tdap

0.5 .
DTaP
1
(primary series)

DTaP
DTaP
14-16
17-21
1. 7 DTwP
DTaP DTaP
DTwP
DTwP 2, 4, 6 18
4 DTwP, DTaP Tdap
11-12

2
5 --
4 5
6 7
2. 7
Td Tdap 7-10
Td 3 0, 1, 6
Tdap Td 1
Tdap
11-18 (11-12 )
Tdap Td
Td Tdap

Td 22,23
Arthus hypersensitivity reaction tetanus diphtheria containing
vaccine 10
( 18 )
Td 10
Tdap Td 1 ( Tdap)
1

15 -- 169
Td 3 0, 1, 6
Tdap Td 1
3. Tdap
Tdap

Tdap 2 3
( 36 )
10

sterile abscess
adjuvant
Arthus hypersensitivity reaction
Guillain-Barr Syndrome (GBS) Brachial

neuritis tetanus toxoid
DTP GBS
tetanus-containing vaccine
10

anaphylaxis 2
DTwP
DTaP
40.5o. 48
3 48
Hypotonic-hyporesponsive episode (HHE)

shock-like state 48
72
Guillain-Barr Syndrome (GBS)

6 tetanus-containing vaccine
Tdap
Td
Tdap
32,33

2
95
100
50-90
10
5-7

DTwP DTaP24,25

acellular
Tdap Tdap-IPV
DTaP 4-6
seroprotective antibody level 3 26-30

5
10 pertussis
toxin, fimbriae, filamentous hemagglutinin 10
pertactin31
1.
(progressive neurological disorder)
--
DTP (encephalopathy) 7

170
- ()
2. - anaphylaxis
purified diphtheria
toxoid, purified tetanus toxoid Inactivated
B. pertussis
1. . Corynbacterium. :
. 1.:
. ..; 2549. . 307-16.
2. American Academy of Pediatrics. Diphtheria.
In: Pickering LK, Baker CJ, Long SS, Kimberlin DW, editors.
Red Book: 2009 Report of the Committee on Infectious
Diseases. 28th ed. Elk Grove Village, IL: American Academy
of Pediatrics; 2009. p.280-3.
3. Overturf GD. Corynbacterium diphtheria.
In: Long SS, Pickering LK, Prober CG, editors.
Principles and Practices of Pediatric Infectious
Diseases. 3rd ed. China: Churchill livingstone Elsevier;
2008. p.754-9.
4. .
2545.
.
2545;38:602-6.
5. Tharmaphornpilas P, Yoocharoan P,
Prempree P, Youngpairoj S, Sriprasert P, Vitek
CR. Diphtheria in Thailand in the 1990s. J Infect Dis.
2001;184:1035-40.
6.
. .. 2553.
: ; 2553.
7. . Clostridium. :
. 1.:
. ..; 2549. . 547-65.
8. American Academy of Pediatrics. Tetanus.
In: Pickering LK, Baker CJ, Long SS, Kimberlin DW,
editorss. Red Book: 2009 Report of the Committee
American Academy of Pediatrics; 2009. p. 555-60.
9. . Bordetella. :
. 1.:
. ..; 2549. . 477-87.
10. American Academy of Pediatrics. Pertussis.
In: Pickering LK, Baker CJ, Long SS, Kimberlin DW,
editors. Red Book: 2009 Report of the Committee on
11. .
.
: , ,
, ,
, . Travel and adult immunization.
: ;
2552. . 59-69.
12. Yeh SH, Mink CM. Shift in the epidemiology
of pertussis infection: an indication for pertussis
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diseases. MMWR Morb Mortal Wkly Rep. 2010;59:
1025,1027-39.
14. Greenberg DP, Feldman S. Vaccine
interchangeability. Clin Pediatr (Phila). 2003;42:93-9.
15. Halperin SA, Tapiero B, Law B, Diaz-Mitoma
F, Duval B, Langley JM, et al. Interchangeability of
two diphtheria and tetanus toxoids, acellular pertussis,
inactivated polioviruses, Haemophilus influenzae type
15 -- 171
B conjugate vaccines as a fourth dose in 15-20-monthold toddlers. Vaccine. 2006;24:4017-23.

16. Greenberg DP, Pickering LK, Senders
SD, Bissey JD, Howard RA, Blatter MM, et al.
Interchangeability of two diphtheria-tetanus-acellular
pertussis in infancy. Pediatrics. 2002;109:666-72.
17. - . : ,
,
, ,
.
2550. :
; 2550..84-92.
18. Prevention of pertussis among adolescents:
recommendations for use of tetanus toxoid, reduced
diphtheria toxoid, and acellular pertussis (Tdap)
vaccine. Pediatrics. 2006;117:965-78.
19. Broder KR, Cortese MM, Iskander JK,
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tetanus, diphtheria, and pertussis among adolescents:
acellular pertussis vaccines: recommendations of
(ACIP). MMWR Recomm Rep. 2006; 55:1-34.
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MP, Ortega-Sanchez I, Lee GM, et al. Preventing tetanus,
diphtheria, and pertussis among adults: use of tetanus
toxoid, reduced diphtheria toxoid and acellular pertussis
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on Immunization Practices (ACIP) and recommendations of ACIP supported by Healthcare infection control
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among health-care personnel. MMWR Recomm Rep.
2006;55:1-34.
(CDC).Updated recommendations for use of tetanus
toxoid, reduced diphtheria toxoid and acellular pertussis

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Wkly Rep. 2011;60:13-5.
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immunizing with tetanus-diphtheria-acellular pertussis
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vaccination campaign of healthcare personnel during a
respiratory illness outbreak. Vaccine. 2010;28:8001-7.
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vaccine safety and efficacy in children, adolescents
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Borkird T, Kosalaraksa P, Bock HL, et al. Reactogenicity
and immunogenicity of reduced antigen content
diphtheria-tetanus-acellular pertussis vaccine (dTpa)
administered as a booster to 4-6 year-old children
primed with four doses of whole-cell pertussis vaccine.
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and 1-year follow-up of 4-8-year-old children with a
reduced-antigen-content dTpa-IPV vaccine. Eur J
172
Pediatr. 2007;166:1229-36.
containing reduced quantities of pertussis antigens as
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formulation tetanus and diphtheria toxoids
adsorbed combined with acellular pertussis vaccine has
comparable immunogenicity but less reactogenicity in
children 4-6 years of age than a pediatric formulation
acellular pertussis vaccine and diphtheria and
tetanus toxoids adsorbed combined with inactivated
poliomyelitis vaccine. Vaccine. 2007;25:1121-5.
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formulation. Hum Vaccin. 2008;4:203-9.
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Ferguson AC, Skowronski DM. A modified vaccine
reduces the rate of large injection site reactions to the
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pertussis vaccine: results of a randomized, controlled
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31. Bailleux F, Coudeville L, Kolenc-Saban A,
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an adolescent and adult formulation combined tetanus,
diphtheria, and 5-component acellular pertussis vaccine,
based on mathematical modeling and 5-year observed
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Burgess MA, Ramalho AC. A randomized trial of
two acellular pertussis vaccines (dTpa and pa) and
a licensed diphtheria-tetanus vaccine (Td) in adults.
Vaccine. 2000;19:628-36.
33. Tran Minh NN, He Q, Ramalho A, Kaufhold
A, Viljanen MK, Arvilommi H, et al. Acellular vaccines
173
16
2 Enders
(mumps) (complement-fixing antibodies)

3
mumps
mump
to mump

mumps

epidemic parotitis

(mumps

virus) family Paramyxoviridae genus
Rubulavirus ( mumps virus, New Castle
disease virus, human parainfluenza virus types 2, 4a,
and 4b) enveloped negative single
stranded RNA
90-300 200
Hippocrates nucelocapsid envelope 3 4

glycoprotein hemagglu 1700 Hamilton tinin, neuraminidase cell fusion activity
.. 1934 host cell
Johnson Goodpasture cytoplasmic membrane
1 nonglycosylated membrane
protein
.. 1945 Habel genome nucleocapsid
174
continuous linear molecule of singlestranded RNA genome repeating protein
subunits 8
hemagglutinin-neuraminidase protein (HN), fusion
protein (F), nucleocapsid protein (NP), phosphoprotein
(P), matrix protein (M), hydrophobic protein (SH)
L proteins5 F HN
1
13 (A to M)
SH protein
6-8
ether lipid
envelope 4o.
-65 o.
embryonated hens eggs9
monkey kidney, human embryonic kidney

HeLa cell cultures (cytopathic effects)
intracytoplasmic
eosinophilic inclusions, rounding of cells giant
multinucleate syncytial cell10

.. 1967 2-5 11
-
12

13,14 .. 1967
99
.. 2001-2005
265 15
6 16 17
18
.. 2006 6,584 18-24
29
8317
genotype G16 13
2 63
18,19
(waning immunity)

Jeryl Lynn strain (A)
G

.. 2008 376
.. 2010
New York New Jersey20
.. 2009 - .. 2010 1,521
11

17-18 61 76

1 88 2
75

.. 2514
.. 2540
(MMR)

21 .. 2552
16 175
20,383 32.1
10
(.. 2543-2552)
.. 2543-2546 (14.74-17.59
) .. 2551 (21.93
) .. 2552
10 .. 2548-2552
.. 2551

.. 2552 5

15
5-9 5
10-14 22
G .. 2550-2551 J
1

50 5-9
90 14 80-90
20

.. 2001 49
15

23

1-2
5
7
9

16-18 ( 12-25 )24
Stensens duct 1

viremia

25,26
diffuse
interstitial edema serofibrinous exudates
mononuclear leukocytes
neutrophil necrotic debris

multinucleate syncytia
intracytoplasmic eosinophilic inclusions

interstitial hemor
rhage polymorphonuclear leukocytes

(direct contact) perivenous demyeliniza(droplet nuclei) fomites tion perivascular mononuclear cuffing
176
microglial cells 27

neuronolysis demyelinization28 29 10
30 ( 1)
submandibular sublingual
sublingual
6 pre 24 sternal pitting edema
submandibular
lymphatic drainage31

2-3 32-36
1 4 1-10
Stensens duct
Trismus 40-50

4
1 1 2
(Glandular)
submandibular sublingual
Epididymo-orchitis
Oophoritis
Transient high-frequency deafness
( 30)
()
60-70
10
25 ()
5 ()
50
1-10
0.1
4
5-15
60
16 177

3

10-2,000 /..
lymphocyte 20-25 neutrophil

70 ./.
6-30
5
3-10

37,38 1 6,000 1 400

2
early onset
7-10

late onset postinfectious demyelinating process

1-2

1.4

Transient high-frequency-range deafness 4.4 39
1
20,000 40 cerebellar ataxia41, facial palsy42,
transverse myelitis43, ascending polyradiculitis44
poliomyelitis-like syndrome45 aqueductal stenosis hydrocephalus
46-48
Epididymo-orchitis49,50 20-30
1 6
75

85 epididymitis
3-4
84 5 20
2 50

51 5

52,53
migratory polyarthritis
10-14
5

30

endocardial
fibroelastosis (EFE)

RNA 70
EFE
EFE
EFE 54, 55
juvenile diabetes mellitus
178

Reverse transcriptase
juvenile diabetes mellitus 56, 57 (RT)PCR assays

24,30
3
6
2-3 2 72
5
2
RNA
PCR

amylase 24,30

2-3 Parainfluenza
amylase lipase
type1 3, coxsackieviruses
cytomegalovirus, enterovirus, lymphocytic
choriomeningitis virus, human immunodeficiency
virus, Staphylococcus aureus, nontuberculous myco bacterium, Burkhoderia pseudomallei,

(serologic studies) phenylbutazone, thiouracil, iodides
IgM phenothiazines
enzyme-linked immunosorbent assay (ELISA) uremia
4 acute
convalescent serum complement fixation,
hemagglutination inhibition (HAI), ELISA neutrali- Mikuliczs syndrome,
zation testing Parinauds syndrome, uveoparotid fever of sarcoidosis
parainfluenza 3 HAI Sjogrens syndrome
parainfluenza
heterologous antibody
parainfluenza 3 HAI
16 179
58

(CDC), American Academy of
Pediatrics (AAP) Healthcare Infection Control
Practices Advisory Committee (HICPAC)
5

5

standard droplet precautions

12
26

2
9-12 4-6

2
1

1
.. 1945 Habel
2
(killed virus
vaccine) .. 1948 ..
1950
.. 1966 Buynak Hilleman

(lived attenuated
vaccine) 59,60
Jeryl Lynn

.. 1967

cell culture chick
embryo
Urabe, NK-M46, S-12, Rubini, LeningradZagreb, Leningrad-3
5 Jeryl Lynn, Urabe,
Rubini, Leningrad-Zagreb Leningrad-3
Rubini

Jeryl Lynn

.. 2553 MMR
Masu
Leningrad-Zagreb

180

61,62

--
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.
MMR .. 2552. : ; 2552.

22.
. .. 2552.
: ; 2552.
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182
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at PIDST conference May 2010.
62. ,
.
16 183
MMR
2553.
41, 2553.
76
185
17
1.2-4.8/1000 / > 60
7.2-11.8/1,000 /8,12,13
Herpes zoster
Herpes zoster .. 2552 20,804
32.78
2000
reactivation
Varicella-zoster (VZV) 65
55-64, 45-54 35-44 14
cell-mediated

immunity (CMI) VZV 1-3 15
VZV dorsal 16
root ganglia
17

(dermatome)
18 19-24
25-31 32-34
35 autoimmune
26-30,36-38
VZV dorsal root ganglia

VZV - herpesvi-
ruses family herpesviridae
double-stranded DNA envelope
glycoprotein spikes
4-6 150-200
VZV

5,7-11
186

VZV
(sensory
dorsal root ganglia)
reactivation VZV

mononuclear dorsal root ganglion
ganglion
demyelination axon

(dermatomal
distribution)
48-72 (macule)
(papule) (vesicle)
3-5 10-15

(thoracic lumbar
dermatome)

VZV VZV

postherpetic neuralgia
50

(postherpetic neuralgia;
PHN) 39,40 PHN

13,40,41
PHN 27
50 <50
PHN 18
PHN
79 35

Tzanck smear
multinucleated
giant cells

immunofluorescent polymerase chain
reaction
50

ophthalmic
nucleoside analogs acyclovir,
valacyclovir famciclovir42
72

PHN
meta-analyses
PHN
42,43-47
17 187

acyclovir
7-10

acyclovir, famciclovir
valacyclovir 7-10
42
opioids, gabapentin
tricyclic antidepressant42,48-54 postherpetic
neuralgia

55,56
CMI VZV 1-3

VZV 1-3,57

CMI
VZV

(lyophilized)
VZV Oka
19,400 PFU
14

ZostavaxTM
-15o
30
0.65 .
1
60
58

.. 1999-200459
> 60 38,500 46
> 70 6.5 > 80

315 642

Burden of illness (BOI) 61.1
(95% confidence interval = 51-69; p< .001)
PHN 66.5 (27 80 )
(95%confidence interval = 48-79.2; p< .001)
51.3
(5.42 /1000 /11.12 /1,000 /;p<.001)
4 59

63
60-69 37.6 70-79
188

4.
59 3-4
50-59 60 5
60 62,63
.. 2005
60

60

14

1

VZV

61

60

72

58,64,65
65

66
1.
PHN

50-59
2. Herpes 20
acyclovir, famciclovir valacyclovir 50-59 11
PHN 50-59

24 70 50-59
14 58
5
3.
17 189

VZV-CMI

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2552. :
; 2553. .
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17 193
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76
195

400
1

4-5 2.5

.. 1981 (plasma derived)
recombinant (.. 1986)

18

HBsAg
10 . 20 .

0.5 . ( 18 )
1 . 3 0, 1 6

HBsAg 2
1. Plasma derived vaccine2,3
HBsAg 10

2. Recombinant vaccine

196

1 (
)
2
9-12 --

20

2
(occult infection)
9-11
2
2 1 .. 2531 12 .. 2533
3 5 .. 2535
2 1 ( 24
2 6 )
90

0.7 .. 2551
()

4
(systemic adverse events)
24 1
( HBIG)
24
2, 4
6 ( 5 )

2, 4 6 4
94 97
hepatitis B immune globulin (HBIG) 6-8
HBIG 5
18 197
(Post exposure prophylaxis)

HBeAg

HBIG HBIG
24
HBIG
HBIG

12
6-8

2 3 2 6

72
plasma derived
yeast derived6,12
1.
2.
3.

4. HBIG

HBIG
HBIG HBIG
HBIG

HBeAg
HBIG
HBIG
13,14

24

1. HBeAg
2. DNA polymerase activity

5 .
3. HBV-DNA
antiHBs HBsAg
HBIG 0.06 ./. 3-5 .
(200 /.)
24-48
198
HBsAg +ve
HBIG + HBV
Responder

Nonresponder HBIG + HBV

HBIG 2
HBsAg-ve
HBV
HBsAg
HBV
HBsAg +ve
anti-HBs
anti-HBs
(Response unknown)
1. >10 mIU/.
1. <10 mIU/.
HBV
2. >10 mIU/.
2. <10mIU/.
HBIG + HBV
HBIG 0.06 ./. IM ( Hepatitis B vaccine : Mahoney FS, Kane M.
Vaccine, 13th edition, plotkin 1999).

0, 1, 6 0, 1, 2, 12

24

HBIG
(
)

HBIG

HBIG

HBIG
HBIG

12
1

HBIG
72
24 0.06 ./. 5
.
HBIG

HBIG 15,16
18 199
HBIG
HBIG gamma globulin

HBIG
HBIG cold ethanol
fractionation anti-HBs
anti-HIV
gamma globulin
passive anti-HIV
HBIG

HBIG
(Pre-exposure prophylaxis)

(intradermal injection)17

(subcutaneous)

aluminium
hydroxide

-
(anterolateral of thigh)
- 1-5

-

18
(Nonresponder)19
nonresponder

1-3

200
1
- HBV marker
-

HBIG
Genetic prediction 20

major
histocompatibility complex (MHC) HLA
HLA B8, SC01, DR3

HBeAg

1.
HBV-DNA

HBV-DNA

HBV-DNA

HBV-DNA mononuclear cells
HBV-DNA
mononuclear cells

HBV-DNA mononuclear cellas
HBV-DNA mononuclear cells
intrauterine infection
2. Escape mutant

S

21

(1,800 - 2,200 )

seroconversion
6-12

HBIG

22,23

18 201

1. lamivudine (3TC)
HBVDNA
HBIG
HBV-DNA

( 90)

3TC
2. HBIG

24

aluminium hydroxide
adjuvant tetanus toxoid

2

25

( 50)

HBsAg 15
HBeAg
26
HBeAg

CD4
202

3-4
27

3 4

GSK
2
3-4

immunizing dose 1 6-12
5
2
1

3-4

.. 2000

37 .

18 203
(HBsAg) 0.7 10-18

()
3.5 18
2.527,28
29

80 .. 2528 10.4
100,000 4.5
100,000 .. 2538
4 215 100,000
90.4 14
100,000
5 1
.. 2541

.. 2533
85
15 0.5

vertical horzontal 2527
0.70
100,000 0.57 100,000
.. 2542 .. 2529 - 2532 0.36 100,000

.. 2533 - 2537

6 18 5
6-19
2229 0.52 100,000
3 .. 2517-2527 0.13 100,000
82.5 6 10 .. 2527-252930
204

(HCV)

170
5

1
3

1.
2.
(anti-HCV )
3. 2 antiHCV HCV-RNA RT-PCR
4 ( HCV
5-10 ) HCV-RNA RT-PCR
Interferon

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18 205
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207

0.1
0.1-0.4
1 40

1

1 5 - 5 0

19
2,3

4,5
2
1. (inactivated vaccine)
2. (lived vaccine)

,
H2
6,7

4

(virus suspension)
ELISA,
RIA unit
2 phenoxyethanol
208
2 0.5
18 1.0 .
18
ELISA, RIA
unit
1 immunizing dose (1-2
18 ) (0.5 .) 1 . (
18 )
virosome

8

( 0.5
)
4
(systemic adverse events)
24

1-13.9

1. 2-4 1
0.5 . ( 1-18 ) 0.5 . 1
6-12
() 2
6-12
20
2.
1 . ( 18 )
1.0 .
2 6-12

1
subclinical
8.6
9,10 subclinical 6.714
94-100 2-4
10011-13
19 209

Maternal passive antibody

1
6-12 17

1 (
)
1 15

18,19

2

30 2 6

3 0, 1 6
36,16
1
2 24

7
20

210

21

2-4

22

1.

2.
(thrombocytopenia)
3.
2-8o .

3
1. Pramoolsinsap C, Poovorawan Y, Hirsh P,

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76
213
20
19
Typhoid Mary ..1907
Mary Mallon New York
53 3
Mary
quarantine
Mary 26 Mary Pneumonia2

Chicago 65-174
100 1

10 -100 1

21
2 .. 20003

.. 1989 Chloramphenical, ampicillin,
trimethoprim
ciprofloxacin 4
430
Ethiopia Egypt Libya
Greece Greece
Pericles
Athens 30
Athens
Athens Thucydides
epidemic typhus
.. 2006 Manolis Papagrigorakis
Athens DNA
DNA sequence Salmonella
typhi
..1829 Pierre
Charles Alexandre Louise
138 50
85

.. 1808-1882 William Budd

..1885
Theobald Smith
Salmonella cholerasuis genus Salmonella
Salmonella 2,460
Daniel Elmer Salmon O-somatic
1
5 A E group D
214
Salmonella subspecies enterica serotype typhi

facultative anaerobe MacConkey agar
Non lactose fermentor
reservoir
endotoxin
Vi antigen (virulence)
invasin non phagocytic cell
oxidative burst
Salmonella

DNA
plasmids bacteriophage bacteria
Salmonella
Salmonella typhi

animal model Salmonella
typhimurium Salmonella
typhi
Stephen J Libby5
Proceeding of the National Academy of Sciences
Humanized Mouse Model Stem cell
()
Salmonella typhi
Stem cell
virulence factor Professor David
Holden6,7 Imperial College London
tract bacterial membrane transport
channel host cell virulence
factor host cell defense mechanism
host cell Salmonella
host cell

Salmonella
8

.. 2552 6,486
10.26
3,624 ( 55.87)
14
ampicillin, tetracycline, nalidixic acid, trimethoprim-sulfamethoxazole, cefotaxime, ciprofloxacin
chloramphenicol 4
5 15-20
12.28 5-9
12-15

(600-800 )

22.80, 14.36,
9.40 2.32

.. 2521 20-40 10
Salmonella typhi
(
) 1000-1 9

helicobacter pylori10

duodenum
(Peyers Patch)
20 215

reticulo endothelial system11

reticulo endothelial system
T cell
3-60
2
5 45
12 5
5 12

10
-20 Rose spot 5 -1012-15
59 23
(259 ) 1 -75 3

()
/ (delirium)
90 10

10 ( 7
)

50 16
2
1015
70 17
18

( 3 - 35)
( 1-5) ( 1-86)
( 1)
( 1-26)19
Salmonella typhi

40-80
Widal test
O-somatic
..1896
Widal test
cut off point O 1 : 80 H 1 : 200
50

(normal curve distribution) 97.5 cut off point

Widal test
screening positive
predictive value negative predictive value

216
10 indirect name linked
immunosorbent assay
6520
serial
Widal test positive predictive value
negative predictive value Widal test

Widal test
Widal test
21
IgM commercial test
Typhidot 6790 54-100 22,23
Tubex 60 5822
Real Time PCR Specific DNA sequence
fli C gene
24

100
model

(reliability)

Salmonella typhi
200325
fluoroquinolone nalidixic acid
38 ampicillin
chloramphenicol trimethoprim sulfamethoxazole
MDR S.typhi (multidrug resistance)

13
chloramphenicol .. 1948
.. 1960
plasmids
amoxicillin 20-50 ././
3-4 14
trimethoprim - sulfamethoxazole 15-20
././ 3-4 14
ciprofloxacin 20-30 ././
2 14 5-7
uncomplicated typhoid fever
azithromycin 10 ./.
5 ./. 2 -5 7
8-10 ./. uncomplicated typhoid fever
ceftriaxone 50 -75 ./. /
12 7

3-5
10
6
dexamethasone

dexamethasone

26
18

Salmonella typhi

20 217
.. 1897 Almroth Edward Wright

.. 1909 Frederick F Russel

Whole cell vaccine field trial

.. 1960
58-81

25-50 12 27
Field trial Ty21a live attenuated
6

96 3 28 67-96 5 42 -53
2.5 29
634 2-6
seroconversion 69
14 seroconversion

6930 metaanalysis 5
2.5 - 3 4831
5
UDPgalactose 4-epimerase

buffer

(enteric coated)
( 37 .)
Vi capsular polysaccharide
2 0.5 . (25 )
3 2-8 .
72 17
Nepal32 64 21 South Africa33
meta-
analysis32 4
3 55
428
Typhim Vi
1-10 48

(
)

2
1. Vi-CRM 197 Violence Capsular
Polysaccharide S.typhi recombinant mutant
Pseudomonas aeruginosa exoprotein A
Vi-rEPA Novartis 2 2-5
1 2
94 87
218
3.8 89 Typhim
Vi Oral typhoid Ty21a Vaccine31
2. Live oral single dose Salmonella enterica
serovar typhi (Ty 2 aro C (-) ssaV (20)) ZH9
5 x109 cfu 5-14 101
50
lipopolysaccharide specific serum Ig G
( 70 1.7 ) /
specific serum IgA ( 50
1.5 ) 97
8 IgG 100
0
18
26 14 2234
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221
(Streptococcus pneumoniae)

1,2

lancet pneumolysin
alpha
partial hemolysis
ethyl hydrocupreine (optochin)
bile salts catalase

90 3
penicillin

4
(asymptomatic
carriers)
35
2-95
21

(cochlear implants)

1

population-based surveillance 5
.. 2548
.. 2550 7,319

10.6-28.9 100,000
5 (
)

7.5-14.0 100,000
5 6

.. 2523-2533
2 (22.2%) Hemophilus
influenzae type b (42.3%)7
222
.. 2530-2540
(42.5%)8
90
penicillin
4, 6B, 9V, 14, 18C,

19F 23F
6A, 6B, 9V,
14, 19A 19F 23F penicillin
19A
7-valent 9

sterile
site 5 1 ..
2543 31 .. 2548
6B
27.8 23F 20.0
14 10.4 19F 9.610

6B
11

penicillin (MIC > 0.1 ./ .) 6.7
.. 2521 10.6 .. 2530
.. 2535-2537
37.2
23F 9V
12
.. 2535-2542
10.5-69.2
10.5-51.3 0-28.013
ANSORP 11
.. 2543-2544
penicillin
26.9 26.9
14

- .. 2551 sterile
non-sterile site
170 170 3
94
60 (29.4%)
2-5 (20.0%) 2 (12.4%)
disk
diffusion chloramphenicol, linezolid, oflaxacin vancomycin
71.8, 100, 100 100
erythromycin, penicillin, tetracycline trimethoprim/
sulfamethoxazole 35.5, 31.1, 28.8
24.1 minimal inhibitory concentration (MIC) broth microdilution
sterile site penicillin
92.0 cefotaxime 90.0
non-sterile site penicillin
cefotaxime 26.9 76.9 15

penicillin cefotaxime
pbp2b
16

170
.. 2551 ofloxacin
93.5 gyrA
21 223
parC fluoroquinolone
4 gyrA
Ser81Phe Glu85Gly
parC Ser79Tyr
3
4 6B 2
nonvaccine type 2 17
9

18-20

3
1.
(invasive pneumococcal disease, IPD)
(bacteremia)
(meningitis)
(endocarditis)
(pericarditis) (peritonitis)
(osteomyelitis, arthritis)
2. (lower
respiratory tract infection) (pneumonia)

3. (upper respiratory tract infection) (sinusitis)
(otitis media)

.. 2529-2540 61
24 19
10
8 6
10.221

.. 2514-2543
138 137
51 38
35 13
/ 2 66

.. 2531
.. 2539-2543 7122

penicillin23
13
224

9,24

polymerase chain reaction (PCR)

penicillin oxacillin disk 1 .
zone of inhibition 20 .
penicillin MIC
zone of inhibition 20 . MIC
penicillin sterile
sites sterile sites
MIC penicillin cefotaxime
ceftriaxone 1

vancomycin meropenem
(nonsusceptible) penicillin
rifampin
MIC
broth
microdilution antimicrobial gradient strips
1 MIC
./.
Penicillin (oral)
0.06
Penicillin (intravenous)
- Nonmeningeal
2.0
- Meningeal
0.06
Cefotaxime or ceftriaxone
- Nonmeningeal
1.0
- Meningeal
0.5
( 9)
0.12-1.0
(./.)
2.0
4.0
None
8.0
0.12
2.0
1.0
4.0
2.0
21 225
amoxicillin
30-40 ././ 2-3 5-7

(craniofacial abnormalities)

10
ceftriaxone
50 ././ 1
Drug
resistant Streptococcus pneumoniae (DRSP)
2 3

amoxicillin 80-90 ././
type I hypersensitivity cefdinir, cefpodoxime
cefuroxime type I hypersensitivity azithromycin clarithromycin
penicillin-resistant
S.pneumoniae clindamycin

3

DRSP
amoxicillin/
clavulanate ( amoxicillin 80-90 ./
./ DRSP)
cephalosporins cefdinir, cefuroxime,
cefpodoxime ceftriaxone
50 ./. 3 25

26

amoxicillin, amoxicillin-clavulanate
macrolides
ampicillin
DRSP
cefotaxime
ceftriaxone 27

13

DRSP
27
cefotaxime ceftriaxone
vancomycin
9
penicillin, cefotaxime ceftriaxone
cefotaxime
ceftriaxone
vancomycin

27

DRSP
penicillin, cefotaxime ceftriaxone
vancomycin
29

vancomycin rifampin
226
penicillin
vancomycin cefotaxime ceftriaxone

penicillin vancomycin + cephalosporin
vancomycin cefotaxime ceftriaxone
penicillin cefotaxime
ceftriaxone
penicillin, cefotaxime ceftriaxone vancomycin cefotaxime ceftriaxone
rifampin
rifampin vancomycin
24-48
( 9)
meropenem chloramphenicol chloramphenicol MIC

4 ./. 9
dexamethasone
6
dexamethasone
9
48
1.
penicillin oxacillin disk
MIC
cefotaxime ceftriaxone 2.
3. dexamethasone

9
1.
(23-valent pneumococcal polysaccharide vaccine, PS-23) polyvalent polysaccharide
23
1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14,
15B, 17F, 18C, 19A, 19F, 20, 22F, 23F 33F
25 .
Pneumo 23
28
2.
(Pneumococcal conjugate vaccine, PCV)19
3
2.1 PCV7
7 4, 9V, 14, 18C, 19F, 23F 2

. 6B 4 .
CRM 197 (a nontoxic mutant of
diphtheria toxin) 20 . aluminum phosphate 0.125 . adjuvant
thimerosal
Prevnar
2.2 PCV10 (PHiD-CV)
21 227
10 1, 5, 6B, 7F, 9V,

14, 23F 1 . 4 3 .
non-typeable Haemophilus
influenzae 18C 19F
3 . tetanus diphtheria
toxoid
Synflorix
2.3 PCV13
PCV7
13 6 PCV7
1, 3, 5, 6A, 7F 19A
1, 3, 4, 5, 6A, 7F, 9V, 14,
18C, 19A, 19F 23F 2.2 .
6B 4.4 . aluminum phosphate adjuvant
Prevnar 13
T-cell
independent antigens mature
B-lymphocytes T-lymphocytes
T-lymphocyte B cells

IgM affinity
maturation memory B cells (anamnestic
or booster response)
2 immunological memory

5-10 29
boosting effect

T-cell independent
T-cell dependent
2
B cell memory booster response
30
PCV10 PCV13
PCV7

PCV7
31,32
IgG
enzyme-linked immunosorbent assay (ELISA) 0.35 ./.

1
3
3
PCV7
1.
IgG
0.35 ./.

PCV7 10
PCV10 (PHiD-CV; GSKs ELISA with
22F-inhibition assay)
PCV7 (non 22F-inhibition assay)
PCV10 cut-off level
IgG
0.2 ./.
0.35 ./.
2. geometric mean
concentration (GMCs)
3. functional antibodies (Opsonophagocytic activity) PCV
opsonophagocytosis
228

opsonophagocytosis activity assay (OPA)

opsonic titer
1:8 cut-off level

50

PCV opsonic
titer 1:8 PCV7
4.

immunologic memory
PCV

3-5 2

0.5 ./
34:
-

(cochlear implants)
- PCV13 PCV7
PCV10 PCV7
PCV10 PCV7 2
3 PCV10 PCV7
- PCV7 4
2-8 o .
PCV13 1 PCV7
8
9,33
- PCV
PS-23 0.5 ./
2 2- 18
PS-23
3
()
2-6
7-11
12-23
24-59 ()
24-71 ()
PCV 3 6-8
PCV 2 6-8
PCV 2 6-8
PCV7 PCV13 1
PCV7 PCV13 2
8
PCV 1 12-15
PCV 1 12-15
PS-23 1
PCV 8
( 33,34)
21 229
PCV7
97
89.1
3537,38,45
57
34
6-7 9-23
tympanostomy tube 2037,45
PS23
PCV7

5 9846

2 78 93.4 47,48

85-9039 penicillin 2
68-85 81 49
PCV7
40,41

56-8142 2
42 65
2 3950
boosting effect
2
4251 PCV7 7
43
44
PCV
PS23 1 5 PCV
PS-23
PS-23 PS-23
PCV
- 2+1
2, 4 12-15
35,36

--

--

37,38
230
5 65
100 92 52
(indirect or herd effect)

5
PCV7
74
( 52)
53
PCV7

19A
54,55 19A
5
PCV7 .. 2003
56
PCV13 19A
PCV10
PCV7 head-to-head comparative trial

PCV7 6B 23F
ELISA PCV10 2, 3 4
cut-off level
(0.2 ./.) 6B 23 F 65.9
81.4 PCV7 3
79 94.1
1, 5
7F
97.3, 99.0 99.5 32

PCV10
0.2 ./. PCV7
7 1, 5
7F 99.6
PCV10

6B 23F
PCV10 PCV7

18C 19F
PCV10
PCV757
PCV10
opsonic titer 1:8 7
PCV7 87.7-100
PCV7 92.1-100
1, 5 7F opsonic titer
65.7, 90.9 99.6
91.0, 96.3
100 32
PCV10
Pneumococcal Otitis Media Efficacy Trial (POET)

11

51.5

33.6
Haemophilus influenzae
35.6 PCV10
21 231
POET58
PCV13

cut-off level, opsonic
titer immunologic memory PCV7
59
PCV7, PCV10
PCV13
5 70.3, 70.3
81.2 60
1.
2.

3.
4.
1. 24
2.
PS-23
PS-23
1.
9,61
2.
PS23
3.

2
1. PCV PS-23
(elective splenectomy)
cochlear implant 2
2. PCV
1-2

diphtheria CRM 197
3.
PCV PS-23

optional vaccine
PS-23 2

4.
232

penicillin
penicillin V 125 .
2 5
250 . 2 5
62
.. 2549
optional vaccine
5 5

cost benefit
(
) (herd immunity)

63

adjuvants
intranasal

immunogens
1. whole-cell pneumococcal bacteria
2. DNA vaccines
3. Protein-based vaccines pneumococcal surface protein A (PspA), pneumococcal surface protein C (PspC), pneumococcal surface adhesion
A (PsaA), pneumolysin (Ply), neuraminidase enzymes
(NanA and NanB)
PspA

PspA
PspA
capsular polysaccharide
pneumococcal protein
1. Prommalikit O, Pengsaa K, Thisyakorn

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4. .
(Conjugated pneumococcal
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, , ,
. .
: ; 2548. . 65969.
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. : ,
, , ,
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19. .
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, ,
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, , . Critical
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, .
. . 2544;40:238-43.
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. :
, , ,
, , .
. :
; 2548. .157-67.
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.. 2554. Update on
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76
239
22
(OPV) (Inactivated
Poliovirus (IPV) vaccine)

World Health Assembly
..
25431

Acute Flaccid Paralysis ( AFP surveillance)
Poliovirus
(Oral Poliovirus (OPV) vac- human enterovirus, family Picornaviridae
cine) single - stranded, positive sense RNA genome
( .. 2554) protein capsid 3 1, 2 3
fecal to oral
transmission oral to oral transmission
pre eradication era 4

OPV (Wild
poliovirus
type poliovirus, WPV) 2

fecal - oral
( 1)5

.. 2552 -
imported case 2554 20 4
endemic countries Afghanistan, India,
Nigeria Pakistan
WPV 1 3
2013 (.. 2556)3
2 Imported cases
240
1
( 5)
.. 2552
2553 1
2552 2553 Russis,

Nepal, Kazakhstan, Tajikistan, Turkmenistan
Senegal endemic
Pakistan

.. 2553
nonendemic

10
.. - .. 2553
AFP 409
Enterovirus 109
imported cases
15
- 72 7 169 409
AFP ( 41.3 )

( 2554)
3 8
1. Endemic countries
Afghanistan, India, Nigeria Pakistan
2. Countries with re-established transmission
imported cases
12 Angola,
Chad, Democratic Republic of the Congo Sudan
3. Countries with imported poliovirus
imported cases
Kazakhstan, Liberia, Mali, Mauritania, Nepal, Niger,
Russian Federation, Senegal, Sierra Leone, Tajikistan,
1 (WPV)6
2552
(23 )
1,604
Endemic countries
1,256
Nonendemic countries
348
( 6)
2553
(20 )
1,294
232
1,062
22 241
Turkmenistan, Uganda OPV
WPV
.. 2540
WPV (Afghanistan, India, Pakistan)
(AFP surveillance)
OPV
.. 25469
AFP 18
( Vaccine Derived Poliovirus, VDPV)

OPV

(Hypogammaglobulinemia)
..
2522 1 (WPV 1)
imported cases
vaccine associated paralytic poliomyelitis (VAPP)
IPV .. 2540
(IPV-OPV) IPV
.. 254310
myocardium
11,12

95

3-6
2-3 (abortive
poliomyelitis) 1-5
aseptic meningitis
2-10
(asymmetric
flaccid paralysis with areflexia)
0.1 - 2
7 - 21

80 10
2-10 10

aseptic meningitis
11

mucosa lymphatic tissue 1-2

paralytic poliomyelitis
motor neurons paralytic disease 100 : 1 1,000 : 110
anterior horn cell
intermediate gray ganglia posterior
horn dorsal root ganglia
(cell culture)
reticular formation, vestibular ()
nuclei, cerebellar vermis deep cerebellar nuclei
242

( 14 )
2 24
Inactivated Poliovirus Vaccine (IPV)
OPV

OPV
standard precaution
contact precaution
Outbreak 13
mass immunization OPV
OPV .. 2493
MRC 5
IPV
vero cell serial passage
neurotropic character Sabin

WHO ..
2
2504 .. 2512 WHO
1. (OPV, Sabin)
OPV VAPP
2. (IPV, Salk)
IPV OPV

Oral Poliovirus Vaccine (OPV)
(1st generation IPV) Salk

3
.. 2493 - 2495
monkey kidney cells
.. 2498 paralytic cases (Cut ter incidence)

( inactivation)
Sabins oral poliovaccine
2 (2nd generation
enhanced potency IPV)
22 243
well characterized cell line

vero cells
microcarriers biogenerators
Mahoney strain
type 1, Mef 1 strain type 2 Saukett strain
type 3 ultrafiltration gel filtration
inactivate (1:4,000)

(DTP )
(HBV) Haemophilus influenza type b (Hib)
OPV 3
(1, 2 3) > 106, 105 105.8
IU/
trivalent monovalent OPV (mOPV) bivalent OPV (bOPV)
mass immunization OPV
BCG, DTP, HBV,
Measles, Hib Rota
IPV 2 3
(1, 2 3) 40, 8 32 D unit
( 2)
OPV
2-8 .
1
IPV 2-8 .
2

OPV IPV
OPV

2 2, 4, 6, 18 4 - 6
3 6-8
4 6 -12 3 4
4 5 4 - 6
IPV 3
2, 4, 6-18 4-6

IPV
VAPP IPV 2 2, 4
OPV 6-18 4-6
(Sequential IPV - OPV)
VAPP 5010
IPV 4
2 IPV
Tetraxim
Pentaxim, Pediacel
ADACEL - Polio
Infanrix IPV/Hib
Infanrix Hexa
Boostrix - Polio
Sanofi Pasteur
Sanofi Pasteur
Sanofi Pasteur
GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline
DTaP, IPV
DTaP, IPV, Hib
Tdap, IPV
DTaP, IPV, Hib
DTaP, IPV, Hib, HBV
Tdap, IPV
244
2 2 2
3 6-18
OPV
4 4-6 ( 3 4
4)
( WPV)
4
1. VAPP
OPV WPV
VAPP
4 / 1/ OPV
OPV 2 3 22 Sabin 3 ( 60 )4
90 97 OPV VAPP
3 14 1 2.4
VAPP
15 1 750,000 12
73 70 VAPP
1 3 4,16 3,200-6,800 23
VAPP ..
2540-2543 1 3-15
4
2. VDPV Sabin virus
4
OPV
neurovirulence
IPV 2 seroconversion circulating VDPV (cVDPV)
95 replicate
2 ( neurovirulence
immunodeficiency-associated VDPV (iVDPV)
) 3
9917,18
IPV
OPV19,20
streptomycin, polymyxin B
neutralizing antibodies IPV 3 neomycin
18 21 IPV

OPV

22 245
IPV
OPV (
IPV OPV
VAPP OPV
severely immunosuppressed )24 OPV
25
IPV
low risk
12

primary series OPV IPV
1
3 4
preeradicating era

OPV
(WHO)
WPV 2
WPV 1 3 WHO

pre eradication era
2 ( 2)4
2
1. Imported cases

2.

12
OPV
Imported cases

OPV
IPV
Imported cases
( IPV)
IPV
Imported
IPV anaphylaxis cases ( India, Pakistan
streptomycin, neomycin Afghanistan)
polymyxin B
(
90 - 95) 3
IPV
OPV ()
7226 )
WHO
IPV
OPV OPV Sequential
246
2 WHO
( 4)
IPV - OPV

1. OPV3 90
) 2. AFP
AFP 2 /100,000
15 80
) 3.
mop up
90 )4
26
1.
Imported WPV 2. VAPP
VDPV 3. cost effectiveness analysis
IPV
IPV
IPV
post eradication era

dose sparing adjuvants

fractional dose
(1/5 full dose) IPV (intradermal) IPV
seroconversion ( > 95)
( 100)
27
adjuvants oil in water emulsions
(MF59 like emulsion)28, Chitosan29

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2550. :
, ,
,
, .
.:
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249
(zoonosis)
Lyssavirus

()

55,000

.. 2535
23

virus-laden
saliva
1
2.2-3

10
14

(intermittent salivary excretory)

62 .. 2524 46 ..
2538 18.8 .. 2547
250
1 12
1
2

0-14

4
500
3-6

( 1)
( 2 1 )
(vampire)
(superficial bite
scratch)
( 30
) .
Australian bat Lyssavirus 4

1

(non-bite exposure)

(
)

()

(contact route)

(cell-culture rabies vaccines)
(purified duck embryo vaccine)

20 60,000
300,000-400,000
( 0.5 100

10

(intradermal Thai
Red Cross regimen, TRC)
100,000

23 251
10-30
3-4 (
300 )
90
(

)

(bite prevention)

80
70
96.57
2.5

( 25)

(pre-exposure vaccination) ()

67-85
(), 10-23
3 ( 2)8
1-40 ( 20 10
)

WHO categories
( 1) 50-60

(
5-80) ( 0.1-1)
50
( 60) ( 12.7)
5

( 10) 70 8-10

252
povidone-iodine
(active immunization)
(rabies immune globulin;
RIG) (passive immunization)
RIG
2
( 1)
1.

3
categories11,12 1

RIG 1 WHO
category 1
10-20
3

WHO category 2 3
1
2. ( 1)

(
)
20
fluorescent antibody test (FA test)
1 (
)
(mouse
inoculation test)
7-28 nested
PCR latex
agglutination test

FA test
13
FA test
( preexposure vaccination)

FA test

(
) 10

14
1.
2.
2
3. (provoked condition)
3
10

3

10

3-12
23 253
- ()
() 3-7
- amoxicillin, amoxi/clav, 2ndor3RD cephalosporins
- (Td or TT)
rabies post-exposure treatment

WHO Categories
1
( pre-exposure)
2 3
(FA test)
post-exposure6
post-exposure
( pre-exposure)
post-exposure
post-exposure
post-exposure
3
1)
2) 2
3)
3
10
post-exposure
3
post-exposure6
10
( 0, 3
7 pre-exposure
vaccination)
254
1 (rabies immunoglobulin, RIG)

(WHO categories)
I
II
III
/ RIG

,

/

( )
a
b
10
c
b
10
c
(pre-exposure vaccination)
3 ( 2
) 10
c

3
(provoked condition)
(unprovoked condition)

10
(
3-4 2
primary immunization
pre-exposure )
10

( 10 )
10-14

(Post-exposure vaccination)

4 HDCV (human diploid cell vaccine
1 . ) PCECV (purified chick embryo cell
vaccine 1 . ) PVRV (purified Vero
cell vaccine 0.5 . ) PDEV (purified duck embryo vaccine 1 .
preservation)

(intradermal)
14
23 255
rabies neutralizing antibody (Nab)

titer 1/5 0.5 IU/.
10-14
21
12

4
11 (standard
intramuscular regimen: ESSEN)
2-1-1 (multisite intramuscular regimen; Zagreb)
(intradermal) Thai Red Cross
(original TRC regimen: 2-2-2-0-1-1 modified TRC
2-2-2-0-2-0)
(8-site intradermal, Oxford)
2 11,12,15
1. (standard
intramuscular regimen: ESSEN: 1-1-1-1-1)
1
(1 . 0.5 .
1 )
(deltoid) (anterolateral of thigh muscle)

RIG
1-1 0 () 3, 7, 14
28 30
28 ( 4
0, 3, 7 14: 1-1-1-1-0)
5
(immunocompetent host)
16

rabies Nab titer

10-14
rabies Nab titer 0.5 IU/.
14
rabies Nab titer 0.5 IU/
. 1 1-2
17
RIG 7

5
2-1-1 (multisite intramuscular regimen; Zagreb: 2-0-1-0-1)
(PDEV) 1 2
( 0)
(deltoid muscle) 2 1 1
7 21 28

(rabies Nab titer)

3

2-1-1 RIG
WHO category 2
PCECV PVRV (
rabies antigenicity 10 IU/) RIG
2-1-1
14 rabies Nab titers 0.5 IU/
. 0.5 IU/
. 1
256
2. (intradermal) Thai
Red Cross (original TRC regimen: 2-2-2-0-1-1
modified TRC 2-2-2-0-2-0)12
(intradermal)
0.1 .
2 ( 0) 3
7 1 28 30 90
2 28 30 (2-2-2-0-2)
RIG

2-8o . 6
- 8
4-10o. ( 7 ) rabies antigenicity

2.5 IU/
18
rabies antigenicity

pre-exposure prophylaxis 3-4 2
primary immunization
TRC ID
15 100,000
1

TRC ID 0.1 . PVRV, PCECV
0.7 IU/
PDEV (1 ./ rabies antigenicity
= 6.9 IU/.) PCECV ( rabies antigenicity

3.6 IU/.) 0.1 .
TRC RIG

0.2 . immunogenicity
PCECV 0.1 .
TRC ( rabies antigenicity = 10 IU/)
RIG
PCECV TRC
HRIG rabies antigenicity
7 IU/. 0.1 . (0.7 IU/1 )
PCECV 0.1 .
TRC
14 1
HRIG PCECV
PVRV TRC intradermal
0.1 . (PCECV = 0.91 IU/0.1 .)
HRIG 0.1 . PCECV
19,20
TRC
rabies antigenicity 1

0.7 IU/21
(multisite intradermal regimen)
8-site intradermal regimen (Oxford regimen)
0.1 . HDCV, PVRV
PCECV (intradermal)
2
2 ( 8 ) (
0) (
4 ) 7 30 90
1 (8-0-4-0-1-1)
RIG
RIG
23 257

WHO categories 3
RIG

WHO
categories 3 RIG

22-26 PVRV 0.05
. 1
0.05 .
1 (4-0-2-0-1-1)
4 0, 3 7
27

ESSEN
TRC

post-exposure 1
TRC
3, 7 28 ( 1IM-2ID-2ID-0-2ID)
rabies Nab titer
intramuscular ESSEN regimen intradermal
TRC regimen28
500

.. 2549

0

3, 7 28 TRC regimen

(
)
purified ERIG

RIG

202 (59
3 )
PVRV+RIG (
0.39 )
1
RIG

1

HDCV, PDEV , PCECV
RIG
29
(Rabies immune globulin, RIG)

RIG

258
category 3
RIG
RIG
(WHO category 3)
RIG
RIG (equine rabies immune
globulin; ERIG)
ERIG RIG
(RIG) 2
1. Human rabies immune globulin (HRIG)

HRIG 20 IU/. HRIG

HRIG
2. Equine rabies immune globulin (ERIG)
ERIG 40 IU/.
purified ERIG
( 1.6-6.9)
purified ERIG highly
purified heat-treated ERIG

purified ERIG
purified ERIG
anaphylaxis purified ERIG
(crude ERIG anaphylaxis
3.8)
RIG 1

( 10-14)
RIG

7
RIG

neutralize receptor
(
)
RIG
()
RIG
RIG
( )

RIG
RIG

(
RIG RIG 2-3

anaphylaxis serum sickness

(type III hypersensitivity intradermal skin
testing ERIG
( intradermal skin testing
)30
wheal
5 . 30-40
( 30-40
HRIG )

ERIG ( purified ERIG)
26 ERIG
0.02 . ( 1:100 )
10
wheal flare
2
anaphylaxis
serum sickness 1.41
23 259
wheal 5 . 10
.
5 .
negative control test wheal 5 .
25.9

HRIG wheal 10 . flare
20 .
anaphylaxis
anaphylaxis

rabies Nab
titer 0.5 IU/.
WHO
category 2 3
RIG
12

14
1
1 1 (
0.1 .) 1 ( 0)
6
2 ( 0 3)
6
PVRV 4
(0.1./) 0
PVRV 2 ( 0
3)
PVRV pre-exposure ID (0.1./) 1
rabies Nab titers ID 4
2
(conventional booster regimen)
5 1 31
4
.. 2541
WHO category 3 5,000
32,33
4
12
5 10
1 0.2
. PDEV PVRV 1
0 3 rabies Nab titers
7
5-10 10 34,35

4 0
1 0
3
260
(pre-exposure post-exposure)

9-17

(
)

WHO category 1 (
)
RIG

( )
1
(
)
36
(
17 )
8.7 1.3 37,38

(
2-4 )
(DPT-IPV)

2-3

3 4 1-2 (primary immunization)
2
23 261
RIG ( RIG
)

1 0.1 .
(deltoid) 0, 7 21
28 ()

3 2
( 0 28)
3 ( 0, 7 28) HDCV PVRV
1 1 rabies Nab
titer 14 ( 379)
rabies Nab titer 30 IU/.
( 0.5 IU/.) 10
2
tetanus toxoid (
aluminium hydroxide tetanus
toxoid )
rabies Nab titers
3 39
0.1 .
1 0, 7 21
28 chloroquine

(
mefloquine
rabies Nab titers)

PVRV (ID) 0.1 . 1
0, 7 21 28
1 40-50 rabies
Nab titers 0.5 IU/.
3 ( 87-100)
HDCV
0.1 . rabies Nab titer

0.1 0.2 .
1 0 3
0.1 . 4
0

5-7
(pre-booster
rabies Nab titer)

(rabies
Nab titer) 0.5 IU/.

Nab titer 6
rabies Nab titer 0.5 IU/.
1
0.1 . 1
1

262

rabies Nab
titer 1-2 rabies Nab titer
0.5 IU/.
(
)
rabies Nab titer
WHO category 2 3
anaphylaxis serum sickness 41

HRIG

ERIG
purified ERIG 1.6-6.9
purified ERIG

serum sickness 90
1-2
3
serum sickness
42,43
HDCV
15-25
2-8
serum sickness 1
2-3
serum sickness 6-11 (

2-21 ) PVRV primary immunization

( 23-39)
( 3) 6-10
( 1) (
5-9)

()
1:80,000 1:12,000-30,000

30-32
23 263
1.
WHO category III

2.

2-3
3.

(deltoid region) (anterolateral
thigh)
4.
5.

( 10 )

44,45
(Immunocompromised host)
rabies Nab titer

2
46,47

CD4 300-400/..

(PVRV) TRC ID RIG
PCECV ESSEN
(rabies Nab)

CD4 300-400/.
.48-50 post-exposure treatment
2 51,52
2 TRC-ID (2-2-2-0-1-1)
4-4-4-0-2-2 ID
2
tetanus toxoid (2-2-2-2-2-0;
double doses ESSEN regimen)
264
Nab CD4
200/.. Briggs PJ

WHO categories 2 353,54

rabies Nab

pre-exposure vaccination
CD4 (
15)55,56
Nab
CD4+T-lymphocyte counts
viral load

57
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Vaccine. 2010;28:2385-7.
76
269
24

B
3 4
Neisseria menin- C, Y W-1351
gitidis

B A C, Y W
135
5 - 10

0.03-0.19
16-100 2 .. 2552

24 34 0.05
5 0.01
14.71
9 ..
2543-2551 ..
2552 .. 2551

N. meningitidis 0 - 4 10-14, 5-9,
25-34, 15-24 35 3

13 A, B, C, D, E, X, Y, Z, W-135,
N. meningitidis
H, I, K L 5
A, B, C, W-135 Y A
Sub-Sahara W-135 2-10 (
3-4 )
270

petechiae /

4
30
20
cefotaxime ceftria petechiae purpura xone penicillin
20 (meningococcemia) penicillin
purpura fulminans penicillin 6-8

(Waterhouse Friderichsen syndrome) Disseminated intravascular coagulation
(DIC)
13
.. 2537-2542 33 2 -75

11.2 45.5 meningo- (close contact)
coccemia 54.5 24
24.2 rifampicin 600 . 12
33.3 12.1 2 >1 rifampicin
3 9.15
10 . 12 2
1 rifampicin 5 . 12
2
quinolone,
ceftriaxone azithromycin9-11
10-20 2

30

24 271
(..1900-1940) killed whole

cell12,13
..1930

inactivated endotoxin
..1940 Scherp Rake

14
15,16

17 .. 1960

18,19 2
bivalent (A C) quadrivalent (A,
C, W135 Y)

T cell20
memory T cell21-23

A C24 C25-28
A, C, Y W-13529-34
(A, C, Y W-135)
..2005
2
1. Bivalent
A C
2. Quadrivalent 4 A, C, Y
W-135 Menomune
A/C/Y/W-135 (MPSV4)
A, C, Y,
W-135 50 .35
A, C, Y,
W-135
2-8o .
1
MPSV4 2
0.5 .

4
2-3 5
1,35
MPSV4 7-10
MPSV4
11-55
(MCV4)
2-10 32
MPSV4 3-5 9,36
MPSV4
2
272

B

terminal complement deficiency

2
1. Monovalent
serogroup C
C
(CRM 197)
(tetanus toxoid) 35
2, 3 4
B
2. Quadrivalent meningococcal (A, C, Y
W-135) conjugate vaccine
1,35
.. 2005 Menactra (MCV4)

A, C, Y W-135
3 4 .
MCV4 48 .1,35 Menveo (MenACWY)
Guillain-Barr syndrome (GBS) Novartis .. 2010
MCV437
38

2-8 o .

momovalent serogroup C conjugate
1
vaccine (Menjugate) 0.5 .
2 -12 3
1 12 0.5
. 1
24 273
Quadrivalent meningococcal conjugate

vaccine 0.5 .
Menactra (MCV4) 2-55
Menveo (MenACWY) 11-55
1 11-12
1 16 2-54
anatomical
functional asplenia, terminal complement component
(C5-C9) deficiency properdin deficiency
primary series
2 2 39
MCV4
(MPSV4)
11 18 18-55 33
11-18
80
A, C, W135 Y
3
MCV4
W135 44 21 MPSV4
C Y
34
2-10
MCV4
MPSV4

MCV4 4
(1700 893
A, 354 231 C, 637
408 Y, 750 426
W135)
MCV4
40
MenACWY
.. 2010
11-55
MCV4 11-17
MenACWY
MPSV441 MenACWY

42
MCV4 (serogroups A, C, Y
W-135) .. 2005
.. 1998 .. 2007
64 0.92
0.33 100,000 43
meningococcal serogroup C conjugate vaccine
9
( 92)
( 97)44 2,
3 4
49
5-11
12 45,46
C
C
46

19 C
47
274
75

C 67 35 1 17
> 25
herd immunity48
MCV4
2-55

anatomical functional asplenia, terminal
complement component (C5-C9) deficiency
properdin deficiency,

2
1,35
11-18
55 MCV
Menveo MPSV4 > 55
MCV4
2-10
2-3

MPSV4

herd immunity
3
2-18
MCV4 MPSV4
2-5 GBS
MCV4 6 49,50
GBS
MCV4 MPSV4 51

2
GBS
GBS MCV4

A, C, Y W 135

N. meningitidis

A B

MCV4

24 275
C

B
B 52-56
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279
(Rotavirus)
5

5

138
1,205
2
family Reoviridae, genus

Rotavirus double - stranded RNA
12 65-75
2 (outer inner
capsid) inner core
(Rota
) 2
VP7 VP4 VP6 inner
25
core VP1, VP2 VP33,4

(group)
(subgroup) (serotype)
VP6 7 A-G
2 I II A-C
D-G
A5 B
6 C
7,8
VP4 VP7 VP4 VP7
neutralizing antibody VP4 protease sensitive protein
P protein VP7 glycoprotein
G protein

10 G 9 P 9

A G
G1, G2, G3, G4 G9 P
P4 P810,11 G P
80
90
G1P[8], G2P[4], G3P[8] G4P[8] 12,13

.. 2538
G9P[8]

280
14-21
.. 2520-2540
G1
G2, G4 G3 ..
2539-2540 G9 3
G1 G218 .. 2541-2542
G1P[8] 22 .. 2544-2546
G9 23
27-3418 .. 2544-2546

6

..
2544-2546
4,057
1,950
838 43

54.8 G9 G2, G4, G1 G3
17.2, 5.3, 0.8 0.1 23

6-13
213 1
12
4.8
586,000
131,000
56,000

6
2 18,26-28

5
1 5
1 50
1 206
24
2
200

6 34
1 1 67
1 2 98
1
10 1 10 2
5 25
The Asian Rotavirus Surveillance

Network (ARSN)

4526

.. 2520-2540

25 281
(fecal-oral-route)

4-57 29
5,30
(Crypt hyperplasia)

disaccharides

osmotic diarrhea

-
nonstructural rotaviral protein (NSP4)
enterotoxin NSP4
31

necrotizing enterocolitis

34-40

ELISA, latex agglutination, Polyacrylamide gel elec
trophoresis (PAGE)
1-2
IgM IgG
2-3
3-8 polymerase chainreaction

32,33
282

1
(ORS)

probiotic
41-46
Tetravalent Rhesus
Rotavirus Vaccine (RotashieldsTM)

G3 reassorted
G1, G2 G4 3
2, 4 6

46-68
70-10047-51
.. 2541
9
2
52,53
37 3-7
(95% CI:12.6-110.1)54
.. 2542 rhesus rotavirus
hyperplasia lymphoid tissue
payer patch 55

56-60
1. Human-derived monovalent live-attenuated
oral vaccine RotarixTM

12 2547
(RIX4414)
G1P[8]
70,000
2. Bovine-human reassortant pentavalent

live-attenuated oral vaccine RotaTeq
Merck G1, G2, G3, G4
P[8] 3
3. Lamb-derived, monovalent live-attenuated
oral vaccine G10P[12] Lanzhou Institute of
Biomedical Products
. 2544
3
60

2
Live, attenuated human rotavirus vaccine
Bovine- human reassortant rotavirus vaccine
25 283
Rotarix
Human-derived
monovalent
G1P[8]
> 106 CCID50/.
RotaTeq
Bovine-human
reassortant
pentavalent
G1 2.2x106
infectious units
G2 2.8x106
infectious units
G3 2.2x106
infectious units
G4 2.0x106
infectious units
P8 2.3x106
infectious units
( 63)
Lyophilize 1 ./
Oral suspension
1.5 ./
Oral suspension
2 ./
1.Live, attenuated human rotavirus vaccine

RotarixTM

G1P[8]
1 . RIX4414
G1P[8]
106 CCID50/. RotarixTM
(vial) (1 .)
(prefilled syringe)
1.5 .

.. 2548

61
6-15
2, 4
8
6-15
2, 4, 6
8
2. Bovine- human reassortant rotavirus

vaccine RotaTeq Merck
(Bovine rotavirus
WC3 strain) reassorted
G1, G2, G3, G4 P[8]

.. 2549

62 (1)
2-8o .
RotarixTM
2-8o .
24
284
63
1. Live, attenuated human rotavirus
vaccine
2
6-15 2 8
4
2. Bovine- human reassortant rotavirus
vaccine 2 .
3 6-15
8
4
6-15 8
4
RotaTeq 1
3
2
- (DTwP, DTaP)
(Hib)
(IPV)
61,62,64

(OPV)

OPV
2 OPV
63,65
OPV

1. Live, attenuated human rotavirus

vaccine
Vesikari score

0-20

11 55,66
RotarixTM

85-96
85-100
70-80
40-75
RotarixTM
10,708

10 19,163 6
3,994
96 80
90
94, 83 96
RotarixTM
RotarixTM
25 285
G1 100
non-G1 94
RotarixTM
G1 83
non-G1 80
G1 96
non-G1 8867-69
RotarixTM

30
RotarixTM
phase III double-blind
randomized placebo controlled

3
2 3 placebo

1

61.2
76.9
49.4 2
3 70
2. Bovine-human reassortant rotavirus
vaccine

0-24

16
74
( >16) 98

G1, G2, G3, G4 G9 74, 63, 82, 48

65
G1, G2, G3, G4
G9 95, 88, 93, 89 100
96
5962
RotaTeqTM

2,036

42.5
(Vesikari score >11)
48.3 >16 7071
RotaTeqTM
54,688
(Vesikari score >11)

39.372
RotarixTM
RotaTeqTM Cochrane Collaboration
34 175,944
73

286
immunodeficiency disease
74-78 79-81
3. latex RotarixTM

oral applicator latex
77,78
RotaTeqTM
4.

(intussusception) RotaTeqTM
5.
TM
61,62
Rotarix
6.
7.
1
8.
2
9.

10.
3

11.

74-85
90-100

85

1.
2. severe combined
25 287
(burden)

10
82
.. 2553
Porcine Circovirus type
1 (PCV1) RotarixTM
PCV1

Rotarix WHO
.. 2553
DNA PCV1 RotaTeq

PCV2
PCV1 PCV2 PCV2

2
Rotarix
RotaTeq
.. 2553

DNA

83,84

PCV

Rotarix RotaTeq PCV

2

85
Human-bovine reassortant
tetravalent oral vaccine National Institutes
of Health
G1, G2, G3 G4 Human neonatal strain-derived
live-attenuated vaccine Graeme Barnes &
Ruth Bishop
monovalent strain G3P[6]
50

2
human-bovine
neonatal-derived strains
288
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, ,
, .
.
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, .
.
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76
295

(WHO)
.. 2010/2011 1.7
4,700
9.4 1

38.0
..2537 49.97 .. 2545
63.11 .. 25522
22
3
(multidrug resistant Mycobacterium tuberculosis: MDR-TB)
3.3
MDR-TB
18 - 24
rifampicin

.. 1921
100
26
.. 1921
Calmette Guerin

Mycobacterium bovis
culture medium
2 (passaging) 230 passages
.. 1921
(liquid vaccine)
(lyophilize)

passage passage 1173
.. 1961
passage 230 Calmette

.. 1921 - 1961
943 passages Mycobacterium bovis 4
virulence immunogenicity 5,6

.. 1924
Mycobacterium
bovis

296
1
( 4)
M. bovis .. 1990
phylogenetic tree
molecular fingerprint M .bovis, M. tuberculosis
restriction-fragment-length-polymorphism
(RFLP)
IS6110 MPT64 .. 1921
IS6110 MPT64
IS6110 MPT64
IS6110
.. 1925-1926 MPT64
.. 1927-1931 24
..
1921

Phylogenetic tree
M. bovis BCG
deletions polymorphisms

.. 1961
.. 1921 1 single nucleotide polymorphism
4 deletions
deletions polymorphisms

2 early strain late
strain BCG Pasteur 1173 P2
late strain Tokyo 172-1
early strain genome sequence
[BCG Pasteur 1173 P2 contain
two separate genetic populations with double and triple
tandem duplications in the DU2 region (a protein encoding region with 58 genes) BCG Tokyo 172-1
26 297
contain two separate genetic population with differ in

the protein encoding RD16 region, one variant having
the full RD16 region the other with a 22 bp deletion in
this region. ] morphology
growth characteristic 7-11

culture medium

2
(lyophilized)
1.
90-95
-
2512 172
30 1
.
12-15 1 .
2
syringe
2.
mycolic acid
M. bovis

.. 1931
methoxymycolic acid M. bovis
methoxymycolic acid
(macrophage)13
3. im-
munogen
immunogen
.. 193114 ESAT-6 CFP-10
M. bovis
MPT64, MPB70, MPB83

.. 1921
vaccine immunogenicity

reactogenicity conversion

protective immunity
lot-to-lot consistency
final lot

biomarker panels mycobacterium growth
inhibition bioassay
molecular biology
(genectic information)
virulent
mycobacterium 15

BCG sub-strain sub-strain

(guinea pig)
early strain
(BCG Tokyo 172-1) late strain (BCG Danish 1331,
BCG Pasteur 1173 P2, BCG Connaught, BCG Tice)
298
2
( 4)

aerosol challenge
16
BCG Glaxo (late strain)

(regional suppurative adenitis)
0.1-38 1,000
(BCG-osteitis) 0.01-330 1,000,000

(WHO) (prevalence) (disseminated BCG) 2
(TB disease) 1,000,000 18 (
40 )

.. 2545 49.95 .. 2551
54.3017 .. 2552 63.112

(disseminated tubercu-
losis) (TB meningitis)
60-90 19
(primary tuberculosis) 1
2-3
26 299
1
Category
Regional disease
Description
Persistent ulcer, abscess, fistula,
or lymphadenopathy limited to the region of inoculation
Extra regional localized disease Infection of a single anatomic site, such as osteitis or
cutaneous abscess, outside the region of inoculation
Disseminated disease
See detailed in table 2
Other BCG syndrome
Syndromes following vaccination in which bacteria are
not identified, such as keloid, uveitis. These syndromes
may have an immune basis
( 18)
(bluish-red pustule)
5-15 .
crust formation
3-4 6-10 crust
3-7 .
10 . 20
3
28-33 hypertrophic scar
2-4 keloid scars
(infants)
1 21
2 2,500

erythromycin, cloxacillin
( ) isoniazid

isoniazid

22

well baby clinic

2
Complication
Local subcutaneous abscess, regional lymphadenopathy
Musculoskeletal lesions
Multiple lymphadenitis, nonfatal disseminated lesions
Fatal disseminated lesions
( 21)
Incidence per 1 million vaccinations

Age < 1 year
Age 1- 20 years
387
25
0.39 0.89
0.06
0.31 0.39
0.36
0.19 1.56
0.06 0.72
300

3

2

8-9 90 (
10 .) 23

(outbreak)

(Pasteur-1173P2)
Mozambique, Zimbabwe, Zaire
Caribbean

(Pasteur-1173P2) 19
Tokyo Moreau
Copenhagen
Pasteur-1173P2
percutaneous multiple-puncture device

intradermal
3 conversion rate
40
intradermal conversion rate
83 lymphoproliferative response M. tuberculosis
IFN -response
percutaneous
intradermal
subcutaneous
intradermal
intradermal
M. tuberculosis24
(BCG lymphadenitis)
1-4

0.013 2325-27

22
AFB
M. bovis
Staphylococcus aureus, Streptococcus group A M. bovis
M. bovis

20
26 301
Russian BCG-osteitis
35 : 1,000,000
BCG-osteitis19
.. 1960-1970
Gothenburg
BCG osteitis 7.3 : 100,000 ..
1971-1978 Gothenburg
Copenhagen
BCG-osteitis 36.9 : 100,000
29 BCG-osteitis

BCG osteitis 222
.. 1960-1988 30,31
96 0-1
1.5 ( 0.25-5.7)
1
2.5 ( 1.7-3.6)
1.5-2
14
24 arthritis

lower extremity ( 57.6)
femur 26.7
metaphysis epiphysis long bone29
(BCG Osteitis)
3
BCG osteitis
3-4
pyrazinamide BCG M. bovis
0.01 : 1,000,000 12 ( 6-24
300 : 1,000,000 ) 97
BCG osteitis
Czechoslovakia
Prague .. 1982 keloid
3.8
( 1-6 ) 2-4 .
10 15 . 9
10-15 . 1 10 .
17 ( 85)
9.1 ( 2.5-19 )
3 20
11.8 (
5-23 )28 spontaneous
regression 20-85

M. bovis

isoniazid, rifampicin

sinus tract
302
3 BCG osteitis
BCG Osteitis
1.
2.
3. osteitis
4.
4.1 M. bovis BCG
4.2 AFB +ve
4.3 (epithelioid cell granuloma)
( 30)
(Disseminated BCG)

(disseminated BCG) 2
1,000,000 18
severe
combined immunodeficiency (SCID), chronic granulomatous disease (CGD)
.. 1921-1982 60
.. 1980-1995 27
5,000
84 immunocompromised
71 2

(failure to thrive)
disseminated BCG
3 418
M. bovis firstline pyrazinamide
disseminated BCG
isoniazid, rifampin, ethambutol, streptomycin
70

pyrazinamide

drug interaction

4 Disseminated BCG
3
1.
2.
2.1
2.2 2

3. systemic
( 18)
26 303
outbreak BCG
adenitis

(lot number)

Pasteur-1173 P2

intradermal

syringe
Zimbabwe outbreak
19
.. 2553
(Serum Institute of India) (Russian 1)

( Tokyo 172)
0.05 .
(0.1 .)

(potency)
PPD

conversion rate 90-95
Glaxo, Tokyo, Pasteur, Copenhagen
conversion rate
Pasteur
conversion rate 64
conversion rate
88 conversion rate

immunogenicity hypersensitivity
induration
0-4, 5-9, 10-14 15
. 32

15
(BCG scar)

50-6033
5334
20-5035,36
304

50 37

(TB
meningitis) (miliary TB)
52-100
2-8021
( 0-80)

5 38

1 -2

intradermal
T-cell 1-2
1-2

(induration)

1
1-2

26 305
5
_________________
________________________ .
induration
induration
(abscess)

(hypopigmented patch)

(keloid)

1-2

2

53

(miliary TB) (TB
meningitis) 37

1

(environmental mycobacterium)
1. (induration)

2. 15 .

(active disease)

(LTBI) isoniazid 6-9
3. 1-9 .
( 6-12
10 .31,39)

4. 10-14 .

Kagina BM .. 2009
306

10

BCG-specific CD4
T cells 40 ( polyfunctional T cells coexpression IFN-gamma, TNF-alpha IL2)
immunity mature
BCG-specific
T cells
disseminated
BCG disease 41
2 7
1 7-14
42
.. 1921
9043

(sanatoria)

(endemic area)
44
(endemic area)

( : wane)
( ..
1931)

(over-attenuated vaccine)
45

10-20
46-48

Wuchereria bancrofti, Schistosoma haematobium

49
cytokines
26 307
Th2-type immune activation Th1

albendazole
(Ascaris lumbricoides)
(live oral cholera vaccine)
IFN-
50,51
Ferreira AP52
Ascaris lumbricoides, Entamoeba histolytica, Strongyloides stercoralis
IFN- IL-10
IL-10
type-2 cytokines response
IFN-

(CMI)

( 3)

43
Blocking hypothesis
(environmental mycobacterium)

(vaccine strain) (CMI)
(block)

(M. tuberculosis)
3 Blocking hypothesis Masking hypothesis

( 43)
308
(nave recipient)

(BCG dissemination)
Masking hypothesis

(
blocking hypothesis)

(nave recipient)

Blocking hypothesis Masking hypothesis
Blocking hypothesis

(tropical regions)
(skin test conversion rate)
(wane)

Malawi
2-3
waning
waning
53 T-cell
responses

waning 54 30
(latitude) (equator)

30 (higher latitudes)
55

Blocking hypothesis

(nave recipient)
Masking hypothesis

10-20

/
(boost existing immunity: Late
26 309
booster vaccine)

(postexposure
vaccine)
6
Type
rBCG30
rBCG::D
ureC-llo+
Description
Live, recombinant BCGTice, over-expressing
Ag85B from M.tb
Live, recombinant BCG,
urease-deficient mutant that
express lysteriolysin O gene
from Listeria monocytogenes
Developer
Improvement over
available vaccines
University of
Stimulates a stronger,
California, LA, USA longer-lasting response
than conventional BCG
Max Planck Institute Promotes leakage of

of Infectious Biology, antigens from phagosome to
Berlin, Germany
improve CD8 responses
via cross-priming
MVA-85A
Live, recombinant,
Oxford University, Stimulates strong primary
replication-deficient vaccinia Oxford, UK
immune response, but
virus, expressing Ag85A\
intended primarily as a
from M.tb
booster vaccine for individuals
previously vaccinated with
BCG
Ag85B-ESAT6 Recombinant protein,
Statens Serum
Stimulates strong primary
composed of a fusion of
Institue,
ESAT-6 and Ag85B from M.tb Copenhagen,
intended primarily as a
Denmark
booster vaccine for individuals
previously vaccinated
with BCG
Mtb72f
Recombinant protein,
GlaxoSmithKline
Stimulates strong primary
composed of a fusion of
Biologicals,
Rv1196 and Rv0125 from Rixensart, Belgium intended primarily as a
M.tb and delivered in oil-inbooster vaccine for individuals
water emulsion, containing
previously vaccinated with
immunostimulant 3BCG
decacylated-monophosphoryl
lipid A and a purified fraction
of Quillaria saponaria
SRL172
Autoclaved M vaccae
SR Pharma, London, Enhances Th1 response to
UK. Current trial led shared mycobacterial
by Dartmountantigens, but also drives
Hitchcock Medical regulatory T cells that
Center, Lebanon, inhibit Th2
NH, USA
( 57)
Stage of development
Phase I trials
completed
Clinical trial
scheduled for 2006
Completed phase I
trials in UK and in
clinical trials in The
Gambia
In phase I trials in
Leiden, Netherlands
Completed phase I
trials in USA and
recruiting for phase II
trials in Lausanne,
Switzerland
Phase I completed.
Phase II running in
Tanzania (DarDar
project) in patients
infected with HIV
310

6

(acute phase)
( 4 - A)

3-5 (TB
disease)

(prophylactic vaccination)

(latent phase) ( 4 - A)

(dormant state)
(LTBI: latent TB infection)

(reactivation phase)
( 4 - B)
(post-exposure, therapeutic vaccination)
reactivation
phase ( 4 - B)
(acute phase)
(acute and
reactivation phase) multiphase vaccination (
4 - C)
DNA vaccine

MHC class I MHC class II
cytotoxic T lymphocytes, helper T cells

HSP65, Ag85, 38 kDa, PstS-3, (ESAT-6, KatG,
( 56)
26 311
MPT63, MPT64, MPT83), (Mtb39a, HSP65, MPT70,

IL-12), (65 kDa, Ag85), 35 kDa
58 DNA vaccine
HSP65 MPT70
DNA
59

prime subunit
booster vaccine
60-62
(Replacing BCG)

rBCG30 vaccine, rBCG::ureC-llo+ vaccine

M. tuberculosis
M. tuberculosis
(virulent
form)
rBCG30 vaccine63
M. tuberculosis: 30-kDa major secretory protein gene
recombinant vaccine phase I
(guinea pig)

rBCG::ureC-llo+ vaccine64
Kaplan G.
T-cell immunity
B-cell
(M.tuberculosis)
CD4+ T-cells CD8+ T
cells MHC class II
molecules ( CD4+ T cells) MHC class
I molecules ( CD8+ T cells)

phagosome
acid-dependent enzymes phagosome
mycobacterial urease pH phagosome

cytoplasm
MHC class II molecules

MHC class I molecules
cytoplasm

Kaplan G.
MHC class II molecules
cytoplasm phagosome

lysine gene
Listeria monocytogenes
phagosome
MHC class I
molecules MHC class II molecules

64

312

(booster vaccine)
Th1response
MVA-85A, Ag85B-ESAT6,
Mtb72f

recombinant protein vaccine Th1-response
adjuvant adjuvant
subunit vaccines
(Augmenting BCG: Late booster alum (aluminum hydroxide), MF59, virosomes
vaccines or postexposure vaccines)
Th2-response
50 adjuvant
65
56
(endemic area)
(Postexposure vaccines)

25-35

(postexposure vaccines)

(TB disease)
(primary immune
preexposure vaccine
response)
(multiphase
vaccination)
immunological memory

Mycobacterium vaccae (heat recombinant killed) (therapeutic
26 313
vaccine)
1
65

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360:1032-3.
317
(measles)

200,000 - 500,000
450 1

measles masel
2 (spots)

2,000
Rhazed ..
1954 Panum 3

2

2
(Expanded Program on Immunization EPI)
27
Measles virus
( Rubeola) genus Morbillivirus
Paramyxovirus4 single-stranded RNA
(spherical) 100-250
5 envelope glycoprotien 3 6
H protien
F protien
M protien
viral maturation
envelope (>37.)

( 2 )
1,4,7

.. 25528
6,071
318
9.57
11.6 ..
2542 - 2552 2
.. 2543 .. 2545
16.49
.. 2551
11.81
1-4 8
(airborne transmission)

4
4 9

respiratory epithelium
(first viremia)
2-3
reticuloendothelial
10,11
2 (second viremia) 5-7
monocyte
12 7-14

lymphoid
hyperplasia
13
multinucleated giant cells

15-17

4
8-12
39 . - 40.5. 14,15
(photophobia)

2-4
Koplik spots16,17

(first molar) 1
2-3
3-4
18 maculopapular rash

48-72

confluent maculopapular rash
discrete maculopapular rash
25-507

18 3-7
(hyperpigmentation)

biphasic9 24-48
24

2-3
27 319

10 7

9

14-20 25
1-2
1. Atypical measles
Koplik spots
(formalin-inactivated measles vaccine)
..19631968 19 3.

(pleuritic chest pain) 2-3 giant cell pneumonia26

maculopapular rash
(petechiae) (vesicle) 27,28

Koplik spots (hemiplegia) (slurred speech)
(ataxia) (aphasia)
19-21 atypical (encephalitis)
measles 1-7
hemagglutination inhibition (HI)
5-6 22 2 30-40
40-70 1
atypical measles
T-cell29

antigen-antibody immune complexes23,24

30
5 20 7

2. Modified measles
(epithelial surface)
30-32
320

1.
(acute otitis media)

14 5
eustachian tube

eustachian tube
Laryngotracheobronchitis (measles croup)

2
9-3233-38
inspiratory stridor

(tracheitis)
(pneumonia)
Staphylococcus aureus
(pneumonia)

39 9
5

(chest x-ray)
interstitial infiltration

parainfluenza,
adenovirus
25-35 Streptococcus
pneumoniae, Staphylococcus aureus, Haemophilus
influenzae
bronchopneumonia
consolidation
4140 pneumomediastinum subcutaneous emphysema41-44

2.
(diarrhea)
5
30 30-70

45
(appendicitis) lymphoid hyperplasia46

giant cell 7
mesenteric adenitis, hepatitis, pancreatitis
stomatitis
3.
Febrile seizure 0.1-2.335,37,46

Encephalitis 1:1,000

lymphocyte
25
15
4,22
Acute dissseminated encephalomyelitis (ADEM)
postinfectious encephalomyelitis
demyelinating
47 5-14
1-3:1,000 22,48

27 321
multifocal neurological signs meningeal irritation

ataxia, myoclonus,
choreoathetosis myelitis
paraplegia, quadriplegia, sensory loss
bowel bladder dysfunction
lymphocyte

(MRI) multiple hyperintense signal
white matter T2
(immune process)47,49,50
myelin
25

22,48

Subacute sclerosing panencephalitis (SSPE)
1-8.5 : 1,000,000 51-53
degenerative disease
demyelination
22,54
20
2 55,56

7-10

myoclonus, dementia,
mutism, central blindness, decorticate rigidity
(EEG)
high-voltage complex of slow waves
and sharp waves

(wild type)
SSPE57
4.
(keratitis)
(vitamin A deficiency) 58
5.
-
(myocarditis)59 (pericarditis)
- 60
disseminated intravascular coagulation (DIC)
- 61
(severe desquamation) cellulitis
-
- T-cell
2-6

maculopapular rash 3-4
Koplik spots

1.
enzyme immunoassay
(EIA)
IgM acute
phase serum IgG 2
322
acute convalescent phase serum 2
(fourfold rising of
antibody) 62
(WHO)
IgM62,63
3
14 1
7
IgM
3
rheumatoid factor
parvovirus B1964
2. (viral culture)

3.
immunofluorescent
4.
polymerase chain reaction (PCR)65
cochrane review .. 200566

2
2
67 2
1
1 2
- 50,000 IU 6
- 100,000 IU 6-11
- 200,000 IU 1

2-4
Ribavirin
ribavirin 67 ribavirin
(aerosol)
68,69
randomized controlled trial

ribavirin
Passive immunization
Immune globulin (IG) IG
0.25 ./.
6
0.5 ./. 15 .
IG
1

IG
27 323
Immune Globulin Intravenous (IVIG)

IG
IVIG
3 400 ./.
(history of
vaccine developement)

..1960
..1963
(killed vaccine)
(live attenuated vaccine)
2 4
atypical measles
monovalent live attenuated measles vaccine
Edmonston B
chick embryo cell

Edmonston 70

..1971
trivalent live attenuated measles-mumps-rubella
vaccine (MMR)67,71
.. 2527 1 9-12
.. 2539 2
1 .. 2540
- (MMR) 9-12
4-6
1 - -

2
- - (MMR)
Trimovax TM
PriorixTM

(MMR)

1
2-8o .

1 MMR
measles
mumps
rubella
(1,000 TCID50) (5,000 TCID50)
(1,000 TCID50)
Priorix
GSK
Schwarz Jeryl-Lynn (Modified) Wistar RA 27/3
Trimovax sanofi pasteur Schwarz
Urabe AM 9
Wistar RA 27/3
324
0.5 .
9-12 4-6
MMR

CDC clinical category class C
CDC immunological
category class 367

9-12
1

4-6
MMR

(cocooning)

-- 9
85-95
96-99 63-95
Moraten
Edmonston B-Zagreb
Jeryl-Lynn
Rubini 72

Rubini 6.3
Jeryl-Lynn 61.6
Rubini Urabe
75-9973
9 .. 2527
1
.. 2526
34,713
1 2,331 .. 2553
2,255 1
395
MMR
12-15

(primary failure)

(secondary failure)
2
95
12 98
15 74
( 1 ) 4
99 5

12

27 325
anaphylaxis 1:1,000,000

MMR

autism inflammatory
5-15 bowel disease76-78
6-12 1-2 75
5

1.
2
9-12 4-6

2. MMR
febrile
convulsion

3.
(thrombocytopenia)
2 1 30,000-100,000

4.

MMR

MMR
25 1-3
5. MMR
1-3 72
MMR
aseptic meningitis
mumps Urabe 74
1:11,000-1:100,00075 L-Zagreb
1:3,000 Jeryl-Lynn
Rubini
1. MMR
MMR Jeryl-Lynn
Jeryl-Lynn
Urabe
encephalopathy / encephalitis 28
6-15 MMR
1:1,000,000
3
326

67,71
2.

3. neomycin anaphylaxis
4.
( 2)
5.
6.
MMR
egg cross-reacting protein chick
embryo cell culture
WI-38 human diploid
lung fibroblasts skin test

30 67,71
7.
prednisolone 2 ./.
2
MMR ()67
Tetanus prophylaxis (TIG)

Hepatitis A prophylaxis (IG)
-
-
Hepatitis B prophylaxis (HBIG)
Rabies prophylaxis (HRIG)
Varicella prophylaxis (VZIG)
Measles prophylaxis (IG)
- ()
- ()
- Red blood cells (RBCs),washed

- RBCs adenine-saline added
- Packed RBCs (Hct 65%)
- Whole blood (Hct 35-50%)
- Plasma/platelet products
Replacement therapy for
immune deficiencies (IVIG)
Respiratory syncytial virus
prophylaxis
Immune thrombocytopenic purpura (IVIG)
Kawazaki desease (IVIG)
(. IgG/.)
250 (10 . IgG/.) IM
()
3
0.02 ./. (3.3 . IgG/.) IM

0.06 ./. (10 . IgG/.) IM
0.06 ./. (10 . IgG/.) IM
20 IU/. (22 . IgG/.) IM
125 /10 . (20-40 . IgG/.)
IM ( 625 )
3
3
3
4
0.25 ./. (40 . IgG/.) IM

0.50 ./. (80 . IgG/.) IM
5
6
10 ./. ( IgG ) IV
10 ./. (10 . IgG/.) IV
10 ./. (60 . IgG/.) IV
10 ./. (80-100 . IgG/.) IV
10 ./. (160 . IgG/.) IV
0
3
5
6
7
300-400 ./. IV
750 ./. IV ( RSV-IGIV)

400 ./. IV
1,000 ./. IV
2 /. IV
9
8
10
11
27 327
20 ./ 14
1
8.
MMR (
) 2
9.

3
MMR 4-6

74
MMR

(
) 6
12-18 4-6 67
2 4
.. 2005
4 quadrivalent live attenuated
measles-mumps-rubella-varicella vaccine (MMRV)

12 -12
28 MMRV
12-23
MMR
67
MMRV 4-6
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76
333
28
Rubivirus 2 clades 13 4
single-stranded RNA spherical
60
lipoprotein nucleocapsid
helix RNA structural protein
3 C (capsid protein), E1 E2
(transmembrane protein) 24S subgenomic
mRNA nonstructural protein 2
replication transcription
E1 attachment, fusion,
hemagglutination neutralization
structural protein 3 hemagglutinin
complement-fixing antigen5,6

amantadine7 cytopathic effect
rabbit kidney cell line RK-13 primary African
green monkey cell5

(rubeola)

De Bergen Orlow
..1750
German measles1
measles scarlet fever
Third Exanthematous Disease of Childhood
three day measles .. 1866 Veale
Rubella
little red2
..1941 Norman McAllster
Gregg
Rubella
(congenital cataract)3

Congenital Rubella Syndrome (CRS)
5 9
80 90

6 9 30
..1964 12.5 8 ..1969

family Togavirus genus
334

.. 2005
5,11-13
(mathematical model)
90 5,14
.. 2004
387
309 97
orthodox protestant 2
14 (11
)
99.3
(95%CI= 95.3-99.9)
genotype 1G15 5.7
9.1 .. 2007 2008
81 15
6 10
genotype 1E16
.. 2527

9,033 3
0.03 ..2529

6
17 ..2540

-- 9
1 2 4 6
1 18
..2552
594 0.94

1.5 1
0 4 2.19
3

14 - 18 ( 12 23 ) (droplet
nuclei) (direct contact)

5 - 7
reticuloendothelial system

bronchoalveolar
lavage
1 2 1 20-22
IgG

23,24

5 - 7

25-28
10
28 335
18
18 20 29,30
cytopathic effect
apoptosis 31,32

momonuclear cell
36,37
2. 1
3,000 38,39

immunological mediated
38
3. 1
5,000 38,40,41
20 50
2
maculopapular
1 5 1 42
4.
33,34
43
24 3
5.
44
(Forchheimer spots)
(Congenital rubella
syndrome: CRS)

1 5 3
70 65-85
21 8 45 30 - 35

12

16

10
1. 1 3 20 46
35

1
47,48
50 45
336
HLA-DR3
HLA-DR2 80
49

50 1

scarlet fever parvovirus, herpesvirus
6 7 enterovirus infectious
mononucleosis toxoplasmosis 51,52

atypical lymphocyte
1.

5,7
()
60
45
-patent ductus arteriosus
20
-peripheral pulmonary stenosis*

12
27
25
(<2,500 )
23
19
17
13
10
* pulmonary arterial hypoplasia, supravalvular stenosis, valvular stenosis, and peripheral

branch stenosis ( 57 58)
28 337
2. reverse
transcriptase polymerase chain reaction (RT-PCR)
6
3.
hemagglutination inhibition (HAI)
enzyme linked immunosorbent assay (ELISA),
passive latex agglutination test radial hemolysis
test
IgG
IgM
fourfold IgG actue convalescent
serum 6,53

rubella titer

rubella titer
rubella IgM

12 monoclonal
antibody rubella antigen
rubella RNA in situ hybridization PCR54,55
2

2
2 6
2

immune globulin (IG)

viremia 56
IG

..1962

..1969

RA 27/3
HPV 77 DE5 Cendehill

-- (MMR)
2 9-12
4-6
MMR 1
.. 2001
3

3 28 57
680

3

0.5
338
Category A: ( patent ductus arteriosus peripheral

pulmonary artery stenosis) pigmentary retinopathy
Category B:
(radiolucent bone)
()
rubella IgM
rubella IgG
Polymerase chain reaction
(suspected)
(probable)
- 2 Category A
- 1 Category A B
(confirmed)
(infection only)
1
20 rubella IgM 1
( 59)
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76
343

enterotoxin (Vibrio cholerae)

..
2397 (.. 1854)
Broad street, Golden Sqaure section

2
Thames

Cambridge Broad
500 10
Broad
1
.. 2427 (.. 1883)

Robert Koch
29

7
.. 1884
comma

rice water stools 2
(pandemic)
7 6
.. 2360 (.. 1817) .. 2469 (.. 1923)
V. cholerae O1 classic biotype

1 7
6 V. cholerae O1 El Tor biotype (
EL Tor
.. 1905)
.. 2504 (.. 1961)

100 2
.. 2514 (.. 1971)
.. 2534 (.. 1991)
3,4
.. 2535 (.. 1992)

O1395
3,4 6
V. cholerae O17
3-5
344
1 .. 1989-2009
( WHO weekly epidemiological record in 30 July 2010)
100,000-120,000 8
90 (
1) 5
35 -1,428 9
V. cholerae

10
dormant
11
biofilm 12

13

8,13
V. cholerae
1-3
0.5-0.8 facultative anaerobe

flagellum
family Vibrionaceae
family Enterobacteriaceae
O somatic H flagella antigen
Vibrio enzyme oxidase glucose,
sucrose mannitol polar flagella O
antigen V. cholerae 200
3 O1 O139

non O1 sporadic
14 V. cholerae O1
specific phenotype characteristic 2 biotype
classical biotype El Tor biotype15 biotype
subspecificity O1 antigen 3
Ogawa O antigen A, B Inaba O
29 345
antigen A C Hikojima antigen A, B C

shift biotype 16
Bacteriophage CTX encode gene

cholera toxin ctx A ctx B toxin
co-regulated pilus (tcp) integrate V. cholerae genome encode A
B subunit cholerae toxin ace gene
encode accessory cholera toxin, zot gene
zonula occludens toxin cep gene
chemotaxis proteins genes
copies V. cholerae O1 V. cholerae O13917
V. cholerae
mucosa toxin coregulated pili chemotaxis proteins
cholera toxin heat

labile toxin E. coli A subunit
1 B subunit 5 17,18 B subunit
GM1 ganglioside receptor
A subunit 2 component A1 A2 linked
disulfide bond A2 component A1
component B subunit, A1 component active
enzyme persistent
activation adenyl cyclase17,19 cyclic
AMP crypt cell

villi

( 2)
cholerae toxin V.
2 ( Butterton, JR, Calderwood,

SB. Vibrio cholerae O1. In : Infections of the Gastrointestinal Tract,
Blaser, MJ, Smith, PD,Ravdin, Ll, et al (Eds), Raven Press, New York, 1995, p. 649.)
346
cholerae O1
zonula occludens toxin tight junction
permeability
accessory cholerae enterotoxin
17
5
1-3

3,4

rotavirus, adenovirus, enterotoxigenic E. coli,
campylobacter

109

20
H. pylori21

O A, B AB22
GM1 ganglioside receptor O
cholerae toxin

IgA anticholerae toxin 23
V. cholerae El Tor biotype
1 20-100
classical biotype 1
2-4

wet mount darkfield phase contrast microscopy
(darting shooting star)
antiserum V. cholerae O1 O139
V. chelorae O1
V. chelorae O139 24

Cary-Blair
transport media
7 25 plate Thiosulfate Citrate
Bile Salt (TCBS) media Tellurite Taurocholate
Gelatin Agar (TIGA)
enteric bacteria 25 V. cholerae
sucrose TCBS colony
TIGA V. cholerae
collagenase colony
cloudy halo20 subculture V. cholerae serotyping specific antisera
cholerae O1 O139
PCR, ELISA Latex agglutination
assay
vibriocidal antibody
29 347
7 Na 75, Cl 65, K 20, HCO3 10 glucose 75 ./

1-5 7-21 osmolarity 250 /26
4 27
rehydration ORS
4

1
2 rehydration
phase 2-4 maintenance phase
Ringers
lactate solution
normal saline tetracycline 30-50 ././ 3 doxycy
20-40 ./. cline 5 ./. norfloxacin 10-20 ././
3 ciprofloxacin 20 ./.
4 azithromycin 20 ./. erythromycin
rehydration phase 30 ././3,4 3
0.5 ./ 29
./. maintenance phase

normal hydration ongoing loss 6
ORS .. 2553 V. cholerae El Tor
5%
5-10%
10%
Capillary refill
1-5
3
( Greenbaun M. Nelson textbook of Pediatrics 18th ed. 2007 313)
348
Ogawa Inaba ampicillin, chloram 3
phenicol norfloxacin ciproflxacin
cotrimoxazole Inaba 32
tetracycline Ogawa
2-3
classical 30
31
Oral vaccine

2

1.
1.1 DukoralTM (WC- rBS) monovalent
oral vaccine V. cholerae O1

recombinant cholera toxin
B subunit 150 .
6 2
7 6
2 2-5 3
100
6 33 34
66-86 4-6
Parenteral vaccine
killed whole cell adjuvant 45-62 1 58-77 2
purified lipopolysaccharide herd protection B subunit
polysaccharide-cholera toxin conjugate vaccine ETEC 60
35
1.2 Shanchol TM mORCVAXTM
V. cholerae O1 (Inaba, Ogawa, Classical
El Tor) 10 9 31 bivalent oral vaccine serogroup O1 O139
50 3-6
V. cholerae O139 2 B subunit
7-28 ETEC
1 2 7
4 6 6 booster 6
(yellow fever vac- 5
cine) DukoralTM, SchancholTM
29 349

WHO oral
mORCVAXTM vaccine 2 WHO
CDC
33

8,39
2.

JBK 70 (V. cholerae O1, El Tor, 31
Inaba & CtxAB), EVD 101 (V. cholerae O1 classical
Ogawa & CtxA), O395-N1 (V. cholerae classical
O395 & CtxA) O395-NT (V. cholerae classical 8,39
O395 & CtxA) V. cholerae
O1

31
1. Brody H, Rip MR, Vinten-Johansen P,
CVD111 (V. cholerae
O1 El Tor), CVD112 (V. cholerae O139), Peru-15 Paneth N, Rachman S. Map-making and myth-making
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O139)31 35 CVD103 Lancet. 2000;356:64-8.
mercury
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1 vibrio
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94-100 classical biotype 82-100
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6 36 Textbook of Pediatrics 18th ed. Philadelphia, Saunders;
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37 25 38 16
5. Cholera Working Group, International
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Large epidemic of cholera-like disease in Bangladesh
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350
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.
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Mar_2010.pdf
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INFECTIONS In: Pickering LK, Baker CJ, Kimberlin
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p. 727-9.
76
30 353
30
89,246
140.64 4
0.004 5
1-3
5-9 578.95
5
10-14 15
487.13, 338.45 58.81

10

Varicellazoster (VZV)

(congenital varicella
syndrome) VZV
10-21 ( 14-16 )4
dorsal root ganglia varicella zoster immune globulin (VZIG)
21 28
48

5,6

VZV - her- 7
pesviruses family Herpesviridae
VZV
double-stranded DNA envelope
glycoprotein spikes
1,2 150-200

(epidermis)
.. 25523 multinucleated
354
giant cells eosinophilic intranuclear inclusion

(cornified)
(basal)
(vesicles)

polymorphonuclear

8 - 20

(cicatricial skin lesion)
(dermatome)
chorioretinitis horner (microphthal VZV mos) nystagmus

hypoplasia
cortical atrophy
24
(macules) (papules)
(vesicles)
(pustules)

42
Streptococcus pyogenes Staphylococcus aureus

4
0.6 2.2
10 S. pyogenes
hemorrhagic 11-15
vesicles
910,16
VZV
(Neonatal varicella) 17,18 acute cerebellar ataxia
25 1 4,000
VZV 15 19 acute cerebellar
ataxia
16,20
8 21,22

VZV 10 (vasculitis)
28 Reye salicylate
30 355
Reye

23,24

16,25,26
1-6 26,27

28-31

1,32
Tzanck
smear
immunofluorescent
enzyme linked immunosorbent
assay (ELISA), complement fixation test, indirect
fluorescent antibody latext agglutination

antihistamine
acyclovir
12

12
salicylate acyclovir 80 ././ ( 3,200 ./)
4 5

acyclovir
1,500 ./2/ 8
30 ././ 8 7-10

VZIG

VZIG
VZV33,34
5
2
>28

<28
<1,000

VZIG 96
96
125 / 10 . 125
625 VZIG
(Intravenous
356
OKAVAX
Varilrix
Varicella Vaccine-GCC
sanofi pasteur
GlaxoSmithKline
Green Cross/
Biogenetech
Immune Globulin, IVIG)

acyclovir33

(IVIG 400
./.)
VZIG 3
IVIG
(Varicella vaccine)
.. 1974
Oka
Oka
35
Oka
36-40

.. 1987
.. 1989

MAV/06 41

42,43
OKA
OKA
MAV/06
> 1,000 PFU

> 2,000 PFU
> 1,400 PFU

(lyophilized)
3
1. Varilrix 1 2,000 pfu
2. OKAVAX 1 1,000 pfu
3. Varicella Vaccine-GCC 1
1,400 PFU
1

-
-- (MMRV)
44
2- 8o .
(subcutaneous)
0.5 . 1

1-12 1-2
12-18 2
4-6 2
4 3
13 2
4
30 357
1-12
1
( VZV > 0.3 gpELISA units)
97 13
1 72-94
94-99 45,46
> 5 gpELISA units

1-12 1
> 5 gpELISA units 85.7
99.6 2 47

11
20 48,49

70-90
9537,40,50

booster effect
Breakthrough disease
42 10
10 1-12
7.3 2.2
1 2 (p<0.001)
2-5 47

breakthrough disease

..1995-200451
8-12
1 5
5 [relative risk 2.6,
95% confidence interval (CI), 1.2-5.8]
meta-analysis
14
.. 1995-2006
1
72.5 breakthrough
disease
1 52
.. 2009

97
39 2 53
84
25
2 53
1
2 10.4
1 14.6
(RR: 0.72, 95% CI: 0.44-1.15)
2 80
1
50
358

5 35 20 Post-exposure prophylaxis

3- 5 3
3- 5 5

2-5
maculopapular VZIG
5-26 96 VZIG IVIG
2 acyclovir 7-10 7

(wild type- VZV) 54 VZIG
37.8 o. acyclovir
10 ataxia,
erythema multiforme, Stevens-Johnson syndrome, 8-21 VZIG
28

55

56
2- 3
Pre-exposure prophylaxis

55
1

30 359
2
99
57
1
2 3-5
4
10-21

10-21

3-5

5

4-5

57

21

56
1.

3
CD4+T-cells 15
58
2.
2 ././ 20 ./
2
1
3.

--

2
4.
1

5. gelatin neomycin anaphylaxis
360

1

4059

100

The Advisory Committee on Immunization
Practice
12 -12
13
.. 2006 The Advisory
Committee on Immunization Practice
12 - 12
2 60
12-15 2
4-6 (
MMRV)
1-12
1 2 12-18
2 4-6
2 4
3 13
2 4 61
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; 2554. .115-28.
31 365
(Human
Papillomavirus - HPV)

recurrent respiratory papillomatosis

(anogenital cancer)

(oropharynx) 1,2
2

500,000 50
250,000

9,999 5,216
.. 2551 24.5
100,000 3 8.6

73.8
16 184

(oncogenic HPV genotype)
31
2

(virus-like particles- VLPs)

11-12
26 high grade
dysplasia ( 16
18)

(type specific)

(oncogenic type)
70-75
16 18
16 18 5
DNA family
Papillomaviridae6 DNA
8,000 2 L1 L2
2 early protein
366
6 E1, E2, E4-8
DNA
2 upstream
regulatory region (URR) 1,000

1
(basal
cell layer)
E1 E2 DNA

(suprabasal) DNA

E6 E7 p53
pRB tumor suppressor
(immortalized)
7 E6 E7 high risk
() low risk ( )
100 40

(genital HPV) alpha genus
(cutaneous verruciformis) beta genus
low risk
6 11
90

high risk 15
16, 18, 31, 33, 35, 45, 52, 56, 58, 59,
61 squmous
intraepithelial lesion (SIL) (low grade , LSIL)
(high grade, HSIL) cervi-
cal intraepithelial neoplasia (CIN) I, II III

16 18
70 8
(disease burden)
(oncogenic human papilloma virus)
16 18
70 squamous cell carcinoma9
80 adenocarcinoma
Pap
16 18
50 high-grade precancerous lesion (cervical intraepithelial neoplasia 2/3 [CIN2/3])
25 low grade CIN (CIN1) 45,
33 31
3, 4 5 10
16

high risk HPV 10
16
(anogenital cancer)
vulva, vagina anus 40, 80
90 11,12

80 50 13

(16)

(oropharyngeal cancer) 14
16 42-74
18 7-2015-17
31 367
50-80 18

19,20
humoral cell
mediated humoral
50 60
( HPV DNA)
21

(persistent infection)
(high-grade cervical dysplasia)

cell-mediated
latent infection basal epithelial

cell

cell mediated
immunity
neoplasia VAIN2/3, vulvar intraepithelial neoplasia

VIN2/3)22 CIN1

CIN2 CIN3
CIN1
CIN2 low grade high grade

(persistent
infection)

high-grade precancerous
(adequate ablation
treatment)
23
Odds ratio
100
(281.9 16 222.5
18)24

Odds ratio 10

high-grade CIN
(invasive cervical cancer- ICC)
( Chlamydia tracho2 6 matis, anogenital herpes simplex)
16
high grade intraepithelial neoplasia
(CIN2/3, vaginal intraepithelial
368
(low risk HPV)

(low-risk HPV)
6 11 90
(condyloma accuminata)
low-grade cervical lesion recurrent respiratory laryngeal papillomatosis
(pediatric onset)
(adult onset)
25
1 (first-generation prophylactic HPV vaccine)

late protein L1
(capsid)
baculovirus
(viral-like particles-VLPs)
5
2
3 6 2
( 1)
1. 4 (Quadrivalent HPV
vaccine- GardasilTM Merck) VLPs
16 18 VLPs
6 11
amorphous aluminum hydroxyphosphate sulfate
(AAHS) 225
2. 2 (Bivalent HPV vaccine- CervarixTM GlaxoSmithKline) VLPs
1 ()
(VLPs)
quadrivalent (GardasilTM)
Merck & Co, Inc.
0, 2 6
0.5 .
40 . HPV-16
20 . HPV-18
20 . HPV-6
40 . HPV-11
Amorphus aluminum hydroxyphosphate sulfate
225 .
Saccharomyces cerevisiae (bread yeast),
expressing L1
2-8o.
( 5, 46)
bivalent (CervarixTM)
GlaxoSmithKline
0, 1 6
0.5 .
20 . HPV-16
20 . HPV-18
Aluminum hydroxide 500 . +
50 . ASO4 (Al(OH)3+ MPL)
Trichoplusia ni in insect cell line infected
with L1 encoding recombinant baculovirus
2-8o.
31 369
16 18
intention- to- treat
aluminum hydroxide
500 3-deacylated monophosphoryl lipid bivalent 92
A (ASO4) 50
16/18 12
3
CIN2
I II
quadrivalent
quadrivalent bivalent 6,11,16, 18

2 serocon- 6,11,16,18
version 99 7 8
26,27 100 (external genital lesion)
36
16 18 7 24-45
1 3 90.5 [95%CI 73,97]
50 100 6,11,16,18
III 83 [95%CI 50,95] 16,18
quadrivalent bivalent 37
quadrivalent

2 100 CIN2+, adenocarcinoma in situ (AIS),
VIN2/3, VAIN2/3 16, 18
3.6 34,36
99-100 29

2 100
high-grade dysplasia 16 18 ( 2)
quadrivalent bivalent
(per-protocol population)
28-35 Pap
intention to treat

A7 A9
2 31 42.6 [95%
CI 15.3,66.4] (CIN1-3, AIS)

370
31 56.9 [95%CI 28,74]38
bivalent 92.5
[96%CI 79.9,98.3] CIN2+
16,18
98.1 [96%CI 88.4,100]
32 bivalent
31
(6-12 ) 78.7
[96.1%CI 70.2, 85.2] 70.4 [96.1%CI 66.1, 88.1]
6 12
2 bivalent humanpapillomavirus vaccine (HPV2)

quadrivalent papillomavirus vaccine (HPV4)
Vaccine/Endpoint/HPV type
Bivalent vaccine (HPV2)
CIN2/3 or AIS32
HPV 16 and /or 18
HPV 16
HPV 18
Quadrivalent vaccine (HPV4)
CIN2/3 or AIS**
HPV 6,11,16,18
HPV 16
HPV 18
VIN 2/3 or Vain2/3**
HPV 6,11,16,18
HPV 16
HPV 18
Genital warts
HPV 6 and/or 11
Vaccine
No.
Cases
Control
No.
Cases
Vaccine efficacy
%
(CI*)
(96.1%CI)
7,344
6,303
6,794
4
2
4
7,312
6,165
6,746
56
46
15
92.9
95.7
86.7
(79.9-98.3)
(82.9-99.6)
(39.7-98.7)
95%CI)
7,864
6,647
7,382
2
2
0
7,865
6,455
7,316
110
81
29
98.2
97.6
100.0
(93.3-99.8)
(91.1-99.7)
(86.6-100)
7,900
6,654
7,414
0
0
0
7,902
6,647
7,343
23
17
2
100.0
100.0
100.0
(92.6-100.0)
(76.5-100.0)
(<0-100)
6,932
6,858
189
99.0
(96.2-99.9)
*Confidence interval
Phase III trial. According to protocol efficacy analysis including females aged 15-25 years who received all 3 vaccine doses,
were seronegative at day 1- month 6 for respective HPV type, normal or low grade cytology at day 1, with case counting
beginning day 1 after 3rd vaccine dose; mean duration of follow up post first vaccine dose: 34.9 months
Combined analysis of one phase II trial and two phase III trials. Per protocol efficacy analysis included females aged 16
-26 years who received all 3 vaccine doses, were seronegative at day 1 and HPV DNA negative at day 1 through month 7
for respective HPV type, with case counting beginning 1 month after third vaccine dose; mean duration of follow-up post first
vaccine dose:42 months.
** Source: Kjaer SK, Sigurdsson K, Iversen OE, et al. A pooled analysis of continued prophylaxis efficacy of quadrivalent
human papillomavirus (type 6/11/16/18) vaccine against high-grade cervical and external genitalial lesions. Cancer Prev Res
2009;868-78.
Source: FDA. Product approval-prescribing information [package insert]. Gardasil [human papillomavirus (Type 6/11/16/18)
vaccine recombinant], Merck & Co, Inc: Food and Drug Administration 2009. Available from: http://www.fda.gov/biolocsbloodvaccine/aprovedproduct/ucm09042.htm. Accesssed May 25,2010.
( 46)
31 371
45 75.7 [96.1%CI 60.4,85.7] 40

63 [96.1%CI 18.4,84.7] 6 12
immune memory
41
16,18
5

1 quadrivalent
3

4,065
6 16-26 5 18
27,39
randomized placebo controlled, double
blinded external genital
lesion 6, 11, 16, 18

quadrivalent 3
external genital lesion
90.4 2.8
5
condyloma accuminata
89.4
quadrivalent 42
III

2
2
quadrivalent 120
48 18
40
CIN2/3
18

98.4 [95%CI 90,100]34

monovalent 16 43
8.5
.. 2006
(US FDA)
372
quadrivalent Advisory committee on Immunization Practice (ACIP)
11-12 13-26

9
HPV 6,11,16,18 (

)44
.. 2009 ACIP quadrivalent
9-26
45
.. 2009
ACIP
bivalent 10-26
46

11-12

quadrivavalent
9-18
47
1

quadrivalent 20

bivalent

45,988 ASO4
48 III 2

1 10,000

IV

quadrivalent 23

49
quadrivalent bivalent
0.5 .
3
2 1 ( bivalent) 2
( quadrivalent) 3
6
2
4 2 3
24

2
16 18
6 11
quadrivalent 3
47
31 373
( )

15
(immediate hypersensitivity)
quadrivalent
bivalent
latex
latex
(single dose vial) latex47
Pap
HPV DNA

47
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32

Bacillus anthracis
B. anthracis
..1876 ..1881
B. anthracis .. 2535-2543 0.02-0.17
102 .. 2538
1 7 .. 2537
.. 25444

..2544 ..2551

24 10

2,3
12 - 7
60
B anthracis

sheep blood agar

edema
toxin lethal toxin

378

3 protective antigen, lethal factor, edema
factor

3
1. (cutaneous anthrax)

2. (gastrointestinal anthrax)

3. (inhalation anthrax)

3-5

inhalation anthrax
oropharyngeal
anthrax anthrax meningitis septicemia
20
5,6

penicillin G tetracycline 7-10

systemic ciprofloxacin doxycycline

ciprofloxacin doxycycline
rifampin, penicillin, ampicillin, vancomycin, imipenem,
chloramphenicol, clindamycin clarithromycin
cephalosporins trimethroprimsulfamethoxazole 7-11
.. 2447
B. anthracis
.. 2497
(alum) adjuvant
.. 2500-2503

32 379
(pre-exposure
prophylaxis)
AVA
0.5 . 5 0, 4 6,
12 18 13 1
0.5 . 4 0, 3, 6
Anthrax vaccine adsorbed (AVA) 6 3 1

BioThraxTM

V770-NP1-R (toxigenic 2 0 3 1
non encapsulated)
0.83 ./ 0.5 . adjuvant 2 0 6-12

PA, lethal factor (LF) edema factor (EF)13

.. 2522
(post-exposure
14,15
Center for Applied Microbiological Research prophylaxis)
AVA 10
Sterne 34F2 adjuvant 0.5 .
LF EF thimerosal preservative
3 0, 2 4 13
60
STI-1
Sterne
AVA 2
suspension
.. 249616-18
95-10020

.. 2500 Lanzhou Institute of Biological

Product 1-2 2 12
A16R
AVA
21
AVA
1,563
6 AVA
3-4
AVA 2-8o .12,19 6
protective antigen (PA)

anthrax vaccine adsorbed (AVA)
.. 2508

.. 251312
380
AVA
.. 2505

92.5

18
65 22

23

24,25

1-2
(Post-exposure prophylaxis)

3 0, 2 4
3

1.
2. 1
anaphylaxis
3.
4.


12
1.
B. anthracis
2 .
-
-
3 .

alum precipitation
90

.. 1999
B. anthracis
32 381

AVA
LF EF adjuvant
19,26,27

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4. . .
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382
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101:13601-6.
383
33
typeable)6 6

(Haemo- -
philus influenzae type b, Hib)
2

6-18
1,2
.. 2543
90
8.13
371,000 7

.. 2543-2544
35-44 3.8
5 100,000 8
3-5
90
.. 2530
5 41
100,000
(coccobacilli) 5 .. 2550
chocolate agar 0.11 100,000 1,2
(non- 7,9
384

hypogammaglobulinemia
10-16

17-22

11,12,23
cerebral
palsy 28,29
330
20-6031

75-9032

nonciliated columnar

epithelium

pleomorphic
coccobacilli

latex

particle agglutination countercurrent immuno electrophoresis
24

beta
25,26 - lactam ( amoxicillin 2nd 3rd generation
cephalosporins)

(Odds ratio 2.2; 95% CI: fluoroquinolones, macrolides, tetracyclines
1.2-3.9)27
aminoglycosides
33 385

.. 1985
18

18
B cell T-lymphocytes memory T
cell
18-71
9033,34
7-9535-37

T- dependent
38
polyribosylribitol phosphate
(PRP)
(outer membrane protein) Neisseria meningitidis

3
1. Polyribosylribitol Phosphate Chemically
conjugated to Tetanus Toxoid (PRP-T)
HiberixTM ActHIBTM
2. Polyribosylribitol Phosphate conjugated to
an outer-membrane protein complex of N. meningitidis (PRP-OMP) outer membrane protein
N.meningitidis Pedvax HibTM
3. Haemophilus b oligosaccharide conjugate

vaccine (HbOC)
Cross reactive material 197 (CRM197)

non-toxic mutant
VaxemHibTM

--
39 1
2-8o .
24 .
0.5 .
2
6

3 ( PRP-OMP 2 )
40-42
2

(congenital or acquired immunodeficiency)
1 18
2

2 2 4-8
1
7-10 43-49

PRP-T PRP-OMP
PRP-T50

386
1 Hib
Hiberix
Act-HIB
VaxemHib
GlaxoSmithKline
sanofi pasteur
Novartis/ Biogenetech
Carrier
Tetanus toxoid
Tetanus toxoid
Non toxic mutant of
Diphtheria toxin (CRM-197)
Infanrix-IPV/Hib
GlaxoSmithKline
Tetanus toxoid
DTaP, IPV
Infanrix-Hexa
GlaxoSmithKline
Tetanus toxoid
DTaP, HBV,IPV
TETRActHib
sanofi pasteur
Tetanus toxoid
DTwP
Pediacel
sanofi pasteur
Tetanus toxoid
DTaP, IPV
Pentaxim
sanofi pasteur
Tetanus toxoid
DTaP, IPV
Quinvaxem
Novartis/ Biogenetech
(CRM-197)
DTwP, HBV
DTwP= Diphtheria and Tetanus toxoids, and whole cell Pertussis; DTaP = diphtheria and tetanus toxoids and acellular
pertussis; HepB = hepatitis B; Hib = Haemophilus influenzae type b; IPV = inactivated poliovirus
( 39)
2 Hib
()
2-6
7-11
12-24
24
*
PRP-T, HbOC
0, 2, 4,
12-18
0, 2
0, 2
PRP-OMP
0, 2,
12-18
0, 2
0, 2
* (congenital or acquired immunodeficiency) 1 18

2 2
2 2 1 7-10
1 3
( 39)
PRP-T
DPT

2 6
2

1 43,46,51
33 387

PRP-OMP 2
70-80
0.1 ./. 90
2 4
0.1 ./.52-54
PRP-T
HbOC PRPOMP 3
PRP-OMP
3 PRP-T

55,56
3 ( PRP-OMP 2 )
40-42 PRP-T

PRP-OMP
outer membrane protein N.meningitidis57
9558-61
6462

99
herd immunity2
DTP
43,63
1.

2.

(congenital or acquired immunodeficiency)
3. 2

25

25
56

388


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type b conjugate vaccine. J Pediatr. 1993;122:517-23.
63. .
. : , ,
, . Update
on Pediatric Infectious Diseases 2008.
; 2551. .123-5.
393
34

DTwP Hib
PRP-T Haemophilus b oligosaccharide conjugate
vaccine (HbOC) 2-5
-- (DTaP)
Hib PRP-T Hib
6
(HepB) DTaP
(IPV)
HepB
7 HepA
1
HepB
8

polyribosylribitol phos
phate-tetanus toxoid (PRP-T)
-- (DTwP) - Act-HIBTM DTwP - (MMRV)
(D.TCOQTM) HiberixTM -
DTwP - (MMR) 9
--
DTwP-HBV (TritanrixTM-HB)
394
DTaP

() 3

( 18 4-6 )
10 Hib, IPV, HepB

DTwP+HepB 3 1
2, 4 6 HepB 1

(DTwP)
DTwP- HepB
DTwP- HepB
DTP-HB
Tritanrix-HB
SII/Masu
GlaxoSmithKline
DTwP-Hib (PRP-T)
DTwP- HepB -Hib (CRM197)
DTaP-IPV
DTaP-IPV
Tdap-IPV
Tdap-IPV
DTaP-IPV-Hib (PRP-T)
DTaP-IPV-Hib-HBV (PRP-T)
HepB-HepA
MMRV
TETRAct-HIB
Quinvaxem
Infanrix-IPV
Tetraxim
Adacel Polio
Boostrix Polio
Pediacel
Pentaxim
Infanrix-IPV/Hib
Infanrix-Hexa
Twinrix
-
sanofi-pasteur
Biogenetech
GlaxoSmithKline
sanofi-pasteur
sanofi-pasteur
GlaxoSmithKline
sanofi-pasteur
sanofi-pasteur
GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline
Hiberix
: CRM197= Non toxic mutant of Diphtheria toxin; DTwP= Diphtheria and Tetanus toxoids, and whole cell Pertussis;
DTaP = Diphtheria and Tetanus toxoids and acellular pertussis; HepA = hepatitis A; HepB = hepatitis B; Hib = Haemophilus
influenzae type b; IPV = inactivated poliovirus; MMRV = measles, mumps, rubella, and varicella; PRP-T = polyribosylribitol
phosphate-tetanus toxoid conjugate; Tdap = tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis.
( 1)
34 395

DTwP
2-5,11,12 DTwP
DTwP-HBV
DTwPHib (PRP-T)
DTwP-HepB-Hib (CRM197)
1

23 primary series

Hib
Hib PRP-T
HbOC
Hib Hib
24-26

DTaP/IPV/ Hib
2, 4, 6 27
6 (DTaP/IPV/HepB/Hib)
28-34
6
(DTaP, Tdap)
DTaP
6
HepB
IPV, HepB Hib
HexavacTM Infanrix hexaTM
IPV DTaP, DTaP/ Hib Tdap HepB Infanrix
hexaTM HexavacTM35
13-16 HexavacTM
DTaP DTaP/IPV 6
DTaP/ IPV/ Hib 36
HepB DTaP DTaP/IPV

DTaP IPV (HepA/
HepB HepB)
HepB 7
Twinrix
HepB 0, 1 TM
6 2, 4 720 EU
6 3, 4 5
20
Hib DTaP DTaP/IPV
6,17-22 DTaP/
HepA/HepB
Hib DTaP/IPV/ Hib () HepA HepB
396
0, 1 6
100
HepA/HepB
37-40
HepA/HepB
HepA HepB
0, 7 21
99
(
GMT 854 mIU/ml
512 mIU/ml) 82
HepA/HepB
84
( GMT 65
mIU/ml 98 mIU/ml)
HepA/HepB
HepA/
41
HepB 87 72
100
89
81 60
100
95
41
10 94
86
3 0, 1
6 2 0, 6
0,12 42-46 2 3
(Hep A) Salmonella typhi capsular poly

saccharide Vi (Vi)
Vi Hep A
2 HepatyrixTM
Viatim

HepatyrixTM GMT
seroconversion
94
9747
ViatimTM

seroconversion 14
86.4
95.6 seroconversion 14
88.2
94.2 (
HepatyrixTM seroconversion )48 3

99

32 36

-- (MMR)

---
(MMRV)
34 397

(MMRV)
Priorix TetraTM
ProQuadTM
49,50
MMRV 12-23
5-12
MMR
MMRV 4-6
MMR
15-26
MMRV
MMR 51
MMRV
MMR

MMRV

MMRV
(ACIP)
--
12-15 4-6
52 12-47
MMRV MMR
MMRV

MMRV
MMRV
CDC

MMRV
15 - 12
> 48 CDC
MMRV
MMRV

MMR

C (MnC) (MnC/Hib)
Menitorix TM
53-54
DTaP3/IPV DTaP3/IPV/HepB (DTaP3;
3 )
2, 3 4 2, 4 6

C
(MnC)+ Pediacel TM MnC+ Infantrix hexa TM

7

(DTaP/HepB/IPV + Hib/ MnC)
7

(DTwP/HepB/IPV/Hib-MnAC)55

398
PnC/Hib, PnC/MnC PnC/MnC/Hib

2 (DTaP2/HepB/Hib, DTaP2/
HepB/IPV/Hib)
5 (DTaP5/HepB/IPV/Hib)
1. , ,
, ,
, . 2010-2011.
2553.
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407
35
50100
10,000
RNA family Flaviviridae 4
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DHF)

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T B cells chemokines
T cell
autoantibody
vasculopathy
autoantibody
Lei HY

cytokines
monocytes, endothelial cell 13,5,8

aspartate aminotransferase (AST)
alanine aminotransferase (ALT)
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time (PT) 9
alkaline phosphatase (AP)

AST/ALT
PTT
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35 409
11
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maculopapular
2. DF

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24-48
12
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39-41
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7

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3
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410
convalescent rash

(
)
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1-3
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infection)

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11-13

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35 411

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100,000/..
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)

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transaminase (ALT)

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PCR

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412

24-48

Normal saline, Ringers lactate,
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35 413

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Dengue infection: A new classification

New classification
Dengue infection
15
414

.. 2472

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(immunopathogenesis)
(enhancing antibody)
(immune complex)
T cell cytokines
enhancing antibody

enhancing
antibody

caused by arbovirus-dengue haemorrhagic fever and

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421
36
Coronavirus 3
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Inactivated virus
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DNA vaccine
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+
+
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+ ( phase I)
426
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58 ferret59
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vectors DNA vaccine immunogenicity
platform
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63
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plasmid DNA encoding
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neutralizing antibody
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small pox
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36 427
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technology clinical trials
immunogenicity
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2007;12:1107-13.
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IJ, Enama ME, Larkin BD, et al. VRC 301 Study Team.
A SARS DNA vaccine induces neutralizing antibody
and cellular immune responses in healthy adults in a
Phase I clinical trial. Vaccine. 2008;26:6338-43.
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ZH, Zhong NS, et al. Intranasal immunization with inactivated SARS-CoV (SARS-associated coronavirus)
induced local and serum antibodies in mice. Vaccine.
2005;23:924-31.
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Xiong S, Zhang MY, et al. Immune responses in
Balb/c mice induced by a candidate SARS-CoV inactivated vaccine prepared from F69 strain. Vaccine.
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58. See RH, Zakhartchouk AN, Petric M,
Lawrence DJ, Mok CP, Hogan RJ, et al. Comparative
evaluation of two severe acute respiratory syndrome
(SARS) vaccine candidates in mice challenged with
SARS coronavirus. J Gen Virol. 2006;87(Pt 3):641-50.
59. See RH, Petric M, Lawrence DJ, Mok
CP, Rowe T, Zitzow LA, et al. Severe acute respiratory syndrome vaccine efficacy in ferrets: whole killed
virus and adenovirus-vectored vaccines. J Gen Virol
2008;89(Pt 9):2136-46.
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Yang Z, Xiao SY, et al. Immunogenicity, safety, and
protective efficacy of an inactivated SARS-associated
coronavirus vaccine in rhesus monkeys. Vaccine.
2005;23:3202-9.
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JB, Gauldie J, Babiuk LA. Severe acute respiratory
syndrome coronavirus nucleocapsid protein expressed
by an adenovirus vector is phosphorylated and immunogenic in mice. J Gen Virol. 2005;86(Pt 1):211-5.
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where are we? Expert Rev Vaccines. 2009;8:887-98.
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UR, Chang YF. Immune responses with DNA vaccines
encoded different gene fragments of severe acute
respiratory syndrome coronavirus in BALB/c mice.
Biochem Biophys Res Commun. 2005;327:130-5.
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Murphy BR, Subbarao K, et al. A DNA vaccine induces
SARS coronavirus neutralization and protective immunity in mice. Nature. 2004;428:561-4.
36 431
66. Zakhartchouk AN, Liu Q, Petric M, Babiuk

LA. Augmentation of immune responses to SARS
coronavirus by a combination of DNA and whole killed
virus vaccines. Vaccine. 2005 ;23:4385-91.
67. Lamirande EW, DeDiego ML, Roberts A,
Jackson JP, Alvarez E, Sheahan T, et al. A live attenuated severe acute respiratory syndrome coronavirus is immunogenic and efficacious in golden Syrian
hamsters. J Virol. 2008;82:7721-4.
433
(Cytomegalovirus; CMV)
-herpesvirus human
herpesvirus 6A (HHV-6A), HHV-6B, HHV-7 CMV
double stranded DNA virus
200-300
DNA (linear, double-stranded DNA)
(capsid) 20
162 capsomeres CMV

T lymphocyte

CMV
(congenital CMV infection)

1
mononucleosis2

CMV

CMV

CMV

CMV
37
CMV
CMV
:
CMV

CMV

1,250
1,3,4
CMV
CMV
47 .. 1981
71.8 .. 1998

20-25
3
CMV
4
CMV

CMV
(host defense mechanism)
434
CMV

(persistent latent infection)
CMV (attachment)
(envelop)
glycoprotein gB gH
neutralizing
antibody viral genome
transcription
CMV
(immediate early) proteins
(delayed early)
proteins DNA
(late phase phase)
DNA
nonenveloped particles
owls eye intranuclear
inclusion 1 CMV

viral shedding
4-6 shedding
CMV
(primary infection)
CMV (seronegative)
(secondary infection)
CMV
CMV CMV

5

(persistent viremia)
CMV

(reactivation) (reinfection)
1
(cell mediated immune response)
CMV
CMV-specific cytotoxic T lymphocyte
CMV6 CD4
100 /..
CMV 7
CMV
CMV

CMV
CMV
microcephaly, intracranial
calcification
cytomegalic cell

CMV

neuronal migration
neuronal stem cell

CMV
Temporal cochlear,
vestibular, auditory canal (Mondini dysplasia)
CMV

CMV
37 435
CMV

intrauterine growth retardation

optic atrophy intracranial
calcification
ALT 100,000/..
direct bilirubin
CMV
CMV

CMV
CMV 3-4 8

CMV

2
1
(mononucleosis syndrome)
CMV
2
Epstien-
Barr Virus (EBV)

tonsillar patch
CMV
EBV1
lymphocyte atypical
lymphocyte
hepatic transaminase 300 IU/L
heterophile
antibody

CMV
( 49
94 )
1

4

CMV

CMV

retinal necrosis

CMV

intranuclear inclusion CMV
CMV
436

plaque-like pseudomembranes

CMV

mononuclear cells infiltration, scattered
microscopic granuloma giant cells

CMV
CMV

interstitial pneumonitis
intracellular
inclusion body

CMV

pyramidal tract

DNA CMV
CMV
CMV (R+ D+)
CMV /
CMV
CD4
50 /.. CMV

CMV
85
CMV

DNA CMV
9
CMV
CMV
50100

viral shedding
CMV 4-12

CMV

pancytopenia

CMV

Pneumocystis jirovecii, Aspergillus spp.
CMV

CMV

37 437
IgM IgG
enzyme immunoassay
CMV

CMV IgG

CMV IgM IgG
antibody avidity testing
CMV

3

2
CMV
(typical cytopathic change)
DNA CMV

CMV
PCR
3

CMV

CMV viral
shedding
DNA CMV
CMV CMV
CMV
CMV
CMV
CMV
IgG

CMV
CMV

PCR DNA
CMV antigenemia assay
pp65 CMV
monoclonal antibody
nucleic acid sequence-based
amplification (NASBA) real-time PCR
CMV
CMV
CMV
CMV
ganciclovir 12 ././
CMV
6
gangciclovir
68 ( 21)
1 10

ganciclovir

ganciclovir
CMV
438

gangciclovir

gangciclovir
CMV
1 valgangciclovir

CMV
CMV
-
CMV
CD4 50 /.. ganciclovir
CMV
CMV
ganciclovir
CD4
6
CMV
ganciclovir 7.5-15 ././
14-21
maintenance
5-6 ././ 5-7
5
ganciclovir implant ganciclovir
cidofovir
foscarnet
CMV
ganciclovir 6 ./.
12 6
CMV

CMV
DNA CMV
CMV (preemptive therapy)
ganciclovir CMV
100 11
CMV
(early onset)
( late onset)
CMV ganciclovir 5 ./.
12

2
ganciclovir 5
ganciclovir valganciclovir
CMV
CMV

CMV (D+/R-)
CMV (R+)

CMV

CMV

CMV
CMV immunoglobulin randomized,
placebo-controlled clinical trials CMV
immunoglobulin (CMV IGIV)
37 439
CMV
1 CMV IGIV
CMV
CMV
CMV IGIV

CMV 12
CMV
CMV

CMV

CMV

CMV

CMV
CMV
CMV
1. Live attenuated virus vaccine

CMV Towne

CMV CMV
13,14 Towne
CMV
CMV

chimeric CMV
2 Towne
Toledo
15
2. Subunit vaccine
Purified recombinant glycoprotein B ( gB)
glycoprotein B

CMV
2
gB MF59 adjuvant
CMV
16
3. DNA vaccine

DNA
gB DNA
CMV
17 1
bivalent CMV DNA
18
Towne DNA
pp65, IE1, gB
pp65 T cell gB
Towne
19 DNA
CMV
4. Vector system
vector

CMV
440
2 modified vaccinia virus Ankara
MVA20 alphavirus vector attenuated variant
Venezuelan equine encephalitis virus
humoral celluar21,22
CMV

Towne subunit

CMV
humoral
1. Pass RF. Cytomegalovirus in Long SS, Larry K Pickering LK, Prober CG, editors. Long: Principles
and Practice of Pediatric Infectious Diseases 3rd ed.
Philadelphia: Elsevier Inc;2009. p.1029-36.
2. American Academy of Pediatrics.
Cytomegalovirus infection. In: Pickering LK,
Baker CJ, Kimberlin DW, Long SS, editors. Red Book:
2009 Report of the Committee on Infectious Diseases.
Pediatrics; 2009. p. 275-80.
3. Amarapal P, Tantivanich S, Balachandra K.
Prevalence of cytomegalovirus in Thai blood donors by
monoclonal staining of blood leukocytes. Southeast Asian
J Trop Med Public Health. 2001;32:148-53.
4. Likitnukul S, Bhattarakosol P, Poovorawan
Y. Seroprevalence of cytomegalovirus infection in
children born to HIV-1 infected women. Asian Pac J

5. Clyde S, Crumpacker II, Jie LZ. Cytomegalovirus in Mandell GL, Bennett EJ, Dolin R, editors. Mandell, Douglas, and Bennetts principles and
practice of infectious diseases 7th ed. Philadelphia:
Elsevier Inc;2010. p.1071-87.
6. Boeckh M, Leisenring W, Riddell SR, Bowden
RA, Huang ML, Myerson D, et al. Cytomegalovirus
disease and mortality in recipients of allogeneic
hematopoietic stem cell transplants: importance of viral
load and T-cell immunity. Blood. 200315;101:407-14.
7. Erice A, Tierney C, Hirsch M, Caliendo AM,
Weinberg A, Kendall MA, et al. Cytomegalovirus (CMV)
and human immunodeficiency virus (HIV) burden,
CMV end-organ disease, and survival in subjects with
advanced HIV infection (AIDS Clinical Trials Group
Protocol 360). Clin Infect Dis. 2003;37:567-78.
8. Fowler KB, Stagno S, Pass RF, Britt WJ, Boll
TJ, Alford CA. The outcome of congenital cytomegalovirus
infection in relation to maternal antibody status. N Engl
J Med. 1992;326:663-7.
9. Deayton JR, Prof Sabin CA, Johnson MA,
Emery VC, Wilson P, Griffiths PD. Importance of
cytomegalovirus viraemia in risk of disease progression
and death in HIV-infected patients receiving highly active
antiretroviral therapy. Lancet. 2004 ;363:2116-21.
10. Nassetta L, Kimberlin D, Whitley R.
Treatment of congenital cytomegalovirus infection:
implications for future therapeutic strategies.
J Antimicrob Chemother. 2009;63:862-7.
11. Goodrich JM, Mori M, Gleaves CA, Du
Mond C, Cays M, Ebeling DF,et al. Early treatment
with ganciclovir to prevent cytomegalovirus disease
after allogeneic bone marrow transplantation. N Engl
37 441
J Med. 1991;325:1601-7.
12. Nigro G, Adler SP, La Torre R, Best
AM; for Congenital Cytomegalovirus Collaborating
Group. Passive immunization during pregnancy for
congenital cytomegalovirus infection. N Engl J Med.
2005;353:135062.
13. Plotkin SA, Smiley ML, Friedman HM,
Starr SE, Fleisher GR, Wlodaver C, et al. Towne-vaccine-induced prevention of cytomegalovirus disease
after renal transplants. Lancet. 1984;1:528-30.
14. Plotkin SA, Starr SE, Friedman HM,
Brayman K, Harris S, Jackson S, et al. Effect of Towne
live virus vaccine on cytomegalovirus disease after
renal transplant. Ann Intern Med. 1991;114:52531.
15. Heineman TC, Schleiss M, Bernstein DI,
Spaete RR, Yan L, Duke G, et al. A phase 1 study of 4 live,
recombinant human cytomegalovirus Towne/Toledo
chimerc vaccines. J Infect Dis. 2006;193:135060.
16. Pass RF, Zhang C, Evans A, Simpson T,
Andrews W, Huang ML, et al. Vaccine prevention of
maternal cytomegalovirus infection. N Engl J Med.
2009;360:11919.
17. Schleiss MR, Bourne N, Bernstein DI.
Preconception vaccination with a glycoprotein B (gB)
DNA vaccine protects against cytomegalovirus (CMV)
transmission in the guinea pig model of congenital CMV
infection. J Infect Dis. 2003;188:186874.
18. Wloch MK, Smith LR, Boutsaboualoy S,
Reyes L, Han C, Kehler J, et al. Safety and immunogenicity
of a bivalent cytomegalovirus DNA vaccine in healthy
adult subjects. J Infect Dis. 2008;197:163442.
19. Jacobson MA, Adler SP, Sinclair E, Black
D, Smith A, Chu A, et al. A CMV DNA vaccine primes
memory immune responses to live-attenuated CMV
(Towne strain). Vaccine. 2009;27:15408.
20. Wang Z, La Rosa C, Li Z, Ly H, Krishnan A,

Martinez J, et al. Vaccine properties of a novel marker
gene-free recombinant modified vaccinia Ankara
expressing immunodominant CMV antigens pp65
and IE1. Vaccine. 2007;25:113241.
21. Reap EA, Morris J, Dryga SA, Maughan M,
Talarico T, Esch RE, et al. Development and preclinical
evaluation of an alphavirus replicon particle vaccine for
cytomegalovirus. Vaccine. 2007;25:74419.
22. Schleiss MR, Lacayo JC, Belkaid Y, McGregor
A, Stroup G, Rayner J, et al. Preconceptual administration
of an alphavirus replicon UL83 (pp65 homolog) vaccine
induces humoral and cellular immunity and improves
pregnancy outcome in the guinea pig model of congenital
cytomegalovirus infection. J Infect Dis. 2007;
195:78998.
76
443
21

HIV
(human immunodeficiency virus)
(acquired immunodeficiency syndrome, AIDS)

(neglected
tropical diseases)

(cognitive development)

38
(disability-adjusted life
year DALY)
HIV/AIDS 84.5 DALY
46.5
DALY
43.5 DALY

1,2
7
(ascariasis)
(trichuriasis) (hookworm disease/
infection)
(lymphatic filariasis)
(onchocerciasis) (dracunculiasis)
(schistosomiasis)
3
(Chagas disease) (African
sleeping sickness) (leishmaniasis)
444
(amoebiasis)

Entamoeba
histolytica Entamoeba
dispar

(Taenia solium)
(cysticercosis)
echinococcosis
(food-borne trematode infections)
2,3
1

(mass treatment)

(re-infection)

44 4

5
1

mucocutaneous
onchocerciasis
HIV/AIDS

HIV/AIDS
3

antipoverty vaccines

(eukaryote)
reverse vaccinology
eukaryotic expression vectors
38 445
Ebers
papyrus 1600
Dubini
.. 1843
7
order Strongylida 4 superfamilies
superfamily Ancylostomatidea
subglobular buccal capsule
(cutting plate) (teeth)
genus species
(caudal bursa) 7 7
2
Necator americanus Ancylostoma duodenale
Ancylostoma ceylanicum

Ancylostoma braziliense
Ancylostoma caninum

creeping eruption
(definitive host)8
(prevalence)
(intensity of infection worm
burden)
1

9,10

Necator americanus
Ancylostoma duodenale
(sub-Saharan Africa)
446


8
Necator americanus
Necator americanus

filariform larva

8

65,000

22 DALY
576 11,12

13,14

( 1)
1. Ancylostoma duodenale
8-11 . 0.4-0.5 .
10-13 . 0.6 .

buccal capsule
ventral chitin
2
1
accessory teeth dorsal
dental plate

species

bursa dorsal ray
3 tripartite
Ancylostoma duodenale spicule 2
7,8
Ancylostoma
caninum 10 . 0.4
. 14 . 0.6 .
buccal capsule 3 ventral
species bursa
(slender ray)
38 447
1 Necator
americanus (A)
cutting plate (B)
(C)
bursa (D) filariform (E)

rhabditoid rhabditiform (F) (
)
8 . 0.27 .
10 . 0.3 . buccal capsule
ventral teeth Ancylostoma
ceylanicum Ancylostoma ceylanicum
Ancylostoma braziliense7,8
Necator americanus
genus Ancylostoma
buccal
capsule cutting plate dorsal 1
ventral 1
species 7-9 . 0.3 .
bursa dorsal ray
2 bipartite spicules 2
2
9-11 . 0.4 .
Ancylostoma duodenale7,8
2. (hookworm egg)
Ancylostoma duodenale 60
40
2
Necator americanus 64-76
36-40

species 7,8
3. (rhabditoid larva)
1 2
1 (first stage larva)
0.25-0.30 . 17

1 3

(bulbous type)
genital primordium
2 (second stage larva)
0.5-0.6 .
7,8
4. (filariform larva)
448
(lung migration) filariform larva
(alveolus)
epiglottis

filariform larva 1
buccal
capsule
epithelium (fourth stage larva)

1
buccal capsule cutting plate

filariform
larva ( 2) hair 5
follicle epidermis Ancylostoma duodenale
corneum
subcutaneous tissue Ancylostoma duodenale
(venule) (neonatal infection)
3 (third stage larva )
(infective stage) Necator americanus
500-600 Ancylostoma
duodenale 600-700

(sheath)
filariform type
2
buccal spears

(striation)
7,8
2 () (
2 10) APR1: aspartic protease; CP3: cysteine
protease; MEP1: metalloproteinase; OPT1: putative transport protein; GST: glutathione-S-transferase; GSH: glutathione
GSSH: glutathione disulphide ( )
38 449
Ancylostoma caninum Ancylostoma

ceylanicum

Ancylostoma duodenale Ancylostoma caninum
Necator
americanus 4-20 Ancylostoma
duodenale 5-7 7,8

Necator americanus 10,00020,000 Ancylostoma duodenale
10,000-25,000
Necator americanus
0.03 . Ancylostoma duodenale
0.15-0.26 .
(unembryonated egg) early cleavage
2-3

1-2 1
3

2
5 8 2
3

7,8
filariform larva

hyaluronidase
hyaluronic acid keratinocyte epidermis
dermis15

neutrophil inhibitory factor (NIF)
glycoprotein 41
neutrophil endothelium
hydrogen peroxide
neutrophil serum
opsonized particle
neutrophil integrin receptor CD11b/CD1816-18
anticoagulant peptide (ACAP-1)

coagulation factor XA

platelet dense granule
fibrinolysis

450
glutathione-S-transferase
IgG acethylcholinesterase

10,18-22
filariform larva
cutaneous larva migrans creeping
eruption ground itch

Ancylostoma caninum

8
lung miqration

pulmonary
infiltrate eosinophilia
lung migration
Loefflers syndrome8

epigastrium

35-40 eosinophilia 38-64
6

acute
gastrointestinal hemorrhage

(hypoalbuminemia)
malabsorption8
8,22

3 8

38 451

koilonychia (angular stomatitis)

congestive heart failure

8,22

(hypochromic microcytic erythrocytes) reticulocyte
ferritin transferrin
eosinophilia
8
(Strongyloides stercoralis)
buccal cavity
genital primordium

charcoal culture
filter paper culture 7,23
agar plate culture
1-2
peptone, beef extract
25-35o .
3-5
Strongyloides stercoralis
Strongyloides stercoralis
direct smear formalin-ether
sedimentation method 10.2 1.9
agar plate culture
direct smear formalin-ether
sedimentation method 14 1.5

2 agar plate culture

direct smear filter
concentration formalin-ether paper culture 1.14 24
sedimentation ethyl-acetate sedimentation
direct smear

1,200 8
1
Mebendazole Ancylostoma
duodenale Necator americanus
100 . 2 3
1 Stoll dilution egg 76-95
count Kato thick smear 8

rhabditoid teratogenic effect
452
Albendazole benzimidazole
mebendazole 200
.
mebendazole
Pyrantel pamoate
Ancylostoma duodenale Necator americanus
11 ./. 1

liver enzymes
Bephenium hydroxynaphthoate
pyrantel pamoate 5
(2.5 ) Ancylostoma duodenale Necator
americanus 3
ferrous sulfate

3

packed red blood
cells 8
1.
IgM
6
IgG
8 22-27 IgE
IgE
27,28 IgE
Ancylostoma secreted protein-2
Necator americanus (Na-ASP2)

29
IgG4

IgG4

Th2
lymphocyte
IgE IgG4
29,30
IgD
IgD cross-link basophil
interleukin-4 (IL-4) IL-4

Th2 cell31,32 secretory
IgA
IgA
33
2. cytokines

Th2 lymphocyte
IL-4, IL-5, IL-13 IgE
IL-5
interferon
gamma (IFN-)

Th1 Th2 cells

Th2 cell

Th1 cell
34,35
38 453
3. (cell-mediated
immune response)
eosinophil
eosinophil
antigen-presenting cells effector
cells basophil
Th2 cell basophil
protease allergens IL-4 thymic
stromal lymphopoietin
natural killer (NK) cells
NK cells

IFN- NK cells IFN-

Th1 cell36,37
49.238
Necator americanus 95.8

Ancylostoma duodenale 0.5 Ancylostoma ceylanicum 0.339

40
41

42
2543
1.
.. 1965
Ancylostoma caninum
(irradiated larvae)

9044
1970

sterile
immunity

45
454
2.

2.1
filariform larva
Ancylostoma caninum

3 metalloprotease
(MTP-1) 2 pathogenesisrelated proteins 43.9
Ancylostoma secreted protein-1 (ASP-1)
21.3 Ancylostoma
secreted protein-2 (ASP-2)46-48
Necator
americanus Na-ASP-1 Na-ASP-2
2

49-51
Na-ASP-1
Na-ASP-2

52 Na-ASP-2
Na-ASP-2

filariform larva
48 recombinant
Na-ASP-2 alhydrogel adjuvant

Na-ASP-2
45

IgE

Na-ASP-2
21
metalloproteinase MTP-1
IgG2
MTP-1

IgE

53,54
2.2

38 455
hemoglobinases (
2) aspartic protease (APR1)
cysteine protease (CP3)
metalloprotease (MEP1)

OPT1 membrane-spanning amino acid
transporter
heme haematin

oxygen
radicals
glutathione
S-transferase 1 (GST1)
heme haematin 10

GST1 APR1
GST1 24
(recombinant protein)
Pichia pastoris
GST1 peroxidase reduced
glutathione electrophiles
heme haematin
oxygen radicals 19,55

GST1
19
19,56
GST1

Wuchereria bancrofti 57
10
APR1 45

aspartic acid
alanine aspartic acid
APR1 58
APR1
58
59 APR1

protease

GST1 APR1

54,60

456

genus Leishmania 2 subgenus
subgenus Leishmania subgenus Viannia
subgenus Viannia hindgut
61 Leishmania (
Leishmania ) subgenus
(flagellate) Leishmania Leishmania (
order Kinetoplastida ) species 2
kinetoplast circular subgenus Leishmania
DNA mitochondria
Leishmania family Trypanosomatidae reticuloendothelium visceral leishma Trypanosoma family niasis
genus Leishmania Ross .. 1903 mucosal mucocutaneous leishmaniasis
Leishman cutaneous leish maniasis Leishmania species
Dum Dum
Donovan
Ross 62

Leishman-Donovan (LD) body .. 1904 Rog-
ers amastigote
genus Leishmania
promastigote ..1911 2 amastigote LeishmaWenyon Baghdad nial form promastigote leptomonad form
(sand fly) ( 3) amastigote reticuloendothelial
..1925 Adler Theodor promastigote cell 2-5
7

Leishmania Giemsa Wright kinetoplast
species basal body
axoneme amastigote
binary fission
Leishmania amastigote
species species amastigote promastigote

kinetoplast basal body
38 457
3 Leishmania (A) amastigotes phagocytic cell

(B) promastigotes
( )
flagellum 1 promastigote
15-20 1.5-3.5 flagellum
15-28
promastigote 4-5
flagellum
mitochondria 1
kinetoplast promastigote longitudinal binary fission
metacyclic promastigote

amastigote phagolysosome
phagocytic cell7 ( 4)
Leishmania donovani Leishmania
major groups 36
32 base pairs63
Leishmania mexicana groups 34
8 29
20 36 Leishmania braziliensis
groups 35 20
3464
Leishmania
species 20 species
65

family Psychodidae
subfamily Phlebotominae 2 genus
genus Phlebotomus
458
4 Leishmania ( )
genus Lutzomyia
1.5-2.5 .

2
600 species
60 species

15-80
larval instars 4

pupa
pupa
2-3

Leishmania 7-10

7,62
Leishmania

Leishmania
38 459
Leishmania major
Th1 lymphocyte NK cell

IFN- interleukin-12 (IL-12)
naive T lymphocyte
Th1 cell
NK cell IFN-
naive T lymphocyte Th2 cell
IL-4 IL-10

Leishmania 7,66-69
1.

amastigote
Giemsa Romanovsky

Histoplasma capsulatum microsporidium Leishmania
kinetoplast
amastigote

23
2.
Leishmania
Leishmania
Novy-MacNealNicolle medium (NNN medium)

fibrin Schneiders Drosophila medium fetal bovine serum
(Hockmeyers medium)
2-3 promastigote wet

mount Giemsa
7
3.

golden hamster

7
4.
(intradermal test)
Leishmanin skin test Montenegro test

delayed-type
hypersensitivity promastigote

48-72
cutaneous leishmaniasis mucosal leishmaniasis diffuse cutaneous leishmaniasis
visceral leishmaniasis 7
5.

indirect immunofluorescence test
promastigote

counterimmuno electrophoresis,
enzyme-linked immunosorbent assay (ELISA)
direct agglutination test 23,70,71
6. DNA

DNA Leishmania
(PCR)
460
species Leishmania niasis
viscerotropic leishmaniasis7,62
kinetoplastid DNA72, small subunit ribosomal RNA73
1.2
74
mini-exon genes
genus Phlebotomus
Phlebotomus argentipes, Phlebotomus pernisiosus
Leishmania donovani Leishmania

Leishmania species infantum genus Lutzomyia Lutzomyia longi 20 species species palpis Leishmania chagasi7,62
1.3

Leishmania donovani
Leishmania
Leishmania infantum
(subclinical infection) Leishmania chagasi

viscerotropic Leishmania tropica
62
62
1.4
1. Visceral leishmaniasis (kala-azar)
visceral leishmaniasis
Leishmania 90
donovani
75
(hypergammaglobulinemia)
1.5
kala-azar ( black
visceral leishmaniasis Leish62
sickness) Dum Dum fever
mania donovani complex
1.1

3 species Leishmania donovani
complex
Leishmania donovani
Leishmania infantum promastigote
reticuloendothelial cell
Leishmania chagasi granuloma histiocyte
Leishmania 3 amastigote epithelioid cell
species giant cell
Leishmania
tropica visceral leishma-
38 461
granulomatous reaction
hyperplasia reticuloendothelial cell
amastigote

Kupffer cell
amastigote
granuloma

amastigote
granulomatous reaction giant
cell
62

submucosa
villous atrophy hyperplasia crypt

62
1.6
2-6

7,62

murmur

hypersplenism autoimmune hemolysis

pancytopenia

portal 62

(latent
infection)

76

neutrophil
eosinophil

62
post-kala-azar dermal leishmaniasis

462
2-10 62
1.7

eosinophil 100 /..
3 ./. 4 ./.
62
1. amastigote
98
amastigote 80-85
2. indirect immunofluorescence test (IFA) promastigote

1:256 95

3. Montenegro test
6
1 90
1.8
pentavalent antimony
sodium stibogluconate meglumine antimoniate
diamidine pentamidine
isethionate paromomycin

amphotericin B lipid
formulation
amphotericin B deoxycholate

miltefosine sitamaquine
75

62
1.9

.. 1960
17
6
stibophen 77
6
78
79 .. 1999
2 9

.. 1996 2

9.7 38.5o .
4 .
7 .
6.9 %
84,000 /.. 4.1 %
5.5 %
amastigote Leishmania DNA
Leishmania PCR
Leishmania indirect
immunofluorescence 1:16384
pentamidine isethionate
3 ./.
3
15
2
1
38 463
9.6 % 168,000 /..

Leishmania
1:32 1:16
10 (relapse)79

898
9 80

Phlebotomus argentipes Phlebotomus major
major
80
Leishmania infantum81
Leishmania species
82 visceral leishmaniasis

2. Cutaneous leishmaniasis
2.1

2 (Old World
cutaneous leishmaniasis) Leishmania
tropica complex 3 species
(1) Leishmania
(tropica) major
Phlebotomus sergenti
Phlebotomus papatasi (2) Leishmania (tropica) minor
Leishmania (tropica) tropica
Phlebotomus papatasi
Phlebotomus caucasicus (3) Leishmania (tropica)
aethiopica hyrax

Phlebotomus longipes Phlebotomus pedifer
(New World cutaneous
leishmaniasis) subgenus Viannia
Leishmania mexicana complex Leishmania
braziliensis complex genus
Lutzomyia 62
2.2
cutaneous leishmaniasis
90

83
2.3

lymphocyte, plasma cell mononuclear cell
fibrosis granuloma
fibrosis
granuloma

leishmaniasis recidivans

amastigote
lymphocyte
diffuse cutaneous
leishmaniasis62
464
2.4
2-8
3

Leishmania major

2-3 Leishmania tropica
Leishmania aethiopica

62
(papule)

leishmaniasis recidivans

20-40

diffuse cutaneous leishmaniasis

7,62
2.5
1. amastigote

Giemsa7,62
2. NNN medium
2-7 Schneiders medium
21 promastigote7,23
3. Montenegro test
3 7
2.6
visceral Leishmaniasis
10-20 visceral
Leishmaniasis 28
pentavalent antimony 20
./. 4
84
pentamidine isethionate amphotericin

B fluconazole
200 . 2 4 6
ketoconazole 600 ./
28 itraconazole 200 .
2 28 dapsone
100 . 2 6 84
ointment paromomycin methylbenzethonium chloride

84
2.7
cutaneous Leishmaniasis

40

.. 1981
199778
3. Mucosal leishmaniasis
mucosal leishmaniasis

38 465

mucosal leishmaniasis
espundia, chiclero ulcer bay sore 62
3.1
2 Leishmania
mexicana complex (1) Leishmania mexicana

Lutzomyia olmeca olmeca (2) Leishmania
amazonensis

Lutzomyia flaviscutellata
(3) Leishmania venezuelensis

Leishmania olmeca bicolor 2
Leishmania braziliensis complex
(1) Leishmania braziliensis

Lutzomyia
wellcomei Lutzomyia intermedius Lutzomyia
pessoai (2) Leishmania panamensis
sloth
Lutzomyia trapidoi (3) Leishmania guyanensis

Leishmania umbratilis sloth (4)
Leishmania peruviana
Lutzomyia verrucarum
Lutzomyia peruensis7,62
3.2
hyperplasia epidermis
necrosis dermis neutrophil eosinophil
mononuclear cell
plasma cell lymphocyte
epithelioid cell Langerhans giant cell
granuloma
necrotizing granulomatous
7
3.3
cutaneous
leishmaniasis

Leishmania braziliensis

7,62
diffuse cutaneous leishmaniasis

62
3.4
28 amphotericin B deoxycholate

pentamidine isethionate
2-4 ./.
3 15 84

466
87,88
3.5
Leishmania
mucosal
leishmaniasis
Leishmania metacyclic promastigote
1,000 89
1 90
Leishmania

Leishmania
genome Leishmania
Leishmania Trypanosoma brucei Trypano-
soma cruzi proteome
6,200 63 promastigote maxadilan
Leishmania 91,92
filamentous proteophosphoglycan
(fPPG) (secretory gel)
promastigote

2 promastigote
86 89 promastigote
3 dermal macrophage
Leishmania keratinocyte Langerhans
Leishmania
promastigote dermal
macrophage 93
Leishmania C3 94
phagocytosis promastigote
promastigote lipophos- amastigote
phoglycan (LPG) promastigote phagosome LPG
promastigote lipid
promastigote microdomains phagosome
promastigote phagosome promastigote
lysosome
(receptor) hydrolases
LPG galectin promastigote
phagosome lysosome promas Leishmania tigote amastigote
38 467
phagolysosome
95-97
promastigote
keratinoeyte
IL-12,
IL-1, IL-4, IL-6 osteopontin IL-6

IL-6
Leishmania

IL-6 Th2 cell
Leishmania
98
Langerhans
dendritic cells

Langerhans
(interstitial space)
promastigote
Langerhans
promastigote vacuole
(pseudopod)
Langerhans
Leishmania
Langerhans
99,100

neutrophil monocyte 101
promastigote MCP-1
CXCL1 (chemoattractant) monocyte neutrophil
102
neutrophil Leishmania braziliensis
tumor necrosis
factor alpha (TNF-) superoxide103
neutrophil Leishmania donovani
neutrophil extracellular traps
(NETs) fibrous traps DNA histone granule neutrophil
104,105 NETs neutrophil
LPG Leishmania
NETs Leishmania
NETs DNase
Leishmania NETs
neutrophil
Leishmania
phagocytosis
NETs
neutrophil

monocyte
2 monocyte dendritic cell
amastigote 106
T lymphocyte
16
CD4+ T lymphocyte Leishmania
T helper lymphocyte
1 Th1 cell IFN-
TNF- Leishmania

T lymphocyte
Th2 IL-4, IL-5
468
IL-13107-110
dendritic cell
Leishmania CD4+
T lymphocyte IL-12 IFN 1
( IFN-, IFN- and IFN-)
nave T lymphocyte Th1
lymphocyte Leishmania major
dendritic cell nuclear factor kappalight-chain-enhancer of activated B cells (NF-B)
IL-12 111-113
Leishmania donovani Leishmania tropica
IL-12 dendritic cell

CD4+ lymphocyte
IL-12
Th1 lymphocyte
dendritic cell NK cell
IFN- CD4+ lymphocyte Leishmania
IFN- NK cell
IL-12 dendritic cell
IL-2 CD4+ T lymphocyte
Leishmania
(innate immunity)
(acquired immunity)114,115
T lymphocyte
T lymphocyte
apoptosis Th1 lymphocyte

nitric oxide L-asparagine
inducible nitric oxide synthase (iNOS)116
Leishmania
IgG

B lymphocyte
Leishmania117
Leishmania
Leishmania

1. macrophage
dendritic cell
LPG Leishmania
macrophage CD40 signalosome
IL-12
Leishmania major macrophage
CD40 signalosome
Erk1/2 mitogen activated protein kinase
IL-10
Leishmania 118
2. cytokine
promastigote
Leishmania species macrophage
transforming growth factor
beta (TGF-) cytokine

lymphocyte, NK cell, dendritic cell, macrophage,
mast cell granulocyte
119

TGF-
cytokine
B lymphocyte
promastigote
B lymphocyte Leishmania
38 469
TGF- cytokine
cysteine protease
TGF- Leishmania 120
TGF- cytokine
Leishmania
major TGF-
respiratory burst
phagocytosis TGF-
iNOS Leishmania121
3. regulatory T (Treg) lymphocyte
Treg
lymphocyte 5-10
CD4+ T lymphocyte Treg cell

Leishmania CD4+CD25+ Treg lymphocyte
FoxP3, TGF- IL-10R1
CD4+CD25- lymphocyte IL-2
IFN- 122 Treg
cell Leishmania
TGF-
Treg lymphocyte
Leishmania CD4+CD25+
Treg lymphocyte
CD4+CD25- T cell IL-10

IL-10
Leishmania CD4+CD25+ Treg
cell 123,124
4.
Leishmania major
macrophage migration inhibitory factor (MIF)
Lm1740MIF MIF
apoptosis
125
promastigote fPPG
maxadilan
IL-6, IL-10 TGF- iNOS
maxadilan
monocyte dendretic cell
IL-6, IL-10, IL-1 IL-10
IL-12, TNF- IFN-
Leishmania
126,127

(zoonotic transmission)
88
1.5-2
7
350

2-4
DALY85

Adler (Hebrew University)

470
128 Leishmania

leishmanization
..1967
leishmanization

leishmanization 80
Leishmania major
leishmanization

leishmanization
129,130
3 (phase
III)
134,135

Leishmania subgenus Vannia
species
136 Leishvacin

Th1 lymphocyte

Th1 lymphocyte
promastigotes Leishmania major
Leishmania tropica

137,138
1
(first-generation vaccines)
promastigote Leishmania
(axenic
culture)

Leishmania
5
Leishmania
Leishmanin skin
test
50

Leishmania amazonensis
IFLA/BR/67/pH8 Leishvacin131-133
2
(second-generation vaccines)

leishmanization
136

gentamicin

dihydrofolate reductase-thymidylate synthase
(DHFR-TS)139 cysteine proteinase140
LPG Leishmania major141
Leishmania DTFRTS
38 471

130

(subunit vaccine) subunit vaccine
1. gpb3 protease
Leishmania amastigote
promastigote

gpb3
142
BCG 143
2. Leishmania homologue for receptors of
activated C kinase (LACK)
amastigote promastigote LACK
IL-12
LACK
vaccinia
144,145 LACK
Leishmania species LACK
Th1 lymphocyte 146
3. Cathepsin L-like cysteine proteinase A
B (CPA CPB)
CPA CPB

Leishmania
CPA CPB
147
4.
3 Leish-111f thiolspecific antioxidant (TSA), Leishmania major stress

inducible protein 1 (LmST11) Leishmania major
elongation factor (Le1F) emulsion adjuvant monophosphoryl lipid A (MPL-SE)
Leish-111f
visceral cutaneous leishmaniasis
Th1 lymphocyte
IFN- TNF-
99148
3
(third-generation vaccine)
DNA

plasmid DNA DNA

Th1 lymphocyte
DNA
3
DNA
LACK,
Leish-111f, CPA CPD DNA
adjuvant
DNA LACK
Leishmania major

CD8+T cell
Th1 cell DNA
IFN- IL-12 129
472
dendritic cell
Leishmania

dendritic cell
Th1 cell
dendritic cell

129-131

3,149

DALY

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483
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HPIV3 12,13,26

RSV cytomegalovirus
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bronchiolitis obliterans 32

RSV HPIVs33,34
RSV genus Pneumovirus

15,222 nucleotides
transmembrane surface proteins (F, G SH), matrix
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surface fusion (F) attachment (G)
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RSV A RSV B 53
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28,51 RSV

RSV
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(hyperinflation) RSV
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RSV

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RSV cellular humoral
cellular
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IgG secretory IgA RSV
RSV RSV
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RSV

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81 RSV neutralizing antibody

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RSV Immune Globulin Intravenous
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RSV palivizumab
RSV
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palivizumab
RSV
palivizumab
RSV
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RSV RSV
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subunit
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RSV meta-analysis
RSV
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RSV co-purified F,
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alum
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37 .

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recombinant
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HPIV3 internal genes BPIV3
1 135
PIVs
RSV human metapneumovirus

(HMPV)
490
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of a recombinant live attenuated respiratory syncytial
498
virus vaccine candidate that is highly attenuated in
infants. J Infect Dis. 2005;191:1093-104.
126. Wright PF, Karron RA, Madhi SA, Treanor
JJ, King JC, OShea A, et al. The interferon antagonist
NS2 protein of respiratory syncytial virus is an
important virulence determinant for humans. J Infect
Dis. 2006;193:573-81.
127. Belshe RB, Hissom FK. Cold adaptation
of parainfluenza virus type 3: induction of three
phenotypic markers. J Med Virol. 1982;10:235-42.
128. Skiadopoulos MH, Durbin AP, Tatem
JM, Wu SL, Paschalis M, Tao T, et al. Three amino
acid substitutions in the L protein of the human
parainfluenza virus type 3 cp45 live attenuated
vaccine candidate contribute to its temperaturesensitive and attenuation phenotypes. J Virol.
1998;72:1762-8.
129. Skiadopoulos MH, Surman S, Tatem JM,
Paschalis M, Wu SL, Udem SA, et al. Identification
of mutations contributing to the temperaturesensitive, cold-adapted, and attenuation phenotypes
of the live-attenuated cold-passage 45 (cp45) human
parainfluenza virus 3 candidate vaccine. J Virol.
1999;73:1374-81.
130. Coelingh KJ, Winter CC, Murphy BR,
Rice JM, Kimball PC, Olmsted RA, et al. Conserved
epitopes on the hemagglutinin-neuraminidase proteins
of human and bovine parainfluenza type 3 viruses:
nucleotide sequence analysis of variants selected with
monoclonal antibodies. J Virol. 1986;60:90-6.
131. Clements ML, Belshe RB, King J,
Newman F, Westblom TU, Tierney EL, et al. Evaluation
of bovine, cold-adapted human, and wild-type human
parainfluenza type 3 viruses in adult volunteers and
in chimpanzees. J Clin Microbiol. 1991;29:1175-82.
132. Karron RA, Wright PF, Hall SL, Makhene

M, Thompson J, Burns BA, et al. A live attenuated
bovine parainfluenza virus type 3 vaccine is safe,
infectious, immunogenic, and phenotypically stable in
infants and children. J Infect Dis. 1995;171:1107-14.
133. Karron RA, Wright PF, Newman FK,
Makhene M, Thompson J, Samorodin R, et al. A
live human parainfluenza type 3 virus vaccine is
attenuated and immunogenic in healthy infants and
children. J Infect Dis. 1995;172:1445-50.
134. Belshe RB, Newman FK, Tsai TF, Karron
RA, Reisinger K, Roberton D, et al. Phase 2 evaluation
of parainfluenza type 3 cold passage mutant 45 live
attenuated vaccine in healthy children 6-18 months
old. J Infect Dis. 2004;189:462-70.
135. Schmidt AC, McAuliffe JM, Huang A,
Surman SR, Bailly JE, Elkins WR, et al. Bovine
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hemagglutinin-neuraminidase glycoproteins make an
important contribution to the restricted replication of
BPIV3 in primates. J Virol. 2000;74:8922-9.
499
(cellular immune system)

monoclonal antibody

(cancer
vaccine)1
cell-mediated
immune response (CMIR) (viral
antigens) antigen-reactive T cells
antigen presenting cells (APCs)
dendritic cells (DCs) activated
T cell DCs T cell
activated T cells
cytotoxic effector cells (CTLs)
CMIR cytokines
40
Interferon (IFN) Tumor necrotic factor

(TNF) activated CTLs

CTLs granzymes perforins
death receptors target cells

Ebstein-Barr virus (EBV)
1 CTLs 100 (1-10/100 CTLs)2
(cancer vaccine)
(Tumor antigen)
cancer antigen viral antigen
peptides
Human leukocyte antigen (HLA)
APCs T cells peptides
intracellular proteins ribosome
HLA class I heavy chain domains endoplasmic
reticulum (ER) CD8+ T cells
peptides endocytosed membrane
500
extracellular proteins ribosomes
HLA class II CD4+ T cells4
2

1. Tumor-specific antigen TSA5

fusion chimeric bcr - abl oncoprotein
chronic myeloid leukemia (CML)
p53 protein tumor suppression gene
p53
transformation
host cell
Li-Fraumeni syndrome Idiotype (Id)

secreted monoclonal immunoglobulin (Ig)
surface Ig clonal B cells
B cells (B cell malignancies)6
2. Tumor-associated antigen (TAA)

polysaccharides

tyrosinase melanin

melanoma tyrosinase

melanoma antigen (MAGE)

oncofetal antigen

carcinoembryonic
antigen (CEA)
alfa-fetoprotein (AFP) oncogenic
virus antigen
EBV
Burkitts lymphoma, Human papilloma virus (HPV)
( 1)
Antigen presentation and T cell proliferation
tumor reactive CTLs
tumor cells
Tumor specific antigens

Mutated oncogenes
Immunoglobulin idiotype
Cryptic frameshift sequences
Tumor associated antigens
Cancer testis antigens
Differentiation antigens
Oncofetal antigens
Widely expressed antigens
Viral antigens
mRas mutation p210 (Bcr-abl), mutated P53 (mP53)

Idiotype (Id)
(may be tumor specific)
melanoma antigen 1 (MAGE) 1, MAGE 3
Gp 100, tyrosinase
Carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP)
mP53
Epstein - Barr virus (EBV), Human papilloma virus (HPV)
40 501
antigenic signal signal 17

second signals cell surface
molecules cytokines, chemokines
Professional APCs
dendritic cells (DCs) 8
co-stimulatory molecules APCs
antigen activated T cells
cell cycle
fibroblasts T cells
9
T cell differentiation
cell cycle
antigen-activated T cells effector cells
T cell differentiation 2
Type 1 (TH1 / TC1) Type 2 (TH2 / TC2)10
Type 1 cell mediated
immune response (CMIR)
anti-tumor 11 anti-viral 12
type 1 effector cytokines IFN
TNF chemokine receptor CSCR3,
CXCR513 perforin
14
Type 2
humoral immune response (HMIR)
type 2 effector cells
interleukin (IL) 4, IL 10, IL 5, IL 13 express
chemokine receptor CCR3, CCR4 CCR815
co-stimulatory molecules
effector cells co-stimulatory molecules
effector T cell
cytokines
activated memory T cells
effector cells cytokines
C4+ helper T cells inflammatory
cells eosinophils macrophages
16
Negative regulation of T cell activation
cytokines co-stimulatory molecule
gene negative regulators
Transforming growth factor (TGF)
T cells (proliferate)
lymphocyte
macrophage IL 10
immunosuppressive
co-stimulatory molecule cytokines
APCs16 cytokines
regulatory T cells (Tregs) 2 classes
Tr 1 cells separate T cell lineage
17 Tr 2 cells
(periphery)
T cells
adaptive
immune response
T cell trafficking
effector T cells
Maintenance of
cytokines co-stimulatory molecule
effector cells
(lymphoid organ)18 activated
T cells
CTL activity
(anti-tumor) co-stimulatory molecular families
502
lectins integrins recruiting
T cells tertiary
chemokines class
effector cells19
(Immunotherapy)
2
1. Passive immunotherapy
()
mature T cells
monoclonal antibody
(McAb)
Rituximab (Rituxin) chimeric anti-CD 20
receptor B lymphocyte
B cell Trastuzumab
(Herceptin) Humanized anti-HER2
Gemtuzumab (Mylotary)
Humanized anti-CD33
acute myeloid leukemia (AML)
2. Active immunotherapy

(tumor vaccine)

1. Whole cell vaccine
whole cell
vaccine APCs

whole cell vaccine cytokines
3
1.1 Autologous vaccine

APCs T cells

1.2 Allogenic vaccine

autologous vaccine
1.3 Gene modified vaccine

(tumor-specific antigen)
Interleukin-2 (IL2),
granulocyte-macrophage colony-stimulating factor
(GM-CSF) (stimulatory
molecules)

20 pre-clinical model
GM-CSF cytokine
(immunogenicity)
21 GM-CSF modified tumor cell vaccine effector cells
22
phase III trials

whole cell vaccine
40 503

2. Antigen Based Vaccines
purified
tumor protein
APCs
T cells
tumor-specific
antigen

T cells
tumor-specific
antigen melanomas
20 4
2.1 Peptide-based vaccines tumorderived protein fragments
APCs
peptide

2.2 Heat shock protein vaccines Heat shock
protein

tumor cells
Heat
shock protein
tumor protein APCs
dendritic cells receptor heat shock
proteins DCs

tumor protein heat shock protein
DCs heat shock protein
(tumor protein)
receptor (CD91 DCs)23

CD8 + T cells24
2.3 DNA vaccines DNA
tumor specific protein plasmid vector
immunogen DNA
DNA
tumor protein
tumor-specific T cells
APCs
2.4 Viral and bacterial vector vaccines
DNA vaccines DNA
DNA viral bacterial vector
viral bacterial vector
2 DNA
vaccine 2
20
pox virus family vector
25
3. Antigen Presenting Cell Based Vaccines (Dendritic
cell vaccine)
Dendritic cells
CMIR DCs
antigen-specific T cells
APCs 1,000 26
dendritic cells
dendritic cells
(tumor-specific antigen)
tumor-specific
T cells 27
clinical trial
melanoma, myeloma
504
1. Zinkernagel R. Immunology taught by

viruses. Science. 1996;272:634-5.
2. Callan M, Tamn L, Annels N. Direct visualization
of antigen-specific CD8+ T cells during the primary immune
response to Epstein-Barr virus in vivo. J Exp MMed.
1998;187:1395-402.
3. Kolb H, Holler E. Adoptive immunotherapy with
donor lymphocyte transfusions. Curr Opin Oncol. 1997;9:
139-45.
4. Germain R, Margulies D. The biochemistry
and cell biology of antigen processing and presentation.
Annu Rev Immunol. 1993;11:403-50.
5. Van den Eynde B, van der Bruggen P.
T cell defined tumor antigens. Curr Opin Immunol.
1997;9:634-93.
6. Tao MH, Levy R. Idiotype / granulocytemacrophage colony-stimulating factor fusion protein
as a vaccine for B-cell lymphoma. Nature. 1993;
362:755-8.
7. Janeway C. Immunogenicity signals 1,2,3
and 0. Immunol Today. 1989;10:283-6.
8. Greenwald R, Freeman G, Sharpe A. The
B7 family revisited. Annu Rev Immunol. 2005; 23:

515-48.
9. Kndig TM, Bachmann MF, DiPaolo C, Simard
JJ, Battegay M, Lother H, et al. Fibroblasts as efficient
antigen-presenting cells in lymphoid organs. Science.
1995;268:1343-7.
10. Murphy K, Reiner S. The lineage decisions
of helper T cells. Immunol Cell Biol. 2002; 2:933-44.
11. Berzofsky J, Terabe M, Oh S. Progress
on new vaccine strategies for the immunotherapy and
prevention of cancer. J Clin Invest. 2004;113:1515.
12. Berzofsky J, Ahlers J, Janik J. Progress
on new vaccines strategies against chronic viral infections. J Clin Invest. 2004;114:450-62.
13. Moser B, Wolf M, Walz A, Loetscher P.
Chemokines : multiple levels of leukocyte
migration control. Trends Immunol. 2004;25:75-84.
14. Lieberman J. The ABCs of granule-mediated
cytotoxicity : new weapons in the arsenal. Immunol.
2003;3:361-70.
15. Luther S, Cyster J. Chemokines as
regulators of T cell differentiation. Nat Immunol 2001;
2:102-7.
16. Pardoll D, Topalian S. The role of CD4+
T cell responses in antitumor immunity. Curr Opin
Immunol. 1998;10:588-94.
17. Sakaguchi S. Naturally arising Foxp3expressing CD25+CD4+ regulatory T cells in
immunological tolerance to self and non-self. Nat
Immunol. 2005;6:345-52.
18. Zinkermagel R, Ehi S, Aichele P. Antigen
localisation regulates immune responses in a doseand time- dependent fashion: a geographical view of
immune reactivity. Immunol Rev. 1997;156:199-209.
19. Bacon K, Baggiolini M, Broxmeyer H.
40 505
Chemokine/chemokine receptor nomenclature. Dendritic cells resurrect antigens from dead cells.
J Interferon Cytokine Res. 2002;22:1067-8.
Trends Immunol. 2001;22:141-8.
20. Ribas A, Butterfield LH, Glaspy JA,
Economou JS. Current developments in cancer
vaccines and cellular immunotherapy. J Clin Oncol.
2003;21:2415-32.
21. Dranoff G, Jaffee E, Lazenby A, Golumbek P,
Levitsky H, Brose K, et al. Vaccination with irradiated
tumor cells engineered to secrete murine granulocytemacrophage colony-stimulating factor stimulates
potent, specific, and long-lasting anti-tumor immunity.
Proc Natl Acad Sci U S A. 1993;90:3539-43.
22. Soiffer R, Lynch T, Mihm M, Jung K,
Rhuda C, Schmollinger JC, et al. Vaccination with irradiated autolgous melanoma cells engineered to secrete
human granulocyte-macrophage colony-stimulating
factor generates potent antitumor immunity in patients
with metastatic melanoma. Proc Natl Acad Sci U S A.
1998;95:13141-6.
23. Binder RJ, Han DK, Srivastava PK. CD91:
receptor for heat shock protein gp96. Nat Immunol.
2000;1:151-5.
24. Mazzaferro V, Coppa J, Carrabba MG,
Rivoltini L, Schiavo M, Regalia E, et al. Vaccination
with autologous tumor-derived heat-shock protein
gp96 after liver resection for metastatic colorectal
cancer. Clin Cancer Res. 2003;9:3235-45.
25. Paoletti E, Tartaglia J, Cox WI. Immunotherapeuticstrategies for cancer using poxvirus vectors. Ann N Y Acad Sci. 1993;690:292300.
26. Dhodapkar MV, Bhardwaj N. Active
immunization of humans with dendritic cells.
J Clin Immunol. 2000;20:167-74.
27. Larsson M, Fontenaeu JF, Bhardwaj N.
76
507
6,000-8,000 1
2,700

2

2,000 (Ayurveda)

(king of
diseases)
3 1,600
4

(Ebers Papyrus)5
(Hippocrates Epidemics)
400
(tertian fever)
(quartan fever)
6
41
(Alexander the Great

of Macedonia)7 340

(Crusades)
(Holy
Land)
11-13

7
.. 1880

(Charles Louis Alphonse Laveran)8

508
genus Plasmodium
species 120 species
5 Plasmodium
falciparum, Plasmodium vivax, Plasmodium malariae,
Plasmodium ovale Plasmodium knowlesi
.. 2009 225
781,000
9

10
5
10
4
P.falciparum
35 P.vivax 7
P.falciparum P.vivax 4.1 ..
1965 0.8 .. 200211 .. 1998

131,055 .. 2008
25,449 10

5
12,13 1
species
2413
(sexual development)
(definitivehost)

(asexual
development)
(intermediate host)8

( 1) 3
1.
2.
(ookinete)
(merozoite) (sporozoite)
(apical organelle)
3.
(gametocyte)
ookinete
1. (oocyst)
sporogony
2. tissue
schizogony exo-erythrocytic schizogony
pre-erythrocytic schizogony
3. erythrocytic
schizogony14
gametocytes
gametocyte
(female gamete)
gametocyte
41 509
1 Plasmodium falciparum [A]

[B] [C] [D]
(1) sporozoite (2) hepatic trophozoite (3) hepatic schizont with merozoites (4) free merozoite (5) ring
stage (6) growing trophozoite (7) growing schizont (8) mature schizont with merozoites (9) immature gametocytes (10) mature gametocytes (11) exflagellation of male gametocyte (12) male gamete (13) female gamete (14) zygote (15) ookinete
(16) oocyst (17) salivary gland sporozoite ( )
exflagellation (male
gamete) 8
1

(zygote)

ookinete

oocyst
sporozoite 1 oocyst sporozoite

1 2 15 oocyst
sporozoite
oocyst
sporozoite
sporozoite

510

8 35 14

sporozoite

hepatic stage exoerythrocytic stage

(schizont)

merozoite
schizogony
merozoite P.falciparum
merozoite 30,000 40,000 sporozoite
1 P.ovale P.malariae merozoite
15,000 P.vivax 10,000
sporozoite 1 P.knowlesi

sporozoite merozoite
14
sporozoite P.falciparum, P.malariae
P.knowlesi
P.vivax P.ovale
P.falciparum, P.malariae P.knowlesi

(relapse)

(hypnozoite)16,17 merozoite

merozoite
1 2 14
merozoite
vacuole
giemsa
ring stage (ring form

young trophozoite)

(pinocytosis)
growing trophozoite
malarial pigment
hemozoin18,19
growing
trophozoite
giemsa
P.falciparum
Maurers
cleft P.vivax P.ovale
Schuffners dot
P.malariae
Ziemanns dot P.knowlesi

Sinton and Mulligans stippling14

schizont
schizogony
schizont

schizont (late schizont)
merozoite merozoite
P.falciparum
merozoite 8 26 P.vivax
12 24 P.malariae P.ovale
41 511
merozoite 6 12 P.knowlesi
merozoite 6 16 14 merozoite
(hemolysis)

asexual erythrocytic cycle P.knowlesi 24
P.falciparum 36 48
P.vivax P.ovale 48
P.malariae 72
merozoite
20,21
(asexual erythrocytic cycle)

merozoite
gametocyte
gametocyte P.falciparum
(crescent form) gametocyte
microgametocyte
gametocyte macrogametocyte
gametocyte P.vivax, P.malariae, P.ovale
P.knowlesi macrogametocyte
microgametocyte
gametocyte
22-24

18.00-04.00 .
1.2 An.minimus

18.00-22.00 .
1.3 An.maculatus

18.00-21.00 .
2. (secondary vectors)
2.1 An.sundaicus

2.2 An.aconitus

2.3 An.pseudowillmori
An.maculatus
P.falciparum P.vivax
1. sporozoite

2.
3.
25
1. (primary vectors)

1.1 Anopheles dirus
512

2 (malarial
paroxysm)
P.falciparum
1) (splenectomy) 2)
(primigravida) 3)
(immunosuppression) 4)
(non-immune
to malaria)26
.. 1990
26
1. (cerebral malaria with
unrousable coma)

10

80

2

27
30

1-2 2-4 28
2.
(severe normocytic anemia)
hematocrit 15
hemoglobin 5 ./.
parasitemia 10,000 1

(thalas-semia)
(hemoglobinopathy)
29
3. (acute renal failure)
400 . 24
12 ./. 24

creatinine 3.0 ./.
P.falciparum
30
creatinine 2
blood urea nitrogen 40 ./.

30,31
4. (pulmonary edema)
P.falciparum

41 513
adult respiratory distress syndrome (ARDS)

(fluid overload)
32,34
5. (hypoglycemia)
(whole blood glucose) 2.2
40 ./.

(coma) extensor

(quinine) (quinidine)
35-38
6. (circulatory
collapse, shock, algid malaria)
systolic 50
5 70

(core-skin temperature)
10 .

metabolic acidosis septicemia

27
7. (spontaneous bleeding, disseminated intravascular
coagulation)
disseminated
intravascular coagulation (DIC)
10
39
8. (repeated
generalized convulsion)
2
24
(febrile convulsion)

26
9. (acidemia/acidosis)
arterial pH 7.25 bicarbonate
15

(hyperparasitemia) 40-42
10.
(malarial hemoglobinuria, blackwater
fever)
hemoglobin

quinine halofantrine G-6-PD
deficiency

43-45
11. (hyperparasitemia) parasitemia

parasitemia
5
parasitemia
514
49
1.

giemsa
1.1 (thin blood film)

1.2 (thick blood

film)

200
giemsa

40 1
P.falciparum P. vivax

1.
(mixed species infection)

2.
3.
2.

4.
immunochromatographic
5. test monoclonal antibody circulating
antigen

P.falciparum
sequestration visceral blood
26
12. (jaundice)
(bilirubin) 50
3.0 ./.

total bilirubin indirect bilirubin
46
13. (hyperpyrexia)
rectum 40 .
schizogony hyperpyrexia
38.5 .
39.5 42 .
42 .
fetal distress47,48
41 515
histidine-rich protein II (HRP II)

lactate dehydrogenase (pLDH)

giemsa
P.falciparum
3. DNA

DNA
(polymerase chain reaction, PCR)
DNA

primer oligonucleotide
DNA
complementary primer DNA
polymerase
DNA DNA
primers

small subunit ribosomal RNA (SSU rRNA)
primers mitochondrial cytochrome b
primers SSU rRNA
5
DNA
PCR primers mitochondrial
cytochrome b
PCR primers SSU rRNA
chloroquine sulfadoxinepyrimethamine

P.falciparum mefloquine, artemether
artesunate, quinine

2. P.vivax P.ovale
chloroquine
hypnozoite
primaquine
3. P.malariae P.knowlesi
chloroquine primaquine
hypnozoite

26
(clinical immunity)50-53 ..1961 1962
1. P.falciparum
P.falciparum clinical immunity
516

3
1) pre-erythrocytic stage vaccines
sporozoite

2) asexual bloodstage vaccines

sporozoite
3) transmission-blocking vaccines
gamete, zygote ookinete
sporozoite

( 2)61

sterile
immunity

54,55 ..1991

IgG

56

.. 1941 1942
sporozoite Plasmodium gallinaceum
(ultraviolet)

57,58 .. 1967
Plasmodium berghei sporozoite

(X-irradiated sporozoite)

sporozoite

(complete protection)59,60

sporozoite (precipitation)
sporozoite
circumsporozoite protein (CSP)
CSP sporozoite
60
P.falciparum

41 517
2
( )
1.
(pre-erythrocytic stage
vaccine candidates)
P.berghei Plasmodium yoelii

sporozoite
sporozoite
50
2-3 6
1 10
sporozoite
exo-erythrocytic stages
epidermis,
dermis hair follicle merozoite

merosomes

merozoite
30 sporozoite
sporozoite
dendritic
cells exo-erythrocytic
stages sporozoite

62-64

sporozoite
10 15
1 apical organelle

sporozoite

518
circumsporozoite protein
CSP, thrombospondin-related adhesive protein (TRAP)
sporozoite-threonine-asparagine-rich protein
(STARP)
1.1 circumsporozoite protein
sporozoite
40 79
N-terminus C-terminus
CSP species
region I region II ( 3)65

(repeats) CSP
P.falciparum 4
(tetrapeptide repeats)
asparagine alanine
asparagine proline (NANP)
asparagine valine aspartic acid
proline (NVDP)
NANP NVDP
P.falciparum
tetrapeptide repeats
40 51 66
CSP
P.falciparum
repeats repeats
CSP P.falciparum B cell epitope

sporozoite 67
sporozoite68
(monoclonal
antibody) repeats CSP P.berghei
69 (ligand)
(recepter) sporozoite 70
sporozoite 71
C-terminus CSP
3 circumsporozoite protein RTS,S ( 2 61)
41 519
T helper epitope 2 Th2R

Th3R cytotoxic T cell epitope
Th3R epitope ( 3)72-76
T cell epitope
codon epitope

Th2R Th3R
codon 66,77,78

T cell epitope

altered peptide ligand antagonism78
codon
epitope
(natural selection)
epitope 66

79
tetrapeptide repeats
CSP P.falciparum
sporozoite

repeats

80,81
repeats B cell
T cell (T-independent B cell stimulation)82
T helper epitopes CSP
B cell (T-B cooperation)
avidity affinity cytotoxic
T cell epitope cytotoxic T
lymphocyte
CSP sporozoite

CSP 83,84
pre-erythrocytic stages
sporozoite
1.2 thrombospondin-related adhesive protein

sporozoite
90 85,86
TRAP

6 (domain) 1) signal peptide
N-terminus 2)
von Willebrand factor type A-domain
3) sulfated glycosaminoglycan
region II CSP 4)
proline asparagine
5)
transmembrane domain 6)
C-terminus cytoplasmic tail
TRAP P.falciparum P.vivax

2
87-89

domain 2, 3
4

immunofluorescence
immuno-electron micrograph CSP TRAP
microneme90,91 TRAP
sporozoite (patch)
CSP sporozoite92,93
TRAP CSP P.yoelli

2
520

pre-erythrocytic
stages
sporozoite 1 CSP
TRAP 2
sporozoite
region II plus
heparan sulfate proteoglycan basolateral

domain
1.3 sporozoite threonine-asparagine-rich protein (STARP) 78
sporozoite threonine asparagine
STARP
sporozoite STARP intron

5 2 exons exon 1
5 24 codons
exon 2
2 45
2
10 25-28

repeats 5 86
IgG
PfSTARP P.falciparum
42.6
6 94
STARP sporozoite

STARP
Hep G2
repeats 10

STARP
Aotus
(owl monkey)
T cell
repeats

CSP, TRAP STARP

pre-erythrocytic stages
sporozoite and liver stage antigen

(SALSA)95 liver-stage-specific antigens 1, 2
3 (LSA-1, 2, 3) sporozoite
CSP
proteasome complex
hepatocyte
(processing)
hepatocyte major histocompatibility

complex (MHC) class I
CD8+
cytotoxic T lymphocyte
CSP
hepatocyte MHC class I CD8+
interleukin-1, interleukin-6 nitric oxide
hepatocyte 43
41 521
2.
(asexual erythrocytic stage vaccine candidates)

2.1 merozoite surface protein 1 (MSP1)

merozoite
merozoite
185 200 kDa97
(antigenic
polymorphism) 98
MSP1 P. falciparum
(PfMSP1) 2
(allelic dimorphism)

(variable block)
(semi-conserved block)
(conserved block)
variable block semi-conserved block
2 17
(block)99 block 2 tripeptide repeats
3 P.falciparum
100
MSP1
(allele) (intragenic recombination)

101
P.falciparum
102
recombination

103
MSP1 P.falciparum
schizont precursor protein

2
(primary processing) 83
30 38 42
(secondary processing)
42 2
33
19
97,104 merozoite
(ring stage)
19 PfMsp-119
epidermal growth factor (EGF)-like domain
2
PfMSP119
P.falciparum105-107
merozoite

104,108 PfMSP1
Aotus
(partial protection)
109-111

PfMSP1
block 2 C-terminus
105,112
522
MSP1 P.vivax (PvMSP1)
PfMSP1
PvMSP1
113,114 P.vivax
PvMSP1
115-117
C-terminus PvMSP1 42
(PvMSP142) 19 (PvMSP119)

118 PvMsp-1
merozoite
PvMSP1 red cell reticulocyte

binding motifs 119,120
PvMSP1
PfMSP1

PvMSP1 PfMSP1

(allele) 2
PvMSP1
(mosaic organization)
PvMSP1
PvMSP1
13 block121 conserved block 7
variable block 6 conserved
block codon
5
2
(dimorphic substitution)
PvMSP1
intragenic recombination
merozoite
glycosylphosphatidylinositol (GPI) anchor122-124
P.falciparum
35 56

MSP2

2
repeats non-repeats

MSP2
2 FC27 3D7
FC27 repeats
2
32 repeats 3
12 repeats 1 5
3D7
repeats
alanine, glycine serine122-124

FC27 3D7
125,126 MSP2
merozoite 127
merozoite
cross-link merozoite128
MSP2
merozoite 129
Irian Jaya
P.falciparum
repeats Msp-2

130-132
41 523

MSP3 P.falciparum (PfMSP3)
43 repeats 7
alanine 1 5 repeats
Msp-3
coiled-coil alpha-helices133,134 MSP3
P.vivax (PvMSP3)
3 PvMSP3-, PvMSP3-
PvMSP3-135
75 105
(coil motif)
PfMSP3
antibody-dependent cellular inhibition
(ADCI)136

cytophilic IgG1 IgG3
monocyte MSP3
Fc receptor cytokines
136,137
merozoite surface protein 5 (MSP5) 2
P.falciparum (PfMSP4 PfMSP5)
40
merozoite C-terminus
epidermal growth factor (EGF)-like
domain138 MSP1 PfMSP4
PfMSP5 139-141

PfMSP4

142
MSP4 MSP5 PvMSP4
PfMSP4 PvMSP5
PfMSP5143,144 MSP4 MSP5
MSP4/5
MSP4/5 P.yoelii

142,145 MSP4 MSP5
2.5 apical membrane antigen 1 (AMA1)

microneme
apical organelle 83
merozoite
trophozoite
schizont
66 merozoite
merozoite
AMA-1 merozoite
merozoite
146,147 AMA-1
merozoite 148
AMA-1
AMA-1
P.falciparum 1) N-terminus
(extracellular domain) 546 2)
(transmembrane domain)
21 3) C-terminus
(cytoplasmic domain)
55 AMA-1
cysteine 16
disulfide AMA-1
3 loop 149

AMA-1 P.falciparum
T helper epitopes
524

T cell epitopes C-terminus CSP

P.falciparum66,150 AMA-1 P.vivax

intreagenic recombination AMA-1
P.knowlesi
rhesus
151,152 AMA-1
Plasmodium fragile recombinant
squirrel
153
AMA-1 P.chabaudi
T cell

154,155 AMA-1
2.6 Glutamate-rich protein (GLURP)

parasitophorous vacuole
220
156 GLURP

157
GLURP 5 9

GLURP 158

GLURP 159
repeats repeats
GLURP
merozoite
monocyte
P.falciparum
antibody-dependent cellular inhibition

MSP3160
cytophilic antibody 138

erythrocyte-binding protein
(EBA-175), serine repeat antigen (SERA), ring-infected
erythrocyte surface antigen (Pf155/RESA) rhoptry
proteins 161,162
3.
(sexual stage vaccine
candidates)
gametocyte

163,164 3
1)
(pre-fertilization) gametocyte
gamete exflagellation
gametocyte
Pfs230 Pfs48/45 P.falciparum 2)
zygote ookinete
(post-fertilization) Pfs25
Pfs28 P.falciparum 3)
late-midgut-stage
chitinase ookinete

proteinase chitinase

41 525
3.1 Pfs230
48 gametocyte
363
310
gamete165,166 Pfs230
repeats glutamine

N-terminus
gamete
310
Pfs230 cysteine
motif cysteine 7
6
167 Pfs230
gametocyte complement
antibody-dependent complement-mediated lysis
168,169
repeats
Pfs230 zygote
repeats
167
3.2 Pfs48/45 48 45
gametocyte, gamete zygote
P.falciparum Pfs48/45
4-cysteine
motif 6-cysteine motif Pfs48/45
Pfs230
Pfs48/45
complement170
epitope
epitope 171
ookinete Pfs48/45

epitope Pfs48/45
172,173
3.3 Pfs25
gametocyte P.falciparum
exflagellation
zygote ookinete
oocyst 174
Pfs25 EGF-like
domain 4 domain 2

175
EGF-like domain
disulfide cysteine
B cell epitope conformational
epitope epitope
epitope
discontinuous epitope176
Pfs25
177
Pfs25

178,179
3.4 Pfs28 P.falciparum
zygote
Pfs25180 secretory signal
N-terminus GPI anchor C-terminus
EGF-like domain
4 180 Pfs28
Pfs25
180

ookinete oocyst
526
1. (antigenic diversity)

1.1
(allele) (intragenic interallelic
recombination)

Hardy-Weinberg equilibrium
genetic cross
181

epitopes

P.falciparum
P.vivax

merozoite
surface protein-1, merozoite surface protein-2, apical
membrane antigen-1 merozoite surface protein-5
100,121,140,144,182-184
repeats

unequal
crossing-over slipped-strand mispairing
185

P.falciparum circumsporozoite
protein block 2 merozoite surface
protein-1 merozoite surface
protein-2 sporozoite threonine-asparagine rich
protein66,100,183,184,186 P.vivax merozoite
surface protein-1 repeats merozoite
surface protein 4 5 121,143,144,187
repeats
epitope
repeats
repeats
1.2 (antigenic
variation)
subtelomere
P.falciparum
var
erythrocyte membrane protein 1 (PfEMP1)
rif Rifin (repetitive interspersed family)
41 527
stevor (subtelomeric variable open reading

frame) Pfmc-2Tm Pfmc-2Tm
(Maurers cleft two transmembrane)

var 60 rif 149 stevor
28 Pfmc-2Tm 11 186,187
messenger RNA
(mRNA) mRNA

var
early growing trophozoite
rif mature trophozoite stevor
Pfmc-2Tm
Maurers cleft
(knob-like
structure) 188,189
PfEMP1
cytoadherence

(visceral blood)
sequestration
receptor
CD36, ICAM-1 (intercellular adhesion molecule-1),
TSP (thrombospondin), CR1 (complement receptor-1),
VCAM1 (vascular adhesion molecule-1) CSA
(chondroitin sulfateA)189 PfEMP1
rosettes

Duffy-binding-like 1 domain DBL-1190
(switch)
PfEMP1
10-2
1

191

PfEMP1
knob
clinical immunity

528
gametocyte
192-194
var
var2csa chondroitin
sulfateA
syncytiotrophoblasts
var2csa

var2csa
195
gametocyte

var, rif stevor

PfEMP1
PfEMP1

196
2.

merozoite
apical organelles

merozoite surface protein-1
merozoite
apical membrane antigen 1
(re-orientation) merozoite
apex erythrocyte
binding ligands (EBLs) reticulocyte binding protein
homologs (RBLs PfRh) tight junction
apical organelles 197
EBLs 3
EBA175, EBA140/BAEBL EBA181/JE SEBL
EBLs glycoproteins
sialic
glycophorin A C sialic acid band
4.1 RBLs 4
PfRh1, PfRh2a, PfRh2b PfRh4
sialic (sialic-acid-dependent
pathway) EBAs PfRh1

sialic
(sialic-acid-independent pathway)
merozoite PfRh2a
PfRh4

gametocyte
1-2
198-200
3. epitopes (cryptic epitopes)
epitope
epitope
epitope

epitope
sporozoite P. yoelii

41 529

CD8+ T lymphocyte
CSP
sporozoite

epitope MSP1, CSP AMA1

T lymphocyte epitopes
B lymphocyte
epitopes

disulfide
epitopes MSP2, CSP, AMA1
TRAP 155,201-203
4. T cell mimotopes altered peptide
ligands (APLs) T cell
T cell (T cell receptor, TCR)
MHC-peptide complexes antigen
presenting cells (APCs)
T cell
(affinity) TCR
MHC-peptide complexes TCR crosslinking cytokine
T cell
TCR agonist T cells
TCR partial agonist
TCR antagonist
1 2
T cell
CD4+ T cell Th1
proinflammatory Th2 anti-inflammatory

P.falciparum MSP1
T cell
CSP
T cell epitopes
T cell interleukin-10
(IL-10) anti-inflammatory
204,205
5. dendritic cells
P.falciparum
malarial pigment hemozoin
T cell
dendritic cell

dendritic cell
apoptosis
dendritic cell merozoite
206-208
6. regulatory CD4+CD25+
Foxp3+ T cell (Treg) Treg
self-tolerance
209 Treg
thymus
Treg thymus
transforming growth factor beta (TGF-) Treg
Th1, Th2 Th17 cells
P.falciparum Treg TGF-
210 P.vivax
Treg
IL-10 211
Treg
530
1. (traditional vaccinology)
Edward Jenner
(vaccinia virus)
(smallpox) ..1796
Louis Pasteur

212
(recombinant
protein) (adjuvant)

213

(autoimmunity)
T cell epitope
2. (reverse vac-
cinology)
genome
214
2.1 genome

CD4+ T cell epitopes
CD8+ T cell epitopes HLA haplotype
2.2
recombinant peptide

tetrameric staining repeats
T cells
ELISPOT intracellular cytokine staining (ICCS)

(cell-mediated immune
response)
B cell epitope
2.3

2.4

(molecular
epidemiology)
2.5
41 531
phase I, II III
2.6

2.7

2.8

phase IV

(molecular evolution)
(population genetics)

(positive selection)

215

(neutral evolution)

1.
(dN)
(dS) dN/dS
1
216 CSP
P.falciparum 3 dN/dS
1
CD4+ T cell epitopes (Th2R Th3R epitopes)
CD8+ T cell epitopes217

P.falciparum STARP, PfMSP4,
PfMSP5, PfAMA1 PfTRAP 87,140,182,186
P.vivax PvMSP4, PvMSP5 PvTRAP
89,143,144
epitopes
epitopes HLA haplotupe
PfMSP5 PvMSP5
2. McDonald-Kreitman (MK) test

(synonymous
polymorphism)
(nonsynonymous
polymorphism) species
(fixed difference)
species MK test
(neutrality index)
218
epitope
MK test
PvMSP5
Hudson-KreitmanAguade test 219
3. Tajima Test

532
1 segregating
site Tajimas D D
directional selection

Tajimas D
balancing selection220
Tajimas D
PfMSP3 PfAMA1
extracellular domain 221,222
balancing selection
Fu and Lis tests
Tajima test
223
4. Wrights Fst F statistics
fixation index
2

Fst Fst

balancing selection224 Fst
PfMSP1
balancing selection

PfMSP1

Wrights Fst
225

reverse vaccinology

T cell
epitopes

reverse
vaccinology
genome
adenine thymine
codon
(codon usage) (
)
(cell-free expression)

214,226
(Adjuvants)

adjuvant
adjuvant
(potency)

adjuvant
adjuvant
41 533

adjuvant
colloid emulsion
adjuvant
adjuvant
adjuvant
2 227
1. adjuvant
(immunostimulant) ligand
Toll-like receptor (TLR), saponin, cytokine
exotoxin

2. adjuvant
(vehicle)
adjuvant
adjuvant
adjuvant mineral salts, emulsion,
virosomes, liposomes microspheres
polymer
adjuvant

adjuvant

(attenuated)
(inactivated)
adjuvant
unmethylated deoxycytidyl-deoxyguanosine (CpGs)

TLR9
species TLR9
species
adjuvant

TLR
(autoimmune responses)
adjuvant Montanide ISA-720
water-in-oil emulsion sterile abscess
228,229
adjuvant saponin
(QS21)

oil-in-water liposome adjuvant
AS01 AS02

adjuvant
RTS,S
Alum monophosphosyl
lipid A (AS04) Alum oil-in-water emulsion
(AS03) adjuvant
RTS,S

adjuvant monophosphosyl
lipid A QS21 oil-in-water emulsion
227

1. Alum Aluminum
adjuvant

adjuvant

Alum
Alum Th1 cell
CTL
230
534
2. MF59 squalene-in-water
emulsion 250
adjuvant Alum
IgG subclass
helper T cell
Th1 lymphocyte
adjuvant
231
3. MPL adjuvant Th1
cell MPL
lipopolysaccharide Salmonella minnesota
hydrophilic polysaccharide
hydrophobic lipid core232,233
TLR4 adjuvant

AS04 aluminum

adjuvant
adjuvant liposome
saponin 234-236
1. Montanides (ISA51 ISA720)

water-in-oil emulsion squalene
mannide-monolate
incomplete Freunds adjuvant237,238
Montanides
ISA720

239,240
2. Saponins Quil-A,
immunostimulating complexes (ISCOM), QS-21,
AS02 AS01 adjuvant triterpene
glycosides saponin
Quil-A
glycosides adjuvant
241 ISCOM
phospholipids, choleslerol Quil-A
(cage-like
particle) 40
242 QS-21 Quil-A
Th1
CTL adjuvant

243
3. MPL
MPL-SE Squalene oil, 3-deacylated
monophosphoryl lipid A carrier
(leishmaniasis)244 AS02
oil-in-water emulsion MPL
QS-21
Th1 lymphocyte
AS01 MPL QS21 liposome236,245
4. (oligonucleotides)
unmethylated CpG TLR9
dendritic cell
pro-inflammatory cytokines tumor necrosis factor
alpha (TNF-), interferon gamma (IFN-) IL-12
CpGs Th1 CTL
adjuvant
246,247
5. Imidazoquinolines
antigen presenting cells (APCs)
inflammatory cytokines chemokines
adjuvant imiquimod
TLR7 resquimod TLR7/8
imiquimod antigen
41 535
presenting cell 235,240
P.falciparum

transmission-blocking vaccines
1.
(whole parasite vaccines)

(whole
killed vaccines)

(live attenuated vaccines)

.. 1941 248

(rhesus macaque) P.knowlesi
P.falciparum Aotus
Saimiri
P.chabaudi,
P.vinckei, P.yoelii P.berghei

adjuvant

.. 1976 Trager Jensen
P.falciparum
249

(infection-cure model)

536
(homologous parasite)
(heterologous parasite)

250-252
P.falciparum
30
5
chloroquine
3
PCR
1

T cell
CD4+ CD8+ T cells
IFN- IL-4
IL-10
nitric oxide synthase mononuclear cells

cell-mediated immune response

253
sporozoite
3
chloroquine
chloroquine
1

cytokine
CD3+ CD45R0+ memory T
cells CD4+ CD8+ T
lymphocytes
254
sporozoite
94 sporozoite

sporozoite
cytotoxic CD8+ T cell

1
sporozoite
sporozoite

sporozoite
UIS3, UISE4 P3bp

sporozoite
41 537
SanariaTM PfSPZ vaccine255

2.
(recombinant protein vaccines)
genome
P.falciparum adenine
thymine 80 codon
expression
vector
codon

glycosylation sites
MSP1
C-terminus 42 (PfMSP142), PfAMA-1
PfEBA175 glycosylation sites

glycosylation sites

256

HLA class I class II
regulatory T cell
epitope
cryptic
epitope 3

epitope
cryptic epitope

altered peptide ligand
antagonism T cell mimotope

CD4+ T cell pro-inflamanatory
(Th1) anti-inflamanatory (Th2)
256

2.1 RTS,S

Water Reed Army Institute of Research (WRAIR)
GlaxoSmithKline (GSK)
.. 1984
circumsporozoite
protein CS

Escherichia coli
CS
257

538
Phase IIb
.. 1994 1996
258,259 CS
GSK
HBsAg (S antigen)
Saccharomyces cerevisae
HBsAg S protein
virus-like particle 260
GSK

tetrapeptide repeats (NANP) CS 16
HBsAg R16-HBsAg
261

tetrapeptide repeats B cell epitopes
C-terminus CS T cell
epitopes 3 epitopes
RTS,S R NANP repeats
T T cell epitopes CS
HBsAg S protein S
S protein CS
RTS,S
Phase I/IIa
.. 1995
2 8 RTS,S Alum
MPL
6
RTS,S Alum
262 adjuvant

adjuvant
RTS,S/AS04 1 8

RTS,S/AS03 2 7
RTS,S/AS02A
( 1)
6 7
RTS,S/AS02A phase I/IIa
40
263-265
phase IIb
3 0, 1 5
15 34

19 47
P.falciparum
CS HBsAg 5 266,267
RTS,S/
AS02A
RTS,S/AS0D
1 4
2,022 0, 1 2
6

29
58
18
35 49
45
26 38
41 539
1 RTS,S
Formulation
RTS,S/AS02A
RTS,S/AS02D
RTS,S/AS01B
RTS,S/AS01E
RTS,S
50
25
50
25
MPL
(g)
50
25
50
25
QS21
(g)
50
25
50
25
Final volume
(g)
0.5
0.5
0.5
0.5
Adjuvant system
(ml)
liposome-based
liposome-based
( 257)
34268,269
RTS,S/AS0D

Haemophilus influenzae type b (Hib)
8, 12 16

expanded program on immunization
(EPI)
66 3

270
RTS,S/AS02
adjuvant oil-in-water emulsion
RTS,S/AS01
adjuvant liposome adjuvant 2
MPL QS21
RTS,S/AS01B
T cell CS
Th1 RTS,S/AS02A
271
phase IIa
RTS,S/AS01B
CD4+ T cell
CS RTS,S/AS02A
RTS,S/AS01B
50 RTS,S/AS02A
32272
18 4
RTS,S/AS01E

RTS,S/AS01 RTS,S/AS01E
5 17
8
53
EPI
phase
III .. 2009
double-blind
2
16,000 7
.. 2011 257
RTS,S/AS01E
50
1
(insecticide
treated bed nets)
(intermittent preventive treatment)
540
2.2
clinical immunity

HLA

P.falciparum

2.2.1 merozoite
surface protein 1 MSP1
C-terminus
epidermal growth factor-like domain
disulfide 2 loops MSP119
19
P.falciparum 3D7 FVO
T cell epitopes tetanus toxoid Alhydrogel
phase I

C-terminus
MSP142 MSP119 MSP133 2
AS02
adjuvant phase I

1 3
phase IIb

MSP1

273-275
2.2.2 apical membrane
antigen1 E.coli Pichia pastoris
AMA1 P.falciparum 3D7
ectodomain N-terminus
2 3 AS02A AS01
adjuvant phase I/IIa

phase
II 1 6

3D7 FVO
2 3
AMA1
adjuvant AS02A
AMA1
clinical immunity

276-279
2.2.3 merozoite
surface protein 2 MSP2
E.coli
P.falciparum 3D7

CS N-terminus
MSP1 RESA Montanide
ISA720 adjuvant
41 541
280,281
6 9
phase I/IIb

P.falciparum
MSP2 3D7
283
MSP2 MSP2
FC27
MSP2 2
2.2.4

P.falciparum
1) PfCP2.9
AMA-1 domain
3 MSP1 C-terminus 19
MSP119 P.pastoris
Montanide ISA720 adjuvant 2) GMZ2
GLURP repeats
C-terminus MSP3
Lactococus lactis
Alum adjuvant
CP2.9
AMA1 MSP119

phase I 2

2
284,285
GMZ2 ADCI
phase I
GLURP
MSP3
merozoite
ADCI 286
3
1)

merozoite
MSP1 AMA1
monocyte cytokines
ADCI 2)

adjuvant
3
3)
3

MSP1 AMA1
disulfide
3 disulfide

epitope
(discontinuous epitope)
epitope
PfMSP119 merozoite
(inhibiting antibodies)
542
merozoite
merozoite
(blocking antibodies)
conformationdependent B cell epitopes epitopes
domain
allotype
steric hindrance inhibiting
antibodies

(inhibitory) (blocking)
(neutral)
PfMSP119 P.falciparum

EGF-like domain
257
3. (synthetic
peptide vaccines)

epitopes

epitope

(protein
carrier)
P.falciparum
3.1 circumsporozoite peptide vaccines
tetrapeptide repeats CS
epitopes
sporozoite

sporozoite
repeats sporozoite

sporozoite
sporozoite

CS sporozoite
sporozoite
CD4+ T cells
cytokines B cell differentiation
CD8+ memory T cells
cytokines IFN-
exo-erythrocytic stage

inducible nitric oxide
synthase (iNOS) nitric oxide
287,288
T cell epitopes B cell epitopes

sporozoite
3.1.1
(branched peptide vaccines)

repeats CS P.falciparum
3 tetanous toxoid
adjuvant (NANP)3-TT conjugate vaccine
41 543
( anamnestic response)

multiple antigen peptide (MAP)
non-cationic polylysine core matrix

(branched peptide)289
3.1.1.1 (TIB)4MAP NANP

3 B cell epitope
T cell epitope NANPNVDP 2
B cell epitopes tetrapeptide
repeats CS T helper
epitope
Th1
anamnestic response
290 phase I
(T1B)4MAP Alum QS21
sporozoite
HLA DQB1*0603,
DRB1*0401 DRB1*1101
25 35
HLA
291
CD4+
T cell Th1
IgG1 IgG3 adjuvant QS21
Alum

sporozoite
NANP cross-link
sporozoite precipitin
sporozoite sporozoite 291
3.1.1.2 (T1BT*)4-P3C
T1B universal T cell epitope
CST.3 epitope C-terminus CS
20 292
48 lysine
oxime
4
lipopeptide palmitoyl-S-glyceryl cysteine (P3C)
Toll-like receptor 2 (TLR2) agonist
TLR-2

P3C adjuvant
(T1BT*) 4 P3C
adjuvant
tetrapeptide repeats sporozoite

Phase I
sporozoite

CD4+ T cell
IgG1 IgG3
IFN-
CD4+ memory T cell T cell
epitope

CD4+ T cell
sporozoite 291,293
3.1.2
(linear peptide vaccines)
3.1.2.1 48 mers linear T1BT* peptide

48
544
T1BT* Montanide ISA720 adjuvant
repeats CS sporozoite

Th2 IgG1
opsonization
sporozoite

291
3.1.2.2
C-terminus CS (long
synthetic peptides, CS LSP vaccine)
sporozoite

CD8+ T cells cytokines
IFN- CS LSP
100
T cell epitopes C-terminus
CS
CD8+ cytotoxic T lymphocytes
CS
IFN-
sporozoite

sporozoite
CS LSP phase I
CD8+ T cell CS
P.falciparum

291
3.2 erythrocytic stage peptide vaccines
phase I 2
3.2.1
glutamate-rich protein (GLURP LSP vaccine)
N-terminus
GLURP P.falciparum
B cell epitopes
IgG1 IgG3
antibody dependent cellular
inhibition ADCI GLURP
merozoite
monocyte

clinical immunity
GLURP LSP Alum
Montanide ISA720 adjuvant
T cell B cell
IFN- mononuclear cells
IgG1

ADCI
294-296
3.2.2
merozoite surface protein-3 (MSP3 LSP vaccine)
clinical immunity C-terminus

PfMSP-3 70
B cell epitopes IgG1 IgG3
T cell epitopes Th1

MSP3 LSP Alum Montanide ISA720
adjuvant Alum adjuvant

MSP3
T cell IFN-
41 545
Montanide ISA720 adjuvant

MSP3
ADCI
GLURP LSU
297-299
3.3 multistage malaria peptide vaccines

2
3.3.1 SPf66 vaccine
tetrapeptide repeats (NANP)
CS MSP1
2 35 55

phase I III
30

SPf66
300-302
3.3.2 malaria peptide virosomes
virosomes unilamellar
liposomal vesicles 150
hemagglutinin (HA) glycoproteins influenza
virosome
antigen presenting cells
virosomes
protein carrier adjuvant303-305
CS semi-conserved domain III apical

membrane antigen 1 AMA1
49 phosphatidylethanolamine
virosomes
CS
sporozoite 44
1
3 0, 2 6

AMA-1
2

2 306,307

adjuvant

(active case detection )
(passive case detection )
546

PvAMA1, PvMSP1,
PvMSP4, PvMSP5, PfCSP PfMSP2

P.falciparum P.vivax 184

(bottleneck effect)184
5
intragenic recombination

184
1. Coluzzi M. The clay feet of the malaria giant

and its African roots: hypotheses and inferences about
origin, spread and control of Plasmodium falciparum.
Parassitologia. 1999;41:277-83.
2. Hoeppli R. Parasites and parasitic
infections in early medicine and science. Singapore:
University of Malaya;1959.
3. Russell PF. Mans mastery of malaria.
London: Oxford University Press; 1955.
4. Sallares R, Bouwman A, Anderlung C. The
spread of malaria to southern Europe in antiquity: new
approaches to old problems. Med Hist. 2004;48:311-28.
5. Garnham PCC. Malaria parasites and
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567
42
2. (Immune
modulating vaccines)
(autoimmune
diseases) 1
( allergic diseases) 1
allergen specific immune therapy
desensitization

mucosal intolerance IgG blocking
antibody (allergen)
IgE cross link mast cell
1. (Antibody allergic inflammatory cascade 2
inducing vaccines)
adjuvant
monophosphoryl lipid A Th2
(target molecule) antiinflammatory response
IgG blocking antibody
(neutralize) anaphylaxis3

3.
T effector cell
(autoimmune T cell mediated inflammation)
immune complex soluble
target overinhibit target enzyme

(non communicable disease)

10

1
568
1 1
(antibody inducing vaccines)
(Alzheimers disease)
(stroke)
(Parkinson disease)
(atherosclerosis)
rheumatoid
(Immune modulating vaccines)
(type I diabetes)
Multiple sclerosis
Myasthenia gravis

(personalized vaccine)

(adjuvant)
target antigen
-amyloid
N-methyl D-aspartate receptor

-synuclein
Cholesteryl ester transfer
protein (CTEP)
Apo B100
Angiotensin I, II
Interleukin-5
TNF-
Insulin, GAD
Myelin basic protein
Acetyl choline receptor
Environmental allergens
neurodegenerative disease
26
(loss of recent memory)

amyloid-A plaques (
beta-amyloid amyloid precursor
protein )
grey matter intracellular
neurofibrillary tangles (NFTs)
hyperphosphorated tau protein
10

(clinical trial phase)
clinical trial 11
9,000 4
A beta 42/QS21 (AN-1792)

(Alzheimers disease vaccine)
A 1-42 peptide amyloid precursor
progressive protein saponin adjuvant QS-21
42 569
1 (Phase I clinical trial)

80
6
5
2 (Phase IIa)
300
.. 2545
A beta 42
6 aseptic
meningoencephalitis leukoencephalopathy6,7
B cell
T cell 11-15
B cell epitope anti-A

15-42 T cell epitope Th1-mediated cellular immune response (T cell induced autoantibody) IL-2 IFN
meningoencephalitis
Th2 lymphocyte
response
CAD-106 A1-6
Qb virus like particle8
aminoterminus A (AD01, AD02)9
HDL-cholesterol

LDL-cholesterol T cell receptor
LDL
10
HDL-cholesterol
cholesteryl ester transferring
protein (CETP) cholesterol
HDL LDL CETi-1
1 2
CETP
90 HDL
11
adjuvant CPG
7909 pre-clinical phase12
(Preventive cancer vaccine)

(Atherosclerosis vaccine)

(atherosclerosis) 13 (hu man papilloma virus) 14

(chronic H.pylori
inflammatory response) 15,16
LDL-cholesterol
570
(Therapeutic cancer vaccine)

long term
memory cell
innate adaptive
immunity

1.

(Castration-resistant prostate cancer) SipuleucelT immunotherapy17

leukapheresis
recombinant fusion protein PA 2024
prostate antigen, prostate acid phosphatase
granulocyte colony stimulating factor (G-CSF)
2 3
512
(3-year survival) 23
32 Sipuleucel-T
Sipuleucel-T

.. 2553
2. (Non
Hodgkins lymphoma, follicular type)
Biovax ID anti-idiotype
immune response
tumor specific immunoglobulin
B-cell idiotype (Id)
idiotype
(autologous
tumor cells) hybridoma

keyhole limpet hemocyanin (KLH)
Id-KLH (subcutaneous
administration) GM-CSF
(remission stage)
tumor specific humoral immunity
cellular immunity
Phase II clinical trial
22 62
Id-specific immune response

(progession-free survival) 38 12
Biovax ID 318

200

30
biotechnology

42 571
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recombinant allergens or allergen constructs. Curr
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3. Mothes N, Heinzkill M, Drachenberg KJ,
Sperr WR, Krauth MT, Majlesi Y, et al. Allergen-specific
immunotherapy with a monophosphoryl lipid
A-adjuvanted vaccine: reduced seasonally boosted
immunoglobulin E production and inhibition of
basophil histamine release by therapy-induced blocking
antibodies. Clin Exp Allergy. 2003;33:1198-208.
4. Lemere CA, Masliah E. Can Alzheimer
disease be prevented by amyloid-beta immunotherapy?
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of the safety and immunogenicity of synthetic
Abeta42 (AN1792) in patients with AD. Neurology.
2005;64:94-101.
6. Orgogozo JM, Gilman S, Dartigues
JF, Laurent B, Puel M, Kirby LC, et al. Subacute
meningoencephalitis in a subset of patients with AD
after Abeta42 immunization. Neurology. 2003;
61:46-54.
7. Gilman S, Koller M, Black RS, Jenkins
L, Griffith SG, Fox NC, et al. Clinical effects of Abeta
immunization (AN1792) in patients with AD in an
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study with the active A immunotherapy CAD106 in
Alzheimer patients [abstract]. Alzheimers Dementia.

2009;5:P113-4.
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Mattner F Schmidt W. Development of Alzheimer
AFFITOPE vaccines-from concept to clinical testing
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10. Hermansson A, Ketelhuth DF, Strodthoff D,
Wurm M, Hansson EM, Nicoletti A, et al. Inhibition of T
cell response to native low-density lipoprotein reduces
atherosclerosis. J Exp Med. 2010;207:1081-93.
11. Davidson MH, Maki K, Umporowicz D,
Wheeler A, Rittershaus C, Ryan U. The safety and
immunogenicity of a CETP vaccine in healthy adults.
Atherosclerosis. 2003;169:113-20.
12. Timmerman JM, Vose JM, Czerwinski DK,
Weng WK, Ingolia D, Mayo M, et al. Tumor-specific
recombinant idiotype immunisation after chemotherapy
as initial treatment for follicular non-Hodgkin
lymphoma. Leuk Lymphoma. 2009;50:37-46.
13. Mast EE, Margolis HS, Fiore AE, Brink
EW, Goldstein ST, Wang SA, et al. A comprehensive
immunization strategy to eliminate transmission
of hepatitis B virus infection in the United States:
recommendations of the Advisory Committee on
Immunization Practices (ACIP) part 1: immunization of
infants, children, and adolescents. MMWR Recomm
Rep. 2005;54:1-31.
14. Borleffs JC, Danner SA, Lange JM,
van Everdingen JJ; Commissie Richtlijnen van de
Nederlandse Vereniging van Aids Behandelaren. [CBO
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Ned Tijdschr Geneeskd. 2001;145:1585-9.
15. Czinn SJ, Blanchard T. Vaccinating against
Helicobacter pylori infection. Nat Rev Gastroenterol
Hepatol. 2011;8:133-40.
572
16. Del Giudice G, Malfertheiner P, Rappuoli R.
Development of vaccines against Helicobacter pylori.
Expert Rev Vaccines. 2009;8:1037-49.
17. Kantoff PW, Higano CS, Shore ND, Berger
ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N
Engl J Med. 2010;363:411-22.
18. Lee ST, Jiang YF, Park KU, Woo AF,
Neelapu SS. BiovaxID: a personalized therapeutic cancer
vaccine for non-Hodgkins lymphoma. Expert Opin Biol
Ther. 2007;7:113-22.
573
Herpes simplex virus (HSV)

herpetic gingivostomatitis genital herpes
congenital herpes infection, neonatal herpes infection,
herpes keratitis herpes simplex virus encephalitis
HSV
(latent infection)
(asymptomatic
viral shedding)
(reactivation)1
43
HSV-2
2
HSV-2
75 HSV-1
252 HSV 1
:
HSV 2
1
5,000 20,000
HSV
6 3
HSV

Herpes simplex virus family Herpesviridae persistent
double-stranded DNA enveloped virus latent infection
subfamily Alpha-
herpesvirinae herpes simplex virus type 1
2 varicella zoster virus subfamily
subfamily Beta-herpesvirinae (primary
( cytomegalovirus, human herpes virus 6 infection) 33-50
7) Gamma-herpesvirinae ( Epstein-Barr (secondary infection)
virus human herpes virus 8)
5
HSV-1
( Herpes simplex virus)
574
25
2 2
1-2

3-5 4
1. (Neonatal herpes simplex

infection) 3
(disseminated infection)

(central nervous system infections)

(skin eyes and mouth, SEM)

3

HSV

2-4
5
2. (Children beyond
neonatal period and adolescents)

HSV-1 gingivostomatitis

submandibular
HSV-2 genital herpes

perineum
Herpetic whitlow HSV

Herpes encephalitis primary
recurrent infection

(focal neurologic)
pleocytosis
lymphocytes erythrocytes
trigeminal neuralgia,
Bells palsy, ascending myelitis postinfectious
encephalomyelitis

DNA gold standard

enzyme immunoassay (EIA)
cytopathogenic effect (CPE)
1-3

48
colonization (contamination)
Tzank smear
43 575
HSV acyclovir,
valacyclovir, famciclovir valacyclovir L-valyl ester
acyclovir
acyclovir famciclovir penciclovir
1. HSV neonatal
HSV infection, HSV encephalitis acyclovir
nucleoside
inhibitor herpes DNA polymerase
60 ././ 3 14
SEM 21
6
2. HSV
acyclovir
topical acyclovir
HSV
acyclovir
acyclovir
foscarnet 7
3. HSV
HSV
neuron reactivate
(recurrent infections)

acyclovir 6
viral shedding 3-5
acyclovir 2
1 8
HSV
HSV
9-13
HSV neuron
(epithelium)
axonal uptake
HSV (replicate)

24
HSV
HSV-1 HSV-2
HSV-1
HSV

T-lymphocyte
T-cell (cellular response) B-cell
(antibody response)

HSV
neuron reactivate
latent
infection

(mode of delivery)

lipopeptide needle-free mucosal
vaccine
CD8 CD4 14,15
576
HSV16
1. (prophylactic vaccine)
(primary infection)
genital
tract genital herpes

(symptomatic
infection)

2. (therapeutic
vaccine)17

recurrent genital herpes

viral shedding
HSV 2
live-attenuated viral vaccine, killed vaccine
subunit vaccine purified viral protein
adjuvant
heterologous viral vector expressing HSV

protein, replication-impaired HSV vaccine
DNA vaccine

Inactivated whole virus
Subunit vaccine (detergent solubilized)
Live-attenuated vaccine (passaged)
Recombinant HSV proteins

Synthetic peptides
Lived-attenuated vaccines (specific
mutations)
Replication-impaired vaccines
Heterologous viral vectors expressing
HSV antigens
DNA vaccines
recombinant HSV glycoprotein adjuvant deacylated monophosporyl lipid A
genital herpes11
HSV
HSV
Live-attenuated/replication impaired
- R7020
Pasteur Merieux
- ICP10DPK
AuRx Inc.
Killed/viral component
- HSV-2 GS
Merck,
Sharpe & Dohme
- Biocine
Chiron
(gD2/gB2/MF59)
- Herpvac
GlaxoSmithKline11
(gD2/MPL-alum)
HSV ( 2)
1. Inactivated or component vaccine
killed viral vaccine,
subunit vaccine purified viral protein
derivates recombinant proteins
live-attenuated vaccine virulent
strain
glycoprotein
adjuvant
(booster reactivity)
18
2. Live-attenuated HSV vaccine

inactivated
43 577
vaccine
recombination
circulating wild-type HSV strain
19
3. Recombinant viral protein vaccine
HSV glycoprotein
gB gD recombinant DNA
Escherichia coli
Biocin (Chiron) HSV
glycoprotein gB gD MF59 adjuvant
neutralizing antibody HSV-2
genital herpes 20
Herpvac (GlaxoSmithKline)
HSV glycoprotein gD alum 2-O-deacylatedmonophosphoryl lipid A (MPL) adjuvant
HSV-2
humoral-mediated cellular-mediated
genital herpes
HSV-1 HSV-2
HSV-1
11
4. Peptide vaccine
HSV-specific T B cell
immunodominant epitopes LEAPS vaccine
(ligand epitope antigen presentation system)
peptide
21
5. Heterologous viral vectors expressing
HSV antigens
genetic engineering
HSV antigen foreign live recombinant
viral vector vaccinia virus, adenovirus, varicella
zoster virus (Oka vaccine strain)

reactivity interference
specific viral vector
13
6. HSV DNA vaccine
plasmid HSV gene
humoral-mediated cellularmediated
22
cytokine/chemokine gene
CCR7 ligands

gD2 DNA vaccine (GENEVAX, Apollon, USA)23-25

(lifelong immunity)

antigenic protein recombinant
protein vaccine polytopes (genes representing
antigenic epitopes) DNA vaccine
adjuvant vector

(cross protection) HSV-1 HSV-2

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76
581
(Lyme Disease)
..
1976

juvenile rheumatoid arthritis1

erythema migrans
(multisystem disease)

2
(Ixodid tick)3
.. 1982 Burgdorfer Barbour
spirochete ixodes dammini ticks
44
Borrelia burgdorferi4 spirochete

(erythema migrans) meningopolyarthritis acrodermatitis chronica atrophicans
(ACA) 5-7
B. burgdorferi8

(vector-borne)
15 9

( 1)
582

13

(Midwest)
B. burgdorferi sensu lato (s.l.) complex10
13 species ( 2)9,14
3 species B. burgdorferi sensu
stricto (s.s.), B. afzelii, B. garinii 3 species
2 species (B. afzelii B.
garinii) B. burgdorferi (s.s.) 15
B. burgdorferi
spirochete flagella (surveillance)
o u t e r m e m b r a n e ..1982
1-5 Mb 11,12 (Centers for Disease
virulence factor surface protein Control and Prevention)
2
. 2006
44 583
3-4
20,000 / 95
(vector borne disease)

5-14
50-59 9
host
(I. scapulris)

20 16

(Ixodid tick)
(feeding habit) animal hosts

B. burgdorferi
2
9
extracellular matrix
innate adaptive immune response macrophage
antibody-mediated killing
16 B. burgdorferi lipoprotein
adaptive T cell independent
B cell22 antibody outer surface proteins C (OspC)
humoral immune system non-lipidated
protein
B. burgdorferi-specific T
helper 1 T-cell
dependent B cell

opsonization complement fixation16

erythema
migrans

B. burgdorferi
B. burgdorferi

3 ( 1)
human plasminogen, plasminogen activator (localized erythema migrans)
spirochete 17 ( 2)
B. burgdorferi
host integrin,18 matrix glycoaminogly- 3
can19 extracellular matrix protein20 Bor-
relia decorin-binding protein (Dbps) A B
decorin21 glycoaminoglycan collagen 2 323
fibrils
3-32
584
70-80

24,25

2

(secondary annular
skin lesion)
15
(neuroborreliosis)26,27
lymphocytic meningitis
(subtle encephalitis with difficult
mentation)
cranial nerve 7 facial palsy
1 2 motor sensory
radiculoneuritis, mononuritismultiplex, cerebellar
ataxia myetitis 5

atrioventicular
block myopericarditis

(fatal pancarditis)28,29
heart block
( 3)
60
2-3

10
1
synovial hypertrophy, vascular proliferation infiltration mononuclear cell
rheumatiod arthritis

B. burgdorferi chronic meningoencephalitis spastic paraparesis, cranial neuropathy, cognitive impairment intrathecal antibody 5 B.
afzelii acrodermatitis chronica atrophicans
30
10 6

oligoarthricular arthritis
5
(chronic neurologic manifestations)
mild encephalopathy 31,32
(antibody production)
33 axonal polyneuropathy
spinal radicular pain
distal paresthesis34,35 electromyogram
diffuse
involvement proximal distal nerve segment
complex
44 585
liquid media Barbour-Stoenner Kelly Medium8,36

erythema migrans37
38
39,40

(endemic area)
B. burgdorferi enzyme link immunosorbent
assy (ELISA) western blot41
(US CDC) 42

immunoblot
43

erythema migrans

immunoglobulin M (IgM)
B. burgdorferi 4

IgG
95-9944
IgG blot
5 10 (18, 23, 28, 30, 39, 41, 45, 58, 66

93 KDa)42 1
IgM

1 IgG
ELISA peptide invariant region 6
B. burgdorferi VIsE lipoprotein

IgG band
western blot45
serologic test 1)
46

2) B. burgdorferi

(Smithkline-Beecham
Lyme Vaccine Trial)
20 asymptomatic IgG seroconversion
western blot 1047 3)
spirochete
1qG ELISA48
IDSA
1 49
localized disseminates infection
doxycycline 100 . 2
14-21 8 50
8
amoxicillin 500 . 3
doxycycline amoxicillin
cefuroxime axetil 500 . 2
51
3 erythromycin 250 . 4
52
ceftriaxone 40-50 ././

( 2 ./)32,53,54 2-4
586
cefotaxime penicillin G

chronic neuroborreliosis

4 atrioventricular
block
(intravenous therapy) cardiac monitoring permanent
pacemaker oral intravenous
Lyme arthritis

PCR
arthroscopic synovectomy

155
24 .

(antibiotic prophylaxis) doxycycline 200 . 1
72 .
Passive Immunization

56
1990 2
Lyme Disease LYMErix
(SmithklineBeecham) ImuLyme (PasteurMeurieux-Connaught) 2

B. burgdorferi outer surface protein A
(OspA)
3 (phase 3 clinical trials)
10,000 LYMErix

.. 1998
15-70 3
1 12
phase 3
76 100

3
3
phase 3
Advisory Committee on Immunization Practice
(ACIP)
.. 199957 LYMErix
15-70
.. 1998 - .. 2000
1.4 Vaccine Adverse
Event Reporting System (VAERS) passive surveillance system

905 58 7.4

10,000 VAERS
56

HLA-DR4 major histocompatibility
locus

44 587

(temporal association)

VAERS

Internet

..
2002 GlaxoSmithKline ( SmithKlineBeecham)

59
1)
(
) 2)

3)
ACIP

LYMErix

United
States Agency for International Development

56

588
1
()
Doxycycline
100 mg orally twice daily for 14- 21 days
Amoxicllin
500 mg orally 3 times daily for 14-21 days
Alternatives in case of doxycycline of amoxicillin allergy:
Cefuroxime axetil 500 mg orally twice daily for 14- 21 days
Erythromycin
250 mg orally 4 times daily for 14-21 days
(8 )
Amoxicillin
250 mg orally 3 times daily or 50 mg/kg per day in 2 divided doses for 14-21 days
Alternatives in case of penicillin allergy:
Cefuroxime axetil 125 mg orally 3 twice daily or 30 mg/kg per day in 2 divided doses for 14-21 days
Erythromycin
250 mg orally 3 times a day or 30 mg/kg per day in 3 divided doses for 14-21 days
Ceftriaxone
2 g IV once a day for 14-28 days
Cefotaxime
2 g IV once a day 8 h for 14-28 days
Na pencillin G
20 million U IV in 6 divided doses every 4 h for 14-28 days
Alternative in case of ceftriaxone or penicillin allergy:
Doxycycline
100 mg orally 3 times a day for 30 days; this regimen may be ineffective for late
neuroborreliosis
Facial palsy alone:
Oral regimens may be adequate
(< 8 )
Ceftriaxone
75-100 mg/kg per day (maximum, 2g) IV once a day for 14-28 days
Cefotaxione
150 mg/kg per day in 3 or 4 divided doses (maximum, 6g) for 14-28 days
Na penicillin G
200,000-400,000 U/kg per day in 6 divided doses for 14-28 days
Oral regimens listed above for 30-60 days or

IV regimens listed above for 14-28 days
First-degree AV block: oral regimens, as for early infection

High-degree AV block (P-R interval>0.3s): IV regimens and cardiac monitoring; once the patient has
stabilized, the course may be completed with oral therapy
Standard therapy for manifestation of the illness; avoid doxycycline
44 589

60 61
62 Eurasia63

(endemic area)

56

vector-borne protein outer membrane protein
OspA surface protein
B. burgorferi s.l. species

(phase
3 clinical trial)10 OspA epitope (LA-2)
(protective immunity) 64,65 LA-2 titer
66
Livey
OspA LA-2 epitope
single recombinant OspA antigen
proximal portion serotype-1
(lack of
arthritogenic epitope) distal portion
serotype-2 recombination OspA antigen
(rOspA1/2)
B. burgdorferi s.l.
serotype-1 (B. burgdorferi s.s) serotype-2

(B. afzelii) OspA molecule
B.garinii
B.valaisiana
recombination OspA
atigen 2 B.garinii
neuroborreliosis
combination vaccine
OspA antigen OspA molecule

Livey
protective epitopes

10
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cines in healthy adults. Vaccine. 1996;14:1620-6.

66. Golde WT, Piesman J, Dolan MC, Kramer
M, Hauser P, Lobet Y, et al. Reactivity with a specific
epitope of outer surface protein A predicts protection
from infection with the Lyme disease spirochete, Borrelia burgdorferi. Infect Immun. 1997;65:882-9.
76
595
45

sheep blood agar 3-4
Group B streptococcus (GBS) Strep- .
tococcus agalactiae -hemolysis GBS 9
capsular polysaccharides (Ia, Ib, II III GBS 2 VIII) 95
(early onset disease) 6 Ia, Ib, II, III V III
(late onset disease) 10
7 3
2
GBS
34-36 10
30 33 .. 2513 0.7-3.7
1,000 11
1
GBS GBS
.. 2533
1.8 1,000 12
(chorioam- early onset late onset 1.5 0.3
nionitis) (endometritis) 1,000
5.8 .. 2535
GBS
early onset
2-9
.. 2541 0.6
1,000 late
Group B Streptococcus
onset 1
GBS
GBS Strep- (colonization) 4.6

tococci Lancefield group B 40.613-15 GBS colonization
facultative GBS
596
26-28 65
GBS colonization
GBS
816
..
2538 GBS
early onset 0.27 1,000
0.1 .. 2544
late onset .. 2538 0.05
1,000 17
GBS colonization 5.1-6.218-20
.. 2547-2548
(rectum)
35-37 GBS
1621 GBS

GBS
early onset 122-29
GBS early
onset GBS

GBS

15,16
GBS early
onset
GBS colonization
GBS
50-65 ( 98)
colonization 1-2
30
GBS late onset 50

GBS 2
(early onset disease)
(late onset disease)
early onset 6
24
late onset 7 3
1 3
31,32 ( 2)
1 GBS early onset

1. GBS colonization
2.
3. 18
4. (chorioamnionitis)
5.
6. 38 o .
7. GBS
( 32)
45 597
GBS early onset

GBS

33,34

80

24-48 35,36
5-10
5013

4-61,2

33 late onset
0.624

GBS late onset

GBS
late onset 38,39 polymerase chain
35
reaction 97
100
37

Penicillin G GBS
early onset MIC Penicillin G Group A strepto-
2 GBS
()
()
( 32)
Early-onset Disease
1
Late-onset Disease
1 3
Ia, III, V
10-15
III, Ia, V
2-6
598
coccus 10
GBS Penicillin G
32
ampicillin, extendedspectrum penicillins, cephalosporins ( cefoxitin),
carbapenem vancomycin
cefotaxime
penicillin
140
erythromycin clindamycin erythromycin
7-20 clindamycin 3-1541-45
GBS tetracycline,
trimethoprim-sulfamethoxazole, metronidazole
gentamicin gentamicin
penicillin ampicillin

10
14-21
28 dexamethasone

GBS
.. 1975
GBS 53
GBS Ia, Ib, II, III,
V opsonization
phagocytosis

GBS
54

GBS
55-59
GBS

GBS
GBS
60

GBS
1. GBS colonization GBS

2.
phase 1 GBS
GBS colonization
III61
3.
GBS
Ia II62,63
4. GBS

GBS
III
( 1) 46-52

45 599
64

GBS

GBS

GBS
GBS

III
GBS
GBS 71
III
18-40

65
GBS

GBS

GBS
GBS
Ia, Ib, II V

66-68
GBS
GBS
65
GBS V

69
GBS
bivalent II III70

600
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al Baker CJ, Rench MA, Fernandez M, Paoletti LC,
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605
46
trypsin-sensitive surface
exposed M protein trypsin resistant T antigen
1
(Streptococcus pyo-
genes group A -hemolytic streptococcus
GAS) 1
.. 1600 .. 1900 (Scarlet
fever) (Acute rheumatic fever, ARF)

GAS
GAS
.. 120 M-protein
1980 GAS ARF serotype M typing 150
streptococcal toxic shock syndrome (STSS) emm typing
emm type
M-protein M type
emm
.. 1880 Pasteur GAS 1, 3, 5, 6, 18, 19

(puerperal 24
fever) .. 1898 Cheadle 49, 55, 57
5 ARF carditis, polyarteri- 59 (pyodertis, chorea, erythema marginatum subcutane- ma) (acute glomerulonephritis,
ous nodules .. 1903 Brown complete AGN) 1, 6 12
() hemolysis blood agar AGN STSS
15 (pyrogenic toxin)
Lancefield (serology) superantigen
-hemolytic streptococcus tumor necrosis factor (TNF)
(group-specific mediator
polysaccharide) 2
606

GAS

2-6
GAS3
GAS .. 2005
10,400 (3.5 )
1,350 ( 13)
4 ARF
ARF
20
3-4 GAS
5
.. 1992 400,000
(Rheumatic heart disease, RHD) 12
RHD 1

RHD .. 2002
0.7-14 ( 4
)
RHD
ARF

ARF

6
AGN ARF

AGN
10-157

GAS host
GAS
herd immunity
GAS
(virulence factor) bacteriophage

CovRS
(
)1 host
ARF RHD
(autoimmune
response)
GAS
HLA class II gene
HLA DR7 allele

HLA
class II antigen-presenting
cells (APCs) macrophage, dendritic cell,
B cell
T cell HLA
T cell receptor (TCR) T cell

HLA
T cell
ARF GAS
46 607
macrophage
HLA class II CD4+ T cell
humoral cell
ARF/RHD
(molecular mimicry
mechanism) T cell
GAS
B cell (autoreactive B cell)
T cell
ARF/RHD5
1

(inflammation)
(immune evasion)
(tissue invasion)
GAS host
plasma protein matrix protein fibronectin,
fibrinogen immunoglobulin (Ig) G adhesin
lipotechoic acid, M protein, hyaluronic acid
capsule, C5a peptidase, fibronectin binding protein
( SfbI FBP54) R28 ( GAS

GAS )
pili (extracellular binding protein) adhesin
1 M protein streptococcal pyogenic
exotoxin (SPEs) pro-inflammatory
SPEs superantigen
SpeA
C erythrogenic toxin
bacteriophage-encode
T cell receptor MHC class II SpeA
STSS

(immune evasion)
M protein M protein
phagocytosis
plasma protein
C3b alternative complement pathway
M protein amino terminal
GAS
M protein

GAS M protein

(alpha-helical coiled-coil fibrillar rods)
carboxy (C) terminus LPxTG motif peptidoglycan
4 ( A - D)
1 A-repeat amino ( N ) terminus
(highly
variable) serotype
M typing ( emm)
C repeat epitope
conserved region M type
B repeat A C repeat
cross react
ARF B
repeat superantigen
GAS
streptolysin O, deoxyribonuclease B,
streptokinase hyaluronidase
GAS
GAS C
608
1 functional domain streptococcal M protein

( 6)
terminus
C5a
peptidase SCPA (surface bound C5a peptidase)
chemoattractant
nonsuppurative post-infectious sequelae GAS

ARF
GAS 3
endemic
ARF

ARF (
) ARF
M type

molecular mimicry
ARF AGN
M protein
cardiac muscle myosin
extracellular matrix ( synovium
glomerular basement membrane)
GAS

VCAM-1 adhesin
CD4+ T cell M protein
myosin

epitope group A carbohydrate, N-acetylglucosamine lysoganglioside
GM1 Sydenhams
chorea SpeB
GAS AGN
cross react
46 609
GAS

nonsuppurative
nonsuppurative
1

2
STSS GAS

2

1, 2
generalized erythematous macular rash
(pharyngitis) 2
(impetigo pyoderma)
2.2 post-infectious immune-mediated1
GAS ARF acute glomerulonephritis (AGN)
GAS 1-3 ARF Jones criteria 2 major 1
(serous rhinitis) major 2 minor criteria
GAS 12
3 2
GAS
2
1. suppurative complication

GAS
peritonsillar
abscess, cervical adenitis, pneumonia, erysipelas, swab
cellulitis, necrotizing fasciitis, lymphangitis, bacter- GAS blood agar
emia, meningitis, septic arthritis, osteomyelitis latex agglutination, fluorescent
postpartum endometritis
antibody assay, coagglutination, precipitation
2. nonsuppurative complication
GAS beta-hemolytic strepto2.1 infection-mediated scarlet fever coccus bacitracin disk GAS
STSS
scarlet fever
1 Jones Criteria Acute rheumatic fever

2 major 1 major 2 minor criteria GAS
Major criteria
Carditis
Polyarthritis
Chorea
Erythema marginatum
Subcutaneous nodules
Minor criteria
Clinical findings:
Fever, arthralgia
Laboratory findings:
Elevated acute phase reactants;
prolonged PR interval
Supporting evidence
Positive throat culture or rapid
test
OR
Elevated or rising
streptococcal antibody test
610
10 GAS
GAS
rapid test
nitrous acid group A carbohydrate
antigen

GAS
rapid test optical immunoassay

chemiluminescent DNA probe

GAS vaccine

1
2 GAS vaccine
ARF 2
90 9
1. M protein vaccines

2. non-M protein vaccines
30 RHD
GAS 1. M protein vaccines1,8

M protein
4
GAS
A-repeat C-repeat M protein vaccines
AGN 2
GAS
1.1 N-terminal GAS vaccines A-re peat
() (highly variable)

STSS opsonization, bactericidal, protective, M type-specific
long-lasting .. 1970
ARF partially purified M3 pro GAS tein

ARF GAS
GAS ARF

Dale
46 611
2 Group A streptococcal vaccines 8

..
1923
1930
1931
1932
1933-1943
1937-1941
1946
1949
1960
1962
1963
1968
1969
1973
1975
1978
1979
2004
2005
21 strain heat-killed GAS

Heat-killed GAS
Heat-killed GAS
Heat-killed GAS
GAS toxin and GAS tannic acid precipitated toxin
GAS tannic acid precipitated toxin
Heat-killed or ultraviolet-inactivated M17 and M19 GAS
Heat-killed M3 and M17 GAS
Partially purified M19 GAS
Cell wall of M5 and M12 GAS
Cell wall of M14 GAS
Partially purified M protein M3 GAS
Highly purified M protein M12 GAS
Highly purified M protein M3 and M12 GAS
Polypeptide fragment M protein M24 GAS
Six-valent N-terminal M protein fragment M1, M3, M5, M6, M19, M24
Recombinant 26-valent M protein vaccine along with Spa
recombinant fusion
protein N-terminus fragments 6 M protein
M1, M3, M5, M6,
M19 M24 epitope cross
react

57/60 ( 95)
recombinant 26-valent M
protein vaccine6

85-90 Streptococcal protective
antigen (Spa)

4 component fusion protein Hexa A.1 (M24,
M5, M6, M19, M29, M14, M24), Septa B.2 (M1.0, M12,
Spa, M28, M3, M1.2, M18, M1.0), Septa C.2 (M2,

M43, M13, M22, M11, M59, M33, M2) Septa D.1
(M89, M101, M77, M114, M75, M76, M92, M89)

ARF
M type
26 valent
6
valent adjuvant 1
1.2 Conserved region M protein vaccines8
C-repeat conserved region

1. C-terminal region M6
2. Selected B and T-cell epitopes Crepeat region M5 (PepVac StreptInCor vaccine)
3. 12-amino acid minimal B-cell epitope
612
C-repeat region (J8)
conserved region

(IgA)

C-repeat
2. Non-M protein vaccines8
M-protein
cross-react
type-specific
non-M protein
2
(extracellular virulence factors)
streptococcal C5a peptidase (SCPA), GAS carbohydrate, streptococcal fibronectin-binding proteins
cysteine protease
proteomic reverse
vaccinology non-M protein
2.1 Streptococcal C5a peptidase
SCPA

A, B, C G
chemokine C5a
phagocyte
colonization SCPA
IgG mucosal IgA
opsonization
M type
B
2.2 Group A streptococcus carbohydrate

M type
2.3 Streptococcal fibronectin-binding

proteins serum opacity factor (SOF),
fibronectin-binding protein 54 (FBP54), FbaA,
streptococcal fibronectin-binding protein 1 (Sfb1)

IgG

2.4 Cysteine protease and streptococcal
pyrogenic exotoxins
- Streptococcal pyrogenic exotoxin A (SpeA)
SpeC superantigen toxin STSS
- extracellular cysteine protease
streptococcal pyrogenic exotoxin B (SpeB) (
pyrogenic
exotoxin ) GAS
SpeA SpeB
STSS

2.5 Streptococcal pili ( T antigen)
Pili GAS, GBS, S.pneumoniae

highly conserved 12
pili variants 90
2.6 New antigens identified by proteomics
and/or genomics reverse vaccinology
Proteomics

46 613
streptococcal
serine esterase (Sse), 2 heme-binding proteins (shp
and HtsA), Streptococcal cell envelope proteinase
(Spy0416 SpyCEP or ScpC) Lipoproteins

GAS

(predisposed)
GAS

GAS
1

phase I
26-valent M protein vaccine Dale 6
conserved region M protein vaccine
phase I
J8 vaccine8 GAS 120 M serotype
150 emm types
aminoterminus M type

preclinic
ARF
B T cell epitopes cross
react host
superantigen

phase III
herd immunity
asymptomatic colonization
emm type
non-vaccine serotype

ARF, AGN STSS
GAS

M protein

non-M protein
1. Kotloff KL. Streptococcus group A vaccines. In: Plotkin S, Orenstein W, Offit P, editors.
Vaccines. 5th ed. Philadelphia: Saunders; 2008.
p.1317-25.
2. American Academy of Pediatrics. Group
A Streptococcal infections. In: Pickering LK, Baker
CJ, Kimberlin DW, Long SS, editors. Red Book: 2009
Report of the Committee on Infectious Diseases. 28th
ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009. p.616-28.
3. Glezen WP, Clyde WA Jr, Senior RJ,
Sheaffer CI, Denny FW. Group A streptococci, mycoplasma, and viruses associated with acute pharyngitis.
JAMA. 1967;202:455-60.
4. Centers of Disease Control and Preven-
614
tion (CDC)[Internet]. Active bacterial core surveillance
report, Emerging infections program network, Group A
streptococcus; 2005. Available from: http://www.cdc.
gov/ncidod/dbmd/abcs/survreports/gas05.pdf
5. Guilherme L, Fae KC, Higa F, Chaves
L, Oshiro SE, Freschi de Barros S, et al. Towards a
vaccine against rheumatic fever. Clin Dev Immunol.
2006;13:125-32.
6. Dale JB. Current status of group A streptococcal vaccine development. Adv Exp Med Biol.
2008;609:53-63.
7. Anthony BF, Kaplan EL, Wannamaker
LW, Briese FW, Chapman SS. Attack rates of acute
nephritis after type 49 streptococcal infection of the
skin and of the respiratory tract. J Clin Invest. 1969;
48:1697-704.
8. Steer AC, Batzloff M, Mulholland K, Carapetis JR. Group A streptococcal vaccines: facts versus
fantasy. Curr Opin Infect Dis. 2009;22:544-52.
615
47
Vancomycin-resistance S. aureus VRSA S. aureus

Staphylococcus aureus

S. aureus 300,000

S. aureus
3
S. aureus
5 1
S. aureus (Invasive S. aureus genus Staphylococci
infection) 19-341
Staphy S. aureus lococcus S. aureus
262
Staphylococci S. aureus
44-483,4
coagulase clumping factor
S. aureus
cloxa- adhesin toxin 20
cillin methicillin (Methicillin-resistance S. aureus 30 Coagulase-negative staphylococci
MRSA) adhesin 10
72-73 toxin1
( 1)10
S. aureus 5
1. Cell wall peptidoglycan
MRSA 23-423,4,6,7
( 1) peptidoglycan
glycopeptides vancomycin endotoxin
(Vancomycin-intermediate resistance S. Cytokines Disaureus - VISA) 8,9 seminated intravascular clotting (DIC)
616
1 S. aureus
( 10)
S. aureus capsular
polysaccharide (CP)
S. aureus
12 CP5 CP8
85
CP5 CP8
10
2. Surface protein
Protein A (Antiphagocytic) S. aureus ( 1)
(Adhesin)
Microbial Surface Components Recognizing
Adhesive Matrix Molecules (MSCRAMM)

passive
immunization S. aureus 10
3. (Extracellular
products) ( 1) 1,10
3.1 Superantigens Enterotoxins
Epidemiolytic toxins (Exfoliatin
A B) Scalded skin syndrome Toxic
shock toxin-1
3.2 Cytotoxin Hemolysin
Hemolysin
S. aureus
Leukocidin Panton-Valentine
leukocidin (PVL)
S. aureus PVL
PVL
3.3 S. aureus
Coagulase, Hyaluronidase
S. aureus
(Colonization) 30 50
S. aureus 11

MRSA1,11
S. aureus

47 617
1 (Extracellular Factors) S. aureus 1
Surface proteins
Protein A
Collagen BP
Fibronectin BPA and B
Clumping factor A and B
Capsular polysaccharides
Polysaccharide capsule type 5
Polysaccharide capsule type 8
Cytotoxins
, , , and -hemolysin
Panton-Valentine leukocidin (PVL)
Superantigens
Enterotoxin A-D
Exfoliatin A, B
Toxic shock syndrome toxin-1 (TSST-1)
Enzymes
V8 protease, Hyaluronidase, Coagulase,
Staphylokinase, etc.
Anti-immune, anti-PMN
Collagen binding
Fibronectin binding
Fibrinogen binding
Anti-phagocytosis?
Anti-phagocytosis?
Hemolysin, cytotoxin
Leucolysin
Food poisoning, Toxic shock syndrome
Scaled skin syndrome
Toxic shock syndrome
Spreading factor, Clotting, Clot digestion, Plasminogen
activator, etc.

S. aureus
28-35 12,13
1 65 12
hemodialysis
peritoneal dialysis

COPD Rhumotoid
arthritis12,13

S. aureus 38

60 MRSA
20 14 S.
aureus sterile site
( 19
15 )15 S. aureus

S. aureus

Hemophilus influenzae type
B Streptococcus pneumoniae
16-18

S. aureus
3

26

(Healthcare-associated infection) MRSA
2-4
MRSA
618
MRSA

MRSA .. 1997-1999
MRSA
Western-Pacific 46
34 26
MRSA MRSA
5 .. 2000
(Nosocomial) (Healthcareassociated) (Communityacquired) MRSA 61, 52 14

19
MRSA
(CA-MRSA HA-MRSA)
MRSA
MRSA 26 67
S. aureus

MRSA
CA-MRSA HA-MRSA20
CA-MRSA

MRSA
2,7,21
S. aureus toxin-mediated
virulence
toxin-mediated
S. aureus

1,10,11
1. Exfoliative toxin A B

epidermis Scalded skin syndrome
Bullous impetigo
2. Toxic shock syndrome toxin -1 (TSST-1)
Superantigen
T-lymphocyte
cytokines

endotoxin

hemodynamic

3. Enterotoxin S. aureus enterotoxin

2-6

S. aureus

(Liquefaction necrosis)
S. aureus

47 619

1,10,11
S. aureus
1.

cellulitis pyomyositis
S. aureus
S. aureus
necrotizing fasciitis

1
2.
S. aureus

systemic
inflammatory response

DIC
S. aureus
2.1 (Infective endocarditis-IE)
S. aureus (Acute IE)

pulmonary
emboli
cardiac murmur
2 Oslers node Janeway lesion S. aureus

septicemia with acute IE
septic emboli ( 2)
hemiplegia
septic emboli 1,22
2.2 (Purulent pericarditis) precordial
friction rub

cardiac tamponade pericardiocenthesis
surgical drainage1,22
2.3
S. aureus pneumonia
(Necrotizing pneumonia)

1
2.4 S. aureus
620

23
2.5
(Acute or Chronic osteomyelitis)
S. aureus systemic

2-3
systemic

fistula tract
S. aureus
brain abscess, epidural
abscess, discitis cavernous sinus thrombosis

venticuloperitoneum shunt11
3.
3.1 Staphylococcal scalded skin syndrome
(SSSS) epidermolytic toxin S. aureus

anti-toxin
antibody
Bullous impetigo
( 3, 4)
3.2 Staphylococcal toxic shock syndrome
TSST-1
1-2
S. aureus
3 Bullous impetigo
epidermolytic toxin S. aureus
( )
4 SSSS S. aureus
( )
47 621

1,11
S. aureus 65 MSSA MRSA

47 18 23

Agar diffusion Kirby-Bauer E-test1

S.
aureus blood agar liquid media
Mueller-Hinton broth 18-24 1

S. aureus

11
(Phenotypic tests)
Coagulase Agglutination
test surface
proteins agglutination
S. aureus Staphylococci 1
S. aureus
2
2
IE

50
1,10

.. 2539-2549
80
44
(Molecular diagnosis)

1
Staphylococcal Cassette Chromosome mec
(SCCmec) mecA
mecA Penicillin-Binding
Protein 2 (PBP2) PBP2a PBP2

SCCmec MRSA 8 24
MRSA
Pulsed Field Gel Electrophoresis
(PFGE), Multi-locus Sequence Typing (MLST)
SCCmec Typing MLST
sequencing
http://www.mlst.net
MRSA
ST30-MRSA-IV (ST30 Sequencing
type 30) Southwest Pacific clone ST30-MSSA
80/81 SCCmec type IV 24
HA-MRSA
aminoglycosides,
erythromycin, clindamycin, fluoroquinolone tetracycline Glycopeptides
vancomycin CA-MRSA

MRSA 2
vancomycin MRSA
622
2 HA-MRSA CA-MRSA25
HA-MRSA

PVL
SCCmec I-III
CA-MRSA
HA-MRSA CA-MRSA
225

Minimal Inhibitory
Concentration (MIC) S. aureus
MIC 4 ./. MRSA
CA-MRSA clindamycin
erythromycin clindamycin
Clindamycin-inducible resistance

D-zone test erythromycin

clindamycin
clindamycin
erythromycin zone D ( 5)10
MRSA S. aureus
vancomycin MRSA MIC
vancomycin 4 ./.
VRSA (MIC 16
./.) VRSA vanA
Enterococci
10,11
CA-MRSA
()
PVL
SCCmec IV-V
S. aureus

MRSA HA-MRSA
CA-MRSA
cloxacillin
(Skin
and soft tissue infection, SSTIs)
5 Clindamycin-inducible resistance
D-zone test
( 10)
47 623

11,26

cellulitis

(septic
phlebitis)

clindamycin, trimethoprimsulfamethoxazole (TMP/SMX), doxycycline
7 linezolid
Streptococcus group A clindamycin
linezolid TMP/SMX doxycycline amoxicillin
impetigo
2% mupirocin ointment26
cloxacillin
SSTIs
CA-MRSA
vancomycin, linezolid clindamycin
clindamycin
1026
311

/
S. aureus 11,26

CA-MRSA cloxacillin

MSSA cloxacillin

S. aureus
vancomycin clindamycin11
S. aureus


S. aureus

()
Passive immunization 2 7
1. Veronate (INH-A21)

Clumping factor A (Clf A) surface protein
S. aureus fibrinogen Clf A

clot
2 Veronate
3
late-onset sepsis
S. aureus 28
2. AltaStaph
Capsular Polysaccharide
5 8
624
3 S. aureus11
Susceptibility
Antimicrobial Agents
Comments
1. Initial empiric therapy (unknown susceptibility)
Vancomycin +
Life-threatening infections
Cloxacillin + Gentamicin
Cloxacillin
Nonlife-threatening infection when rate of MRSA are low
Clindamycin
Nonlife-threatening infection when rate of MRSA are substantial AND
prevalence of clindamycin resistance is low
Vancomycin
Nonlife-threatening infection when rate of MRSA are substantial AND
prevalence of clindamycin resistance is high
2. Methicillin-susceptible S. aureus
Cloxacillin
Cefazolin
Clindamycin
Serious penicillin allergy AND clindamycin susceptible strain AND
nonlife-threatening infection
Vancomycin
Serious penicillin allergy AND clindamycin resistant strain
3. MRSA (Oxacillin MIC 4 ./. )
HA-MRSA
Vancomycin
Alternatives
TMP/SMX, Linezolid
Fluoroquinolone
(If susceptible)
CA-MRSA
Vancomycin
Life-threatening infections
Clindamycin
Pneumonia, septic arthritis, osteomyelitis, SSTIs
(If susceptible)
4. VISA (MIC 4-16 ./.)
Choices
Linezolid, daptomycin
Tigecycline
Optimal therapy is not known, depend on susceptibility test results
S. aureus
S. aureus adjunctive adjunctive therapy
therapy 27
S. aureus 30

3. Paglibaximab
Lipoteichoic acid 27
( 1)
1/2
S. aureus sepsis

27,29
2/3

Surface proteins
S. aureus
Tefibazumab MSCRAMM ( 1)
47 625
S. aureus
29,31
(
1, 2 3)
3 ( 4)27,29,31,32

Component
proteins
Conjugated capsular polysaccharide
(CP) 5 8 (StaphyVAX) 2
S. aureus
3
3,600
S. aureus

5 components CP5, CP8, Teichoic acid,
Non-toxic mutants -toxin PVL
PentaStaph 27
Component proteins

S. aureus
Heteropolymers, Lipoteichoic acid (LTA) conjugated
Autoinducing peptides (AIPs) Accessory
gene regulator (agr) 27,29
colonization

S. aureus S. aureus

Opsonization

27
4 27,29,31,32
Live whole-cell
Killed whole-cell
Component Protein or Capsule
Conjugated CP5 and CP8
IsdB
(Iron surface determinant B)
Multi-components
(IsdA, IsdB, SdrE, SdrD)
Exotoxin
Mutant of -hemolysin
Mutant of TSST-1

Staphypen
StaphyVAX (Nabi)
V710 (Merck)
3
2
626
S. aureus

S. aureus Biofilm neutralize

toxin

S. aureus (Immunotherapy)

Dis. 2006;6:70-1.
4. Nickerson EK, Hongsuwan M, Limmathurosakul D, Wuthiekanun V, Shah KR, Srisomang P,
et al. Staphylococcus aureus bacteraemia in a tropical setting: patient outcome and impact of antibiotic
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Smayevsky J, Bell J, Jones RN, et al. Survey of infections due to Staphylococcus species: frequency of
occurrence and antimicrobial susceptibility of isolates
collected in the United States, Canada, Latin America,
Europe, and the Western Pacific region for the SENTRY Antimicrobial Surveillance Program, 19971999.
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O, Sawanpanyalert P, Aswapokee N, Piboonbanakit
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629
48
4 (adenovirus serotype 4; Ad4) 7

(Ad 7) (military recruits)

(adenovirus) 11

12-14
Rowe ..19531 ..1999
Ad7
Fort Leonard Wood Missouri Ad7d2 Ad7h
2
15,16
..2006-2007 Ad14

38
(pharyngitis) (conjunctivitis) 517
(pneumonia)

(immunocompromised
patients)
3-7
double stranded, nonenveloped DNA virus genus
hemorrhagic cystitis Mastadenovirus, family Adenoviridae
4,7
10
15 56. 30
8-10
0.25% sodium dodecyl sulfate
..1971 0.5 ./.

(live, oral enteric-coated adenovirus vaccine)
630
antiserum
51
biochemical, biologic, immunologic
A F4

pharyngoconjunctival fever
(summer camps)
(childcare centers)

-18

6 5
Ad1 7
Ad4 Ad7
epidemic keratoconjunctivitis
Ad8 Ad37
Ad3, Ad7, Ad32, Ad40 Ad41
(disseminated disease)
Ad3, Ad7 Ad23
4,19-21

22-24
non-enveloped alcohol
chlorhexidine
immersion in
1% solution of sodium hypochlorite 10
autoclaving25,26

23,24
(tracheostomy tube)
(gown) (mask) 27
(prevalence)
50
28,29
C (Ad1, Ad2, Ad5, Ad6)
(endemic)
2
Ad4, Ad7,
Ad14 Ad21

A C

2 8

48 631

(latent state)
30
(reactivation)

secretory IgA
serum-neutralizing,
hemagglutination-inhibiting complement-fixing
antibodies 7 31
IgA IgG


32
tumor necrosis
factor-, interleukin-1 interleukin-6 2-3
cytotoxic T-cells
33,34
interleukin-1 tumor necrosis factor-

35
(common cold) (pharyngitis)

(exudative tonsillitis)
(cervicaladenopathy)
(bronchitis) (bronchiolitis)
(pneumonia)
Ad1, Ad2, Ad3, Ad5

Ad736,37
Ad3, Ad4, Ad7 Ad21
Ad3 Ad7

necrotizing pneumonia 38-41 Ad7
(genotype) 7h40,41
Pharyngoconjunctival fever
follicular conjunctivitis

Epidemic keratoconjunctivitis
Ad3, Ad8, Ad19 Ad37

(subconjunctival hemorrhage)23

periorbital
bacterial cellulitis

Ad3, Ad5, Ad7, Ad31, Ad40 Ad41
(gastroenteritis)

2
2-5
mesenteric lymphadenitis
(intussusception)42,43
632
(hepatitis)
44-47
Acute hemorrhagic cystitis

Ad11 Ad7
Ad21
adenovirus-associated hemorrhagic
cystitis

100
48

nephritis, orchitis, hemolytic uremic syndrome
(myocarditis) (pericarditis)

Ad7 Ad2149,50
(meningitis)
(encephalitis)
(transverse myelitis)51 7
4,21,52
1, 2, 4, 5, 6, 7, 11, 29, 31, 32, 34
35 1

(colitis)

cytopathic
effect cell culture
cluster of grapes 3-5
neutralization
hemagglutination-inhibition
direct fluorescence assay (DFA)

PCR
(serology)
acute
convalescent serum complement
fixation enzyme immunoassay
50
53
trifluridine,
ribavirin cidofovir54-56
48 633

ribavirin

20,47,55,57 cidofovir 5
./.
1-1.5 ./. 3
probenecid

58-62
Intravenous Immunoglobulin (IVIG)

60-64

immunoglobulin
Ad4 Ad7
(inactivated)
..1957
90
11,65
3 Ad3
52 66
SV-40
67
..1960

Ad7
68
Ad4 Ad7

69,70
Ad4
5071,72
Ad4
Ad7
Ad7
Ad473
Ad4 Ad7

Ad7 9573-75
Ad21
Ad21
76-79
Ad21
11
..1971-1996
(Wyeth Laboratories Incorporated)

(enteric-coated) 2
Ad4 () Ad7 ()
104.5 TCID50
human-diploid fibroblast cells (
634
WI-38) Minimal Essential Medium, Eagles
solution, (neomycin sulfate, gentamicin
sulfate amphotericin B), fetal bovine serum
sodium bicarbonate
cellulose acetate, phthalate, alcohol, acetone, castor oil, magnesium stearate amberlite
Ad4 Ad7

2

..1996 ..1999

2
Ad4 1
Ad7 1

4
neutralizing humoral antibody (IgG,
IgM IgA)78
secretory IgA

25 .. 2001 Barr Labo- 80

ratories, Incorporated of Pomona
Ad4 Ad7
50

9081 Ad4
16 .. 2011 Barr Labo- Ad7
ratories Ad4 74,75,82
Ad7
(multicenter, double (WI-38) blind, randomized, placebo-controlled study)

4,040
Ad4
Ad7 FD&C yellow dye #5 (tartrazine) Ad4 (vaccine efficacy)
FD&C yellow dye #6 99.3

Ad7
Ad7
Ad7
2-8 . 93.8 neutralizing antibody

2
1:8
neutralizing
48 635
antibody 1:8 5.3

Ad4
83
Ad7
Ad4 Ad7
(double-blind, randomized, placebocontrolled study) 3,031
1,009
63 37
17-42
21

35 ( 1.2)

56
(hematuria) (gastroenteritis)

12 ( 1.2)
1 56
28
17-50 ..1971
67

..1983
11

6
gentamicin sulfate, neomycin sulfate amphotericin B FD&C

Yellow 5 (tartrazine)
Ad7 bronchial asthma

36-40

7

28
636
28

Ad4 Ad7
..1971

11,84-86

Subunit vaccine
..1963 subunit vaccine
87
crystalline hexon fiber antigens
Ad5 neutralizing
antibody 88
subunit vaccine
Recombinant vaccines

H5N1
chimeric 89
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76
643
49
8
0-6 6-12 1-5
(Epstein-Barr virus, EBV) 5-15 15 48, 30, 83, 90
human herpesvirus-4 (HHV-4) 93
human herpesvirus
1 3
memory B cell
(reactivated)

2
infectious
mononucleosis (IM), lymphoproliferative disease
hyperplasia
lymphocytic interstitial pneumonitis (LIP) lymphocyte
oral hairly leukoplakia (OHL) reticuloendothelium

3
hyperplasia
granuloma
(droplet transmission)

EBV
1.
0-15
(acute primary EBV infection)
68.4-72.74,5

4-6
55.6-99.54-7 infectious mononucleosis (IM)
644
40
IM

(Hoaglands sign)

lymphocyte atypical lymphocyte
atypical lymphocyte
atypical
lymphocyte 10
IM
80

aplastic anemia 3,9
2. X-linked lymphoproliferative disease (XLP)

signaling lymphocyte activation molecule
(SLAM)-associated protein10 T cell
T, B natural killer cell
IM 30 acquired
hypogammaglobulinemia 25 malignant lymphoma11
3. Chronic active EBV infection (CAEBV)
6

basal ganglia12
T cell (CD4 ) NK cell13
EBV
monoclonality 80
malignant lymphoma 12
4. Viral associated hemophagocytic syndrome

(VAHS)

pancytopenia, coagulopathy histiocytic erythrophagocytosis 13
5. Fatal infectious mononucleosis

hemophagocytic 14
6. Fulminant EBV+ T-cell lymphoproliferative
disorder
chronic active EBV 15

pancytopenia
monoclonal proliferation
activated cytotoxic T cell (TIA-1+) CD4
CD8 phenotype15 fatal IM uncontrolled
polyclonal B cell proliferation
7. EBV-associated malignancies16

7.1 Burkitts lymphoma African type
submandibular area
American type
abdominal lymphoma 20
EBV genome
7.2 Posttransplant lymphoproliferative
disease AIDS-related
lymphoma primary CNS lymphoma
peripheral
non-Hodgkin lymphoma EBV genome
30-50
oral
49 645
hairy leukoplakia lymphoid interstitial pneumonitis
7.3Hodgkins disease EBV DNA

Hodgkins Reedsternberg cell
40-60 viral genome
monoclonal
7.4 Nasopharyngeal carcinoma epithelial

malignancy

7.5
EBV
genome
80
4
17 heterophile
antibody

guinea pig kidney cell
mononucleosis CMV, toxoplasmosis, HHV-6
heterophile antibody 18
EBV antigens19,20
viral capsid antigen (antiVCA IgM IgG) early antigen (EA)
Epstein-Barr nuclear antigen (EBNA)
1

polymerase chain reaction (PCR), EBV-encoded RNA

in situ hybridization, Immunohistochemistry
viral load PBMC

1

heterophile antibody, monospot, monocheck
EBV-associated mononucleosis (IM)

heterophile antibody 20-30
VCA IgG VCA IgM EA (D)
+
+
+/
+
+/+/
+
+/( 20)
EBNA
+/+
646

hemophagocytic lymphohistiocytosis
prednisolone 1 ././ ( 20
./) 7 20
acyclovir
IM EBV lymphoproliferative syndromes 20
EBV lymphoproliferative disease

EBV-specific

(solid organ transplant)

acyclovir
(latency)16,20 interferon
alpha, monoclonal antibody CD21 CD24
rituximab monoclonal antibody
CD20 B cell antigen adoptive transfer
autologous EBV-specific cytotoxic T lymphocyte

11

(reactivation) oropharyngeal
epithelium B cell oropharyngeal epithelium
lytic cycle

cell fusion receptor glycoprotein
CR2 (complement receptor) B lymphocyte CR2
glycoprotein gp350
21
B lymphocyte
immortalized continuous B-lymphoblastoid cell
line (LCL)
lytic cycle

cytotoxic T cells (CTL) CD4 CD8 T cell
B cell

posttransplant lymphoproliferative disease (PTLD)
EBV gene expression
(EBV-associated diseases)
(lytic cycle latent
proteins)
B lymphocyte
episome / integrate
pheno
type EBV latency 3 21
IM
1. Latency I (lytic)
Burkitts lymphoma (BL) EBV
49 647
EBNA1
2. Latency II
nasopharyngeal carcinoma (NPC) Hodgkins
lymphoma (HL)
EBNA1 latent membrane proteins (LMP)
1 2
3. Latency III IM, PTLD XLP
latentinfection protein EBNA1, 2, 3A, 3B, 3C LMP
1 2
(cell-mediated immunity)
CTL EBV proteins
CTL lytic cycle
EBNA3A, 3B, 3C
epitopes LMP 1 LMP2
CD4 T cell
EBNA1
EBNA1
HLA class II CD4 T cell 21

IM (Vaccines associated
with primary EBV infection)
EBV seronegative PTLD
XLP EBV seronegative

NPC HL
21
latency
CTL

1. A whole virus vaccine

DNA

(whole-killed virus vaccine)

16
2. Synthetic peptide vaccines
lipid carriers ISCOMS

(immunostimulating complexes) (delivery systems) miscles, liposomes, solid matrixantibody antigen (SMAA)
CTL
membrane antigen (MA)
MA neutralizing
antibodies neutralize
plasma membrane
3 glycoproteins 350,000, 220,000 85,000
(gp350, gp220 gp85)
648
2
22
lytic protein
gp350
cotton-top tamarins high titred EBV

phase I subunit vaccine
gp350/220 with a single adjuvanted surface
glycoprotein randomized, double-blind
67
23
phase II randomized,
double-blind recombinant EBV subunit glycoprotein 350/aluminum hydroxide and 3-Odesacyl-4-monophosphoryl lipid A (ASO4)
181 EBV
seronegative 3
IM
78
1
seroconversion gp350
98.7 18 24

EBNA3
CTL
IM
phase I
immunogenicity HLA
B*0801-restricted peptide epitope FLRGRAYGL and
tetanus toxoid formulated in a water-in-oil adjuvant,
Montanide ISA 720 HLA B8
EBV seronegative
23

2-12 1 2
EBV seroconversion (acquired EBV)

IM 4 4 EBV
seroconversion IM25
3. Recombinant vector vaccines
poxviruses recombinant expressing EBV antigen

recombinant vaccinia virus expressing major EBV

membrane antigen BNLF-1 MA (gp350/220)
9
membrane antigen
neutralize 3 9

16 10
26
1. . .
: , , , , .
. :
; 2550. .275-86.
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(Infectious mononucleosis). : ,
, . .
: ; 2536. .119-25.
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, ,
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9. , ,
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. . 2524;
20:15-30.
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membrane antigen. Dev Biol Stand. 1995; 84:171-7.
651
(Ebola hemorrhagic
fever)
.. 2519
.. 2551
25-90

biosafety
level 4

1

2 3

50
family Filoviridae Filo

Marburg family Filoviridae

U 6

Marburg4
RNA
(non-segmented, negative-sense single stand RNA)
19
7 nucleoprotein
(NP), virion protein (VP) 24, VP30, glycoprotein (GP),
VP35, VP40 RNA-dependent RNA polymerase4
5
(amino acid sequence)
Ebola-Zaire, Ebola-Sudan,
Ebola-Reston, Ebola-Cte dIvoire Ebola-Bundibugyo Ebola-Zaire, Ebola-Sudan
Ebola-Bundibugyo
Ebola-Zaire
60-90 Ebola-Sudan
Ebola-Bundibugyo 40-60
25 5-7 Ebola-Cte dIvoire
1 8
652
Ebola-Reston 4
2, 7 2
.. 2537
Ebola-Cote dIvoire Cote dIvoire
5
1
8
(
.. 2538 Ebola-Zaire
) .. 2519 315
.. 2551 819
2,100 10.. 2537-2540
1,500 Ebola-Zaire 3 Gabon
30-60
60-70
.. 2543-2544
Uganda Ebola-Sudan 425
53

.. 2544-2546
Ebola-Zaire Gabon
5
302
.. 2519 84
.. 2547 Ebola-Sudan
(
) 17
284 151 ( 53) 20 41 25
.. 2550
318 280 Bundibugyo Bundibugyo

( 88) Uganda 149
256
.. 2550-2551 Ebola-Zaire
2
Ebola-Sudan Ebola-Zaire 187 32
.. 2522 88 47
34 22 5

.. 2532-2533 (zoonotic virus)
Ebola-Reston
Reston
50 653
5,10

91 11
Cote dIvoire Gabon5, 8

42 ()

proinflammatory cytokine
coagulation factors disseminated intravascular coagulopathy (DIC)
7,12
1.

macrophage dendritic cells
1,5
1.
12

2. Systemic inflammatory response
60o .
cytokine, che30
mokine proinflammatory cytokine
2. tumor necrosis factor (TNF)-alpha, interleukin (IL) 1beta, IL-6, macrophage chemotactic protein nitric
oxide13
universal precaution
contact precaution vascular permeability
14
3. (Coagulation

defect)
ma3. crophage tissue factor (TF)15

3 extrinsic coagulation pathway
2 38.3o . coagulation factor proinflam
matory cytokines macrophage
654
TF

D-dimer 24
coagulation factor
15,16
4. adaptive immunity
dendritic
lymphocyte
(apoptosis) dendritic
(maturation)
lymphocyte

17 VP24
VP35 interferon
18,19
6-11
21,22

1 5
11
7

1. hypovolemic
shock adrenal insufficiency4
2.

7
3.
2-21 4-10
4.
(septic shock)

5.
hepatocellular necrosis

2-3

4

1. Complete blood count (CBC)
1,000 /..

(multiple organ failure) 6-8 21
50
2.
7,20
6-16
(multifocal hepatic necrosis)
aspartate
2 (AST) alanine (ALT) aminotransferase
50 655
AST ALT
23
3. (coagulogram)
DIC
prothrombin time, partial thromboplastin times D-dimer

biosafety level 4
1. nucleic acid

7,11
-
enzyme-linked immunosorbent assay
(ELISA)
- reverse transcription-polymerase chain reaction (RT-PCR)
- Marburg
2.

3.
IgM 2
30-168
IgG 6-18
11
IgM IgG (fourfold)

1. Antisense oligonucleotides RNA
interference positively charged phosphorodiamidatemorpholino oligomer (PMO plus)
translation VP24
PMO plus 30-60
60 PMO
plus 24
2. Anticoagulation
2.1 Recombinant nematode anticoagulant
protein c2 (rNAPc2)
rNAPc2 tissue factor coagulation pathway Ebola-Zaire
rNAPc2 10 24
rNAPc2 33
25
2.2 Recombinant human activated protein
c(rhAPC) anticoagulant
Ebola-Zaire rhAPC
rNAPc226
3. recombinant
vesicular stomatitis virus (rVSV) expressing
Multivalent Ebola vaccine
3 (Ebola-Zaire, Ebola-Sudan
Ebola-Cte dIvoire) rVSV
3
27
30
Ebola-Sudan 100
Ebola-Zaire 5028,29
656

1 plaque
pas- forming unit (PFU) passive imsive immunization munization neutralized
passive immunization 34 passive
.. immunization
2519
inter- neutralized
feron 1 2
Ebola-Zaire (convalescent
serum) 450 . 6
Ebola-Sudan 330
. 10 30
.. 2538 Ebola-Zaire
(conventional vac cine)
8
7 (
12.5) live attenuated vaccine
80

31
10

10
32 passive
immunization 33
1. Conventional vaccines
replication-deficiency Ebola virus lacking

VP30 VP30
(replication-deficient)
passive monoclonal immunization 35

34 2. Vector-Based vaccines
passive immunization
(vector)
50 657
(replication competent/defective)

2.1 Adenovirus
adenovirus

innate adaptive
adenovirus adenovirus
5 (Ad5) E1 adenovirus
Ad5 (replication-defective adenovirus) E3 E4
Ad5 36
recombinant (r) Ad 5expressing Ebola-Zaire
glycoprotein (GP)
Ebola-Zaire
1 37

rAd5 expressing EbolaZaire, Ebola-Sudan [multivalent vaccine (EBO7)]
2
38
rAd5-based vaccine
Ad5
Ad5 608539,40
2.2 Human parainfluenza virus 3 (HPIV-3)
rHPIV-3 expressing Ebola-Zaire
GP + NP
Ebola-Zaire 41,42
rHPIV-3-based vaccine
rAd5-based vaccine
HPIV-343
2.3 Vesicular stomatitis virus (VSV)
VSV
VSV
adenovirus Human
parainfluenza virus rVSV
rVSV
44
rVSV expressing Ebola-Zaire GP 1
Ebola-Zaire
45 27
3. DNA-based vaccines
DNA-based vaccines
DNA DNA

cytotoxic T-cells 46

DNA-based vaccines
autoimmune disease
integration host genome
DNA-based vaccines
DNAbased vaccines vector-based
vaccines
3.1 DNA prime/ rAd5 Ebola-Zaire GP
DNA-prime DNA vaccine GP Ebola-Zaire, Ebola-Sudan,
Ebola-Cte dIvoire NP Ebola-Zaire
3 rAd5 expressing EbolaZaire GP DNA prime/ rAd5
Ebola-ZaireGP Ebola-Zaire
47
3.2 DNA prime/rAd5 expressing Ebola-Zaire,
Ebola-Sudan GP
658

GP
Ebola-Sudan Ebola-Zaire GP
Ebola-Bundibugyo .. 2551 406
DNA prime/rAd5 expressing Ebola-Zaire,
Ebola-Sudan GP
(cross protective heterogenus species)48

2.

1.
2.
4. Virus-like particles (VLPs) vaccine
3.
VP40, NP GP

4.
VLPs

live
attenuated vaccine
Ebola-ZaireVLPs
3 6
1. Center for Disease Control and Prevention
Ebola-Zaire 1000 PFU
4 [Internet]. Bioterrorism agents/diseases. [cited 2011
Ebola-Zaire VLPs March 1]. Available from: http://www.bt.cdc.gov/agent/
3 agentlist-category.asp#a
2. Jahrling PB, Geisbert TW, Dalgard DW,

Johnson ED, Ksiazek TG, Hall WC, et al. Preliminary
49
report: isolation of Ebola virus from monkeys imported
to USA. Lancet.1990; 335:502-5.
50
3. Barrette RW, Metwally SA, Rowland JM,
1.
Xu L, Zaki SR, Nichol ST, et al. Discovery of swine
as a host for the Reston ebolavirus. Science.2009;
325:204-6.
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76
663

enteric adenoviruses, astroviruses, human calciviruses
E. coli, Shigella
Campylobacter
antigenic
diversity

(gastrointestinal
mucosal immunity)
51
Enterotoxigenic E. coli
E. coli facultative anaerobe

E. coli 6
diarrheagenic E. coli2 E.
coli virulent
factor 13
1 Diarrheagenic E. coli virulent factor

Adhesins
CFA
Toxins
LT, STa, STb
ETEC
probe LT
ST toxins
EAEC
AAFI, EAST1
Adherence assay probe

AAFII
AAF1
EPEC
EAF
probe EAF adherence
STEC (EHEC) EAF

Shiga-toxins HUS
probe shiga toxins
EIEC
EAF

probe invasin
: AAF = adherence fimbriae, CFA = colonizing fimbriae, EAEC = enteroaggregrative E. coli

EAF = EPEC adherence factor, EAST = E. coli aggregrative secretory toxin, EHEC = enterohemorrhagic E. coli, EIEC =
enteroinvasive E. coli , EPEC = enteropathogenic E. coli , ETEC= enterotoxigenic E. coli, HUS = hemolytic uremic syndrome,
LT = heat-labile toxin, ST = heat-stable toxin, STEC = shiga-toxin producing E. coli
( 3)
664
Enterotoxigenic E. coli ( ETEC)
5
70-80
ETEC 280-400
2 ETEC
( 20-70)
(traveler diarrhea) ETEC
(foodborne outbreak)3
ETEC
(fecal-oral route)
108 109

cholerae ETEC
fimbriae colonization
factor antigens (CFAs) coli surface antigens
(CSs) CFAs ETEC
20 7
CFA/I CS1 CS64
fimbriae ETEC

fimbirae
cross protection 5 CFAs receptor

enterocyte enterotoxin 2
heat labile toxin (LT) heat stable toxin ( ST)
LT cholera toxin (CT)
1 A subunit 5 B subunit LT
adenylate cyclase intracellular cyclic AMP
secretory diarrhea LT
ST peptide toxin
18-19 amino acid ST immunogenic candidate immunogen
ETEC
(natural history)
ETEC
ETEC

ETEC
ETEC candidate vaccine

(inactivated ETEC vaccine)
(live candidate vaccine)
1. ETEC
26
2 ETEC
ETEC
Toxoids (CTB, LT, mutant LT, LTB, CTB/LTB hybrid)

transcutaneous
Inactivated CF-expressing whole bacterial cell + toxoid
Purified CFs CF tip proteins

transcutaneous
Heat-stable enterotoxin toxoids
transcutaneous
: ETEC= enterotoxigenic Escherichia coli, CF = colonization factor, LT = heat labile toxin,
CTB = cholera toxin subunit B, LTB = heat-labile toxin subunit B
( 6)
51 665

- Cholera-ETEC vaccine whole cell
killed vaccines
Goteborg formalinkilled ETEC 5 strains express fimbriae
CFA/I CS1-CS6
recombinant cholera toxin B subunit (rCTB)
2-12
7
intestinal lavage antibody secreting cells (ASC)

rCTB fimbrial
endemic area

rCTB-killed ETEC vaccine

ETEC
828 placebo-controlled phase III
trial

ETEC 779
6-18 350
1
rCTB-killed
ETEC vaccine
6 protective antigen CFA
recombinant technology10,11 LT
toxoid hybrid LTB/CTB toxoid (
cholera ETEC) mucosal
adjuvant LTR192G/L211A strong
adjuvant activity
sublingual
(mucosal vaccine)12
2. ETEC
36
- Live attenuated ETEC vaccine
genetically attenuated ETEC vector
ETEC immunogenic ETEC
3 ETEC
Vaccine approach prototype
Attenuated nontoxigenic ETEC bacteria
expressing colonization factor
Hybrid Shigella/ETEC live vector vaccine
ACE Biosciences
Center for Vaccine Development ( CVD)

Avant Immunotherapeutics
Vibrio cholerae Peru 15 expressing

cholera toxin subunit B
Salmonella expressing heat-labile toxin
Emergent Biosolutions
subunit B
Vibrio cholerae CVD 103-HgR expressing
Berna Biotech/Crucell
CS3
: ETEC= enterotoxigenic Escherichia coli, CS = coli surface antigen
( 6)
666
deletion mutation aroC, ompC, ompF express CS2 CS3 CS1+CS2+CS3
phase I mucosal immunity
CF 13,14 3
strain ACM2023, ACM2025, ACM2027
express LTB CS4-CS6, CFA/1 CS1-CS3

immunogenicity
- Multivalent Shigella/ETEC vaccine
attenuated Shigella 5 Shigella dysenteriae 1, S. flexneri 2a, S. flexneri 3a,
S. flexneri 6 S. sonnei live vector
express ETEC CFA/I, CS1-6
LT ETEC

systemic IgG mucosal IgA
ETEC Shigella 15,16

ETEC Shigella

- Attenuated Vibrio cholerae Salmonella strain vector ETEC

attenuated Shigella attenuated Salmonella serovar
Typhi V. cholera O1 strain express CTB/
LT B subunit CFs ETEC
17,18
cholera
vaccine 6-18
3
3
19
Shigella species
Shigella family Enterobacteriaceae, non-motile, nonencapsulated Shigella

4 A (S. dysenteriae), B
(S. flexneri), C (S. boydii) D (S. sonnei) serotype O
47 O
lipopolysaccharide
outer membrane protein lipopolysaccharide core oligosaccharide
lipid A
Shigella

6
10

S flexneri
S. sonnei 20 (
4) Shigella
Shigella
51 667
4
Shigella
160
1.1

Serogroup (%)
S. flexneri
60
S. sonnei
23
S. dysenteriae
10
S. boydii
6
( 20)

epithelium cell transcytosis M cells lymphoid follicles

S. dysenteriae Shiga toxin
hemolytic uremic syndrome5
100,000
10,000
()
18
72
2
1
1. Live attenuated Shigella vaccine

- S. flexneri 2a, SC602
88 79 8-10
1

LPS
Shigella
21
- FS bivalent vaccine

S. sonnei
O Shigella invasion plasmid S. Flexneri 2a22
Shigella vac-
cine Shigella 65-75
5 LPS Shigella vaccine 1-3

668
17,500

(passive surveillance) 5-6
S. flexneri, S. sonnei
Shigella 61-65, 50-72
48-52

2. (killed whole cell) subunit vaccine

- Shigella LPS conjugate vaccine
3 1,5
S. dysenteriae type 1 LPS conjugate
tetanus toxioid
S. flexneri 2a LPS conjugate recombinant Pseudomonas exoprotein A
S.sonnei LPS conjugate exoprotein A
3

- invasin
invasin extracellular protein
23 invasion complex vaccine S. flexneri
S. sonnei

challenge homologous strain
(bivalent vaccine)
2 24,25
S. flexneri 2a Invaplex50 32
3 2

(systemic and mucosal immune
response)

multivalent vaccine S. flexneri 2a,
S. sonnei S. dysenteriae126
Shiga-toxin producing
E. coli (STEC)5
E. coli lysogenized phage encode

Shiga toxin Shiga-toxin producing E. coli
(STEC) enterohemorrhagic E. coli (EHEC)
STEC serotype O157:H7

(endemic)

100

27
STEC colonize
STEC STEC
serotype O157:H7
hemorrhagic colitis Shiga toxin

hemolytic uremic syndrome (HUS)
20
intestinal
51 669
perforation cerebro-vascular accident28
STEC
O157
polysaccharide capsular type O

5
- E. coli O157:H7 Type III secreted protein
vaccine
type III-secreted supernatant protein
entero-hemorrhagic E. coli
29 3
3
36.5

9930 Bioniche Life
Science Inc.

colonization

STEC31
Campylobacter
Campylobacter
Campylobacterales 2 families
Helicobacteraceae, Campylo bacteraceae
genera Campylobacter, Arcobacter
Sulfurospirillum Campylobacter
microaerophilic spiral
s
flagella genus Campylobacter 14 species 7
subspecies C. jejuni
C. coli C. upsaliensis, C.
lari C. fetus
Campylobacter

4
2
ETEC
32
Campylobacter
terminal
ileum enterotoxin
noninflammatory diarrhea
epithelium
dysentery inflammatory diarrhea
epithelium lamina propria
mesenteric lymph node
mesenteric lymphadenitis

Campylobacter
Guillain Barr syndrome
670
5,33
Campylobacter
Campylobacter

Campylobacter
5
Candidate vaccine
LT
E. coli mucosal adjuvant
Campylobacter
colonization 87
truncated recombinant flagellin subunit
LT multivalent vaccine express
3 Campylobacter, Shigellas
ETEC
34
(multivalent vaccine) ETEC, Shigellas

Cholerae
1. Girard MA, Steele D, Chaignat CL, Kieny

MP. A review of vaccine research and development:
human enteric infections. Vaccine. 2006;24:2732-50.
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4. Peltola H, Siitonen A, Kyrnsepp H, Simula
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diarrhoea by oral B-subunit/whole-cell cholera vaccine.
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placebo controlled pilot study evaluating efficacy and
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51 671
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9. Sack DA, Shimko J, Torres O, Bourgeois
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double-blind, safety and efficacy of a killed oral vaccine for enterotoxigenic E. coli diarrhea of travelers to
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10. Tobias J, Lebens M, Blin I, Wiklund
G, Svennerholm AM. Construction of non-toxic Escherichia coli and Vibrio cholera strains expressing
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coli colonization factor I fimbriae. Vaccine. 2008;
26:743-52.
11. Tobias J, Holmgren J, Hellman M, Nygren
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of major colonization factors of enterotoxigenic Escherichia coli, alone or together, on non-toxigenic E.
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C, Luci C, Sun JB, et al. Sublingual immunization
induces broad-based systemic and mucosal immune
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13. Turner AK, Beavis JC, Stephens JC,
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15. Barry EM, Wang J, Wu T, Davis T, Levine
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candidate vaccine strains in guinea pig model. Vaccine.
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16. Barry EM, Levine MM. Multivalent Shigella
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p.723-7.
17. Levine MM. Immunogenicity and efficacy
of oral vaccines in developing countries: lessons from
a live cholera vaccine. BMC Biol. 2010;8:129.
18. Czerkinsky C, Holmgren J. Enteric vaccines for the developing world: a challenge for mucosal
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A, Sultana GN, Qadri F. Enhanced immunogenicity
of an oral inactivated cholera vaccine in infants in
Bangladesh obtained by zinc supplementation and
by temporary withholding breast-feeding. Vaccine.
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Hamer D, Griffiths JG, Maguire JH, Heggenhougen
HK, Quah SR, editors. Public Health and Infectious
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21. Rahman KM, Arifeen SE, Zaman K,
Rahman M, Raqib R, Yunus M, et al.Safety, dose,
immunogenicity, and transmissibility of an oral live
attenuated Shigella flexneri 2a vaccine candidate
(SC602) among healthy adults and school children
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Shigellosis. In: Barrett ADT, Stanberry LR, editors.
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Diseases.1st ed. London: Academic Press; 2009.
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672
23. Kaminski RW, Turbyfill KR, Oaks EV.
Mucosal adjuvant properties of the Shigella invasin
complex. Infect Immun. 2006;74:2856-66.
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a Shigella flexneri 2a and S. sonnei bivalent invasin
complex (Invaplex) vaccine. Vaccine. 2006;24:2290301.
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complex vaccine from Shigella flexneri 2a. Vaccine.
2008;26:1353-64.
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M, Porter C, Baqar S, et al. Safety and immunogenicity
of a Shigella flexneri 2a Invaplex 50 intranasal vaccine
in adult volunteers. Vaccine. 2010;28:6076-85.
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Hutwagner L, Griffin PM. Escherichia coli O157:H7
diarrhea in the United States: clinical and epidemiologic
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28. Tarr PI, Gordon CA, Chandler WL. Shiga
toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005;365:1073-86.
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Townsend H, Rogan D, et al. Decreased shedding
of Escherichia coli O157:H7 by cattle following
vaccination with type III secreted proteins. Vaccine.
2004;22:362-9.
30. Peterson RE, Klopfenstein TJ, Moxley
RA, Erickson GE, Hinkley S, Bretschneider G, et al.
Effect of a vaccine product containing type III secreted
proteins on the probability of Escherichia coli O157:H7
fecal shedding and mucosal colonization in feedlot
cattle. J Food Prot. 2007;70:2568-77.
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Diseases.1st ed. London: Academic Press; 2009.

p.1013-29.
32. Coker AO, Isokpehi RD, Thomas BN,
Amisu KO, Obi CL. Human campylobacteriosis in
developing countries. Emerging Infectious Diseases.
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33. Israeli E, Agmon-Levin N, Blank M,
Chapman J, Shoenfeld Y. Guillain-Barr syndrome-a
classical autoimmune disease triggered by infection
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Oct 5.
34. Jagusztyn-Krynicka EK, Laniewski P,
Wyszynska A. Update on Campylobacter jejuni
vaccine development for preventing human
campylobacteriosis. Expert Rev Vaccines. 2009;8:
625-45.
673
52

(prophylactic vaccine)

/ (therapeutic
.. 2524 vaccine)
25
60

.. 2527

(envelope)
(virologic and immunologic challenges)

20

674

1
reverse transcriptase

HIV-1
M
9 clades circulating recombinant forms
(envelope,
Env) clade
20 envelop clade
351,2

nonhuman primate
HIV-1 specific humoral immunity

virus-specific neutralizing antibody
(NAb) titers HIV-1 Env
subunit immunogens
Env
broadly reactive
NAbs HIV-1 Env glycoprotein
trimer N-linked glycosylation

conserved epitope
highly immunogenic variable
loop
conserved region
chemokine receptor binding site
CD4
receptor 3
N-linked glycans
NAb
broadly reactive
NAb activity
conserve region Env glycoprotein
CD4 binding site4

NAb
conserved
region membrane proximal external region (MPER)
gp41 epitope lipid
membrane viral entry
(immunogen)
immunogen broadly
reactive NAbs broadly reactive
monoclonal antibodies
nonhuman primate
broadly
reactive NAbs immunogen
(engineered antigens)
Env trimers Env immunogen

immunogen
52 675
CD4 binding site, MPER structurally

conserved element V3 loop
non-neutralizing antibodies
antibody-dependent cell-mediated virus
inhibition, complement activation phagocytosis
HIV-1 specific cellular immunity

T lymphocyte

virus-specific CD8+T lymphocyte (CTL)

5
long-term nonprogressors6
specific HLA alleles Gagspecific T-lymphocye response

cellular immune response
CTL
epitopes T lymphocyte
epitope
T lymphocyte (breadth)

T lymphocyte

(animal model)

macaque
Simian immunodeficiency virus (SIV)
chimeric SHIV
7
macaque
(homologous
virus challenge) 8
9
SIV

2 10
1. Traditional strategies
live attenuated virus, whole killed
virus protein subunits

live attenuated virus11,12
whole killed
virus13 protein subunits14
neutralizing antibodies
CD8+ T lymphocyte response
Toll-like
receptor adjuvants protein subunit
15
2. Novel strategies
plasmid DNA vaccine lived recombinant vector
HIV-1 antigen
2.1 DNA vaccine

676

16
(adjuvant)
DNA vaccine
in vivo electroporation
2.2 recombinant vectors attenuated
replication-incompetent viruses
Adenoviruses poxviruses virus
vectors heterologous DNA prime,
vector boost

virus vectors
vesicular stomatitis virus (VSV),
adeno-associated virus (AAV), Venezuelan equine
encephalitis (VEE) virus, cytomegalovirus (CMV),
herpes simplex virus (HSV) measles virus
bacterial vectors Samonella,
Listeria BCG
17
1.

2.

3.
(whole-killed)
(attenuated)
4.

5.

18

1 .. 2530
NAbs recombinant
soluble monomeric gp120 gp16019
broad NAbs
DNA
viral vector CD8+ CTL
STEP study20 rAd5 vector
CTL
( IFN
)

broadly neutralizing
humoral immunity broadly reactive effective cellmediated immunity RV144

160
(www.iavireport.org/trials) 4
52 677
2b 3
AIDSVAX B/E (VAX003)
3 .. 2546 14 AIDSVAX B/B
(VAX004) 3
21
gp120 clade B E AIDSVAX B/E

AIDSVAX B/B

22
NAbs
2b STEP (HVTN 502)

Phambili (HVTN 503)

CTL MRKAd5 gag/pol/nef
homologous prime-boost regimen (STEP study)
.. 2550

Phambili study
STEP
study T lymphocyte IFN
enzyme-linked immunosorbent spot (ELISPOT)
77 23

1 2

adenovirus serotype 5 (Ad5)

4 20
18
epitopes
NAbs long-term
nonprogressor elite controller
STEP study
T-cell-based vaccine
CTL
IFN HIV antigen

IFN
in vitro HIV inhibition assay24
macaque nonhuman primate (NHP)
Ad5 vectors

3
RV144 vaccine study25

31.2
community-based, randomized, multicenter,
double-blind, placebo controlled efficacy study
prime-boost
678
strategy recombinant canarypox vector
vaccine, ALVAC-HIV (vCP1521) 4
recombinant glycoprotein
120 subunit vaccine (AIDSVAX B/E) 2
16,402

40.4 47.6

3.7

CD4+ T cells
NAb
NAb
(heterogenous strains)

antibodydependent cell-mediated cytotoxicity (ADCC)

somatic hypermutation
3-4 NAbs

immunogen
NAbs

HIV-1 immunobiology

1)

2) vector
3)

T-cell-receptor cytokine
immunogen
1. Gaschen B, Taylor J, Yusim K, Foley B,

Gao F, Lang D, et al. Diversity considerations in HIV-1
vaccine selection. Science. 2002;296:2354-60.
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the obstacles of HLA and viral diversity. Nat Immunol.

monoclonal antibody 2001;2:473-5.
NAbs
3. Chen B, Vogan EM, Gong H, Skehel JJ, Wiley
26,27 DC, Harrison SC. Structure of an unliganded simian
immunodeficiency virus gp120 core. Nature.
NAbs 2005;433:834-41.
4. Li Y, Migueles SA, Welcher B, Svehla K,

NAbs (mutation) Phogat A, Louder MK, et al. Broad HIV-1 neutralization
52 679
mediated by CD4-binding site antibodies. Nat Med.

2007;13:1032-4.
5. Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod
G, Borkowsky W, et al. Temporal association of cellular
immune responses with the initial control of viremia in
primary human immunodeficiency virus type 1 syndrome.
J Virol. 1994;68:4650-5.
6. Musey L, Hughes J, Schacker T, Shea T,
Corey L, McElrath MJ. Cytotoxic-T-cell responses,
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1997;337:1267-74.
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Gulizia RJ, Katinger H, et al. Neutralizing antibodies
have limited effects on the control of established HIV-1
infection in vivo. Immunity. 1999;10:431-8.
8. Berman PW, Gregory TJ, Riddle L, Nakamura
GR, Champe MA, Porter JP, et al. Protection of
chimpanzees from infection by HIV-1 after vaccination
with recombinant glycoprotein gp120 but not gp160.
Nature. 1990;345:622-5.
9. Connor RI, Korber BT, Graham BS, Hahn
BH, Ho DD, Walker BD, et al. Immunological and
virological anlyses of persons infected by human
immunodeficiency virus type 1 while participating in
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10. Barouch DH. Challenges in the development
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neonatal rhesus monkeys with cell-free SIV. Science.
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12. Baba TW, Liska V, Khimani AH, Ray NB, Dailey
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and adult macaques. Nat Med. 1999;5:194-203.
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protection in macaques. Science. 1989;246:1293-7.
14. Pitisuttithum P, Gilbert P, Gurwith M,
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Randomized, double-blind, placebo-controlled efficacy
trial of a bivalent recombinant glycoprotein 120 HIV1 vaccine among injection drug users in Bangkok, T
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Miles AP, Saul A, et al. Toll-like receptor agonists
influence the magnitude and quality of memory T cell
responses after prime-boost immunization in
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Caulfield MJ, Davies ME, et al. Comparative
immunogenicity in rhesus monkeys of DNA plasmid,
recombinant vaccinia virus, and replicationdefective adenovirus vectors expressing a human
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Fitzgerald DW, Mogg R, Li D, et al. Efficacy
assessment of a cell-mediated immunity HIV-1
vaccine (the Step Study): a double-blind, randomised,
placebo-controlled, test-of-concept trial. Lancet.
680
2008;372:1881-93.
21. Flynn NM, Forthal DN, Harro CD, Judson
FN, Mayer KH, Para MF; rgp120 HIV Vaccine Study
Group. Placebo-controlled phase 3 trial of a recombinant
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of MN-rgp120-immunized chimpanzees from
heterologous infection with a primary isolate of human
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173:52-9.
23. McElrath MJ, De Rosa SC, Moodie Z,
Dubey S, Kierstead L, Janes H, et al. HIV-1 vaccineinduced immunity in the test-of-concept Step Study:
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24. Chen H, Piechocka-Trocha A, Miura T,
Brockman MA, Julg BD, Baker BM, et al. Differential
neutralization of human immunodeficiency virus (HIV)
replication in autologous CD4 T cells by HIV-specific
cytotoxic T lymphocytes. J Virol. 2009;83:3138-49.
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Vaccination with ALVAC and AIDSVAX to prevent HIV-1
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26. Walker LM, Phogat SK, Chan-Hui PY,
Wagner D, Phung P, Goss JL, et al. Broad and potent
neutralizing antibodies from an African donor reveal a
new HIV-1 vaccine target. Science. 2009;326:285-9.
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WR, Seaman MS, et al. Rational design of envelope
identifies broadly neutralizing human monoclonal
antibodies to HIV-1. Science. 2010;329:856-61.
681
53

(intramuscular, IM)
(subcutaneous, SC)

1
1
Immunization route
Advantages
Disadvantages
Parenteral
Powerful systemic immune
Invasive
response
Limited mucosal immune
Accurate dosing
response
Nasal
Non-invasive
Mucociliary clearance
Mucosal and systemic immune Inefficient uptake of soluble
response
antigens
Easily accessible
Application device needed
Little degradation (compared to
oral)
Oral
Non-invasive
Vaccine digestion in stomach
Mucosal and systemic immune and gut
response
Inefficient uptake of soluble
Large surface area
antigens
Mucosal tolerance
Pulmonary
Non-invasive
Delivery of antigen highly variable
Mucosal and systemic immune from
response
person to person
Little degradation (compared to Dry powder inhaler or nebulizer
oral)
needed
Clearance from lungs
Dermal
Non or minimally invasive
May require (minimally) invasive
Large, easily accessible
technology
application area
(e.g. tattooing, microneedles)
High density of immune cells in Patch or application device
skin
needed
Mucosal immune response
Less established technology
possible
( 13)
682
(Transcutaneous vaccination)
epidermis, dermis
subcutaneous tissue 1 epidermis
stratified squamous epithelium
barrier stratum corneum
keratinocyte1
epidermis dermis
1.5-3 . fibroblast skin
organelles
dermis
subcutaneous tissue
Langerhans cell (LC) (epidermal

langerhans cell)
immature LC keratinocyte epidermis process
antigen immature LC
mature LC
MHC class II mature
LC T cell

nitroglycerin

(abrading,

scraping) vibrating permeability

keratinocyte pro-inflammatory 22
cytokine interleukin 1
antigen presenting
1. Stripping and abrading
cell (APC) MHC
class II ICAM-13

1 epidermis, dermis subcutaneous tissue barrier

stratum corneum ( 2)
53 683
2
(transcutaneous vaccination)
( 2)
2. Electromagnetic energy

ultrasonic
(keratinocyte)4-6
3. Kinetic deposition

Jet injection (JI)

7
mass vaccination
8,9 8
JI
10,11

(adjuvant)
alum
JI
delayed local reaction 8,12
track
(Respiratory vaccination)
mucosal
immunity mucosal
immunity
systemic immunity

mucosal
immunity

(herd
immunity)

epithelial cell, intraepithelial DC, macrophage
microfold (M) cells
M cell specialized epithelial cell

684
endocytosis DC lymphocyte
Lymphoid organ

M cells
deposition
posterior nasal passage

(nasal
vaccine delivery) 313
intraepithelial DC alveolar macrophage

process antigen APC

B cell plasma cell IgA
14
immune response immune tolerance15 immune tolerance

(state of unresponsiveness)

tolerance
(mucosa)
(mucosal vaccine)
unresponsiveness

16

3

(nasal vaccine delivery)
(1) (mucoadhesion)
17
(2) uptake M-cell DC

(3) activation maturation DC
(4) B-cell T-cell

AccuSprayTM (Becton Dickinson
( 13)
and Company, US) syringe

3
powder device inactivated

mutant diphtheria toxoid CRM197 Norwalk
virus liquid delivery device
53 685
diphtheria and influenza18
1. Hadgraft J. Skin, the final frontier. Int J

Pharm. 2001;224:1-18.
2. Bal SM, Ding Z, van Riet E, Jiskoot W,
Bouwstra JA. Advances in transcutaneous vaccine
delivery: do all ways lead to Rome? J Control Release.
2010;148:266-82.
3. Steinhoff M, Brzoska T, Luger TA. Keratinocytes
in epidermal immune responses. Curr Opin Allergy Clin
Immunol. 2001;1:469-76.
4. Mitragotri S, Blankschtein D, Langer R.
Ultrasound-mediated transdermal protein delivery.
Science. 1995;269:850-3.
5. Mitragotri S, Kost J. Low-frequency sonophoresis: a review. Adv Drug Deliv Rev. 2004;56:589601.
6. Lavon I, Kost J. Ultrasound and transdermal
drug delivery. Drug Discov Today. 2004;9:670-6.
7. Hingson RA, Figge FH. A survey of the

development of jet injection in parenteral therapy. Curr
Res Anesth Analg. 1952;31:361-6.
8. Ruben FL, Smith EA, Foster SO, Casey HL,
Pifer JM, Wallace RB, et al. Simultaneous administration of smallpox, measles, yellow fever, and diphtheriapertussis-tetanus antigens to Nigerian children. Bull
World Health Organ. 1973;48:175-81.
9. de Quadros CA, Hersh BS, Nogueira AC,
Carrasco PA, da Silveira CM. Measles eradication:
experience in the Americas. Bull World Health Organ.
1998;76(Suppl 2):47-52.
10. Reis EC, Jacobson RM, Tarbell S, Weniger
BG. Taking the sting out of shots: control of vaccination-associated pain and adverse reactions. Pediatr
Ann. 1998;276:375-86.
11. Mitragotri S. Current status and future
prospects of needle-free liquid jet injectors. Nat Rev
Drug Discov. 2006;5:543-8.
12. Parent du Chatelet I, Lang J, Schlumberger
M, Vidor E, Soula G, Genet A, et al. Clinical immunogenicity and tolerance studies of liquid vaccines
delivered by jet-injector and a new single-use cartridge
(Imule): comparison with standard syringe injection.
Imule Investigators Group. Vaccine. 1997;15:449-58.
13. Slutter B, Hagenaars N, Jiskoot W.
Rational design of nasal vaccines. J Drug Target.
2008;16:1-17.
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686
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in understanding the natural barriers. Pharm Res.
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687
gene-based vectors

gene-based vectors (DNA
vaccine)

(preclinical disease models)

gene-based vectors
(DNA vaccine)

54
regulatory sequences
native conformation
inactivated virus recombinant
protein

CD4 CD8

live-attenuated viruses

3

12
688
1
(innate immunity)
helper T cells, cytolytic T lymphocytes
(CTLs)

(viral vectors)
attenuated viruses
(mucosal delivery)

(prime-boost)
( 2)

(antigen processing)
Cytolytic T lymphocytes (CTLs)
major histocompatibility complex (MHC) class I
(cellular immunity)

CTLs
CTLs

CTLs

3
envelope (Env)
(humoral response) (cellular

response)

MHC
class I CTLs
helper T cells (Th) 5
54 gene-based vectors 689

(adaptive immunity) CTLs, helper T cells
(innate immunity)

(preclinical
study)

DNA plasmids DNA
plasmids

(potency)

expression vectors

(adjuvants)

enhancer/promoter
6
2
gene-based
vectors

CTLs

2 gene-based vectors
cellular
humoral
vectors

(prime-boost)
packaging cell lines

viral vectors
vectors
viral vectors
vectors
prime-boost

690

(lymphoma)
T-helper cells
32
(Delivery of DNA
vaccine)

plasmids
(formulations)
transfection (viral vectors)
(bacterial vectors)

DNA
plasmids
plasmids
plasmids

formulation Vaxfectin
adjuvant

Th1 T helper cells8 DNA plasmids
microparticles 1-10
antigen-presenting cells (APCs)
DNA plasmids
9

Salmonella Shigella10,11

APCs

Viruses
HIV
Rabies
Ebola
Bacteria
Influenza
Hepatitis B, C
Herpes simplex
B. Burgdorferi
C. Tetani
S. Typhi
Parasites
Malaria
Leishmania
Schistosoma
House dust mite
Peanut
Cancer
Breast (Her2/neu)
Colon
Prostate
Allergy
( 2)
Diabetes
Myeloma
Lymphoma
Fibrosarcoma
Autoimmune diseases

12
13
14 SIV/HIV
15
gene gun
gold beads DNA plasmids

CTLs, Th cells
DNA plasmids
hepatitis B surface antigen (HBsAg)
16
recombinant HBsAg hepatitis

DNA vaccine gene gun
17
gold beads

gold beads
Biojector plasmids
APCs 18
Rabies virus, Filovirus, Flavivirus, Togavirus,

Bunyavirus
anthrax

nucleoprotein
(prime) recombinant adenovirus
(boost)
19
Mycobacterium tuberculosis

Bacillus of Calmette and Gerin (BCG)
BCG
20 BCG
BCG

polyvalent booster BCG

mycobacteria
15 18 BCG21
(booster) BCG
3

infectious hematopoietic necrosis virus (IHNV)
22 West Nile virus 23
4

(host genome)
692
West Nile-Innovator
Apex-IHN
Oncept
West Nile virus

Infectious
haematopoietic
necrosis virus
Melanoma
2005
2005
2010
( 2)
tolerance
24

prime-boost

viral vectors

HIV adenovectors25 modified
vaccinia Ankara (MVA) 26

MVA27

28
gene-based vectors

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served nucleoprotein. Vaccine. 2005;23:5404-10.
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695

()

55

(adjuvant)

(Live vaccine)
(attenuation of virulence)

(vector)
696

(reversion)

(attenuation)
(overattenuated)

(underattenuated)

vaccinia

vaccinia

(Serial passage in cell culture)

()

(serial passage)
(unnatural cell
substrate)

(oral poliovirus vaccine) Albert Sabin
55 697
(yellow fever vaccine) 17D

58
(Japanese encephalitis
vaccine) SA14-14-2
100
(primary hamster kidney cell)
1
(measles vaccine)
(mumps vaccine) (varicella-zoster vaccine)

89-12 2

Sabin
10-56
480, 481 472
5
1, 2 3 4-7
2 16681
primary dog kidney 53

53
5
NS1 NS3

8,9

(over attenuation)

SA14-14-2 1

SV40
porcine circovirus 10
(Reassortment)
(segmented RNA genome)

698

(RRV-TV)
4
rhesus
RRV

G1, G2 G4
G3
11-13 (RV5 PRV)
WC3

5
G1, G2, G3,
G4, P(8) 13-15

RRV-TV
(intussusception)

16

reassortment segmented genome

PR8 17

hemagglutinin neuraminidase

18

-
(Temperature-selected mutant)

(cold-adapted
strain)
(temperature-sensitive mutant)
cold-adapted strain

cold-adapted strain
(rubella virus vaccine)
MMR
RA27/3 WI-38
MRC-5 30.19
20,21
25.
25.

55 699

hemagglutinin neuraminidase
18
8,9
respiratory syncytial virus
22

(Generation of recombinant virus)
point mutation

1 4
(deletion) 3
30

23
8

messenger RNA

24,25

700
hemagglutinin
furin
26,27
Japanese encephalitis virus

(chimeric virus)

Flaviviridae28
17D
prM E
Japanese encephalitis
virus
8

28

recombination

West Nile virus
29

30

chimeric virus

(mosaic virus)

herpes simplex
1 2
herpes
simplex 31
single cycle virus
(trans-complement)
(
)

55 701

(
)

receptor

single cycle virus

capsid

capsid
32
(Recombinant viral vector)

()
(vector)

poxvirus vaccinia

vaccinia
33,34

fowlpox canarypox

adenovirus herpes
virus
poxvirus
Vesicular stomatitis virus
alphavirus Sindbis

35

adenovirus vector pox virus vector
prime-boost strategy
36,37

HIV-1

ALVAC HIV-1 (vCP1521)
canarypox
gp160 gag pro HIV-1
702
(booster) gp120

gamma interferon
HIV-1
38
adenovirus serotype 5 gag, pol,
nef 39 HIV-1

ovine atadenovirus40
(Serial passage)

BCG
Mycobacterium bovis
231 13 BCG

BCG

41
BCG
BCG
42,43
44
(Mutagenesis)

Salmonella typhi Ty21a
galactose

45
46,47

(Generation of recombinant bacteria)

Vibrio cholerae
Inaba 569B subunit A
cholera toxin CVD 103-HgR
48
49
50

Peru-15 Vibrio cholerae O1 El Tor Inaba
55 703
ctxA, rtxA, zot ace

toxin recA
cholera toxin B subunit
recombination
flagella51,52
(Recombinant bacterial vector)

Salmonella typhi, Vibrio cholerae,
Salmonella flexneri, Listeria monocytogenes,
BCG Streptococcus gordonii
Salmonella typhi,
Vibrio cholerae, Salmonella flexneri
BCG

(Inactivated vaccine)

adjuvant

cell-mediated
immune response

(Inactivated bacteria)

thimerosal phenol
(whole cell)
innate
immunity

WC
Vibrio cholerae biotype
classical El Tor serotype Inaba
Ogawa formaldehyde
WC-BS Vibrio
cholerae cholera toxin B
subunit
53,54
WC-BS WC
cholera toxin B subunit toxin
enterotoxigenic E. coli WC-BS

enterotoxigenic E. coli
(Inactivated virus)

formaldehyde
adjuvant

704

SA 14-14-255
(Subunit vaccine)
1. (Protein-based)

Bordetella
pertussis

formaldehyde glutaraldehyde

(genetic inactivation) 56

Haemophilus
influenzae57 cholera toxin
B subunit
B subunit
WC-BS

A subunit
55 705
53,54

HBsAg Saccharomyces
cerevisiae
22
(virus-like particle)
58 adjuvant

papillomavirus L1

59,60

papilloma

fusion protein

2. (Peptide-based)
circumsporozoite
Plasmodium falciparum

HBsAg RTS,S
61

conformational epitope

adjuvant
RTS,S
circumsporozoite fusion protein
HBsAg
adjuvant 62
3. (Carbohydrate-based)

(antiphagocytosis)

T-independent
706

2

T-dependent response

T-dependent
tetanus toxoid, diphtheria toxoid,
diphtheria toxoid CRM197
outer membrane protein complex Neisseria
meningitidis carrier
63
H. influenza, N. meningitidis S. pneumoniae
(DNA-based)

CpG innate
immunity codon
(codon optimization)
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715
(primary congenital immunodeficiency diseases) x-linked agammaglobulinemia,

chronic granulomatous disease
(secondary
immunodeficiency disease)

(inactivated vaccines)

(live attenuated vaccine) 1,2
56
1,2
1.

Pneumococcal vaccine
Inactivated influenza vaccine
Hib vaccine
2.
inactivated vaccine

3.
2
4. BCG,
OPV, MMR, Varicella, MMRV, live JEV, Rota virus,
live attenuated influenza vaccine (LAIV), Zoster, yellow fever, Ty21a typhoid
(
)
5.

716

(cocooning strategy)
OPV Small pox

MMR, varicella rotavirus

vaccine

rotavirus vaccine
6. passive immunization immune globulin

3
(Primary immunodeficiency)

11
humoral immunodeficiency

(intravenous
immunoglobulin; IVIG)
IGIV
cell-mediated immunodeficiency severe combined

immunodeficiency (SCID)

phagocyte
chronic granulomatous disease
(live attenuated
virus vaccine)
(live attenuated bacterial vaccine) BCG
Ty21a typhoid vaccine
complement deficiency

S.
pneumoniae N. meningitidis
1 meningococcal vaccine
serogroup B
4

2 ././ 20 ./
10 .
14

1,2
1.
56 717
1 1

B-lymphocyte
(humoral)
( x-linked
agammaglobulinemia
common variable
immunodeficiency)
( selective
IgA deficiency IgG
subclass deficiency)
T-lymphocyte (cell-
mediated and humoral) ( severe
combined immune
deficiency
complete DiGeorge
syndrome)
(
DiGeorge syndrome
Wiskott-Aldrich
syndrome, ataxiatelangiextasia)
Complement
Complement,
properdin
factor B
Phagocytic function Chronic granulomatous
disease, leukocyte
adhesion deficit
myeloperoxidase
deficiency
BCG, OPV, live

typhoid vaccine,
( measles/
yellow fever vaccine, MMR varicella
smallpox live- vaccine)
attenuated influenza
vaccine
OPV, BCG
yellow fever vaccine
IVIG
measles
varicella vaccine
meningococcal
vaccine
* 1. : BCG, oral typhoid vaccine 2. : OPV, MMR, MMRV,

live-attenuated influenza vaccine, yellow fever vaccine, rotavirus vaccine, varicella vaccine, zoster vaccine, smallpox vaccine

1
2. (replacement
therapy) physiologic maintenance
3.
( 2 ././
20 ./
10 .)
718
4.
( 2 ././
20
./
10 .)
14

2
5.
( 2 ././
20 ./
10 .)
1
6.

(anatomical asplenia)

(functional asplenia)
(encapsulated
bacteria) S. pneumoniae, Hib
N. meningtidis 5-9
S. pneumoniae Hib1,2,9,10
2 3
Meningococcal vaccine

10

(elective splenectomy)
S.pneumonia Hib
14 1,10

1

10
14
14

3

56 719
2 Pneumococcal vaccine
5,6
2-6
7-11
3 PCV13 2 1 12-15
2 PCV13 2 1 12-15
(PCV 13 2 2 )
12-23
2 PCV13 2
23-71 PCV PS-23 2 PCV13 8
PS-23 1 PCV13 8 PS-23
1 5 PS-23
PCV 1-3
1 PCV13
PS-23 1 PCV13 8 PS-23 1 5
PS-23
* < 2 PCV13 24-71 PCV PCV13 2
8 6-18 PCV13 1 PCV7 PS-23
3 Hib vaccine
7,11
2-6
7-12
12-14
15-59
5 *
3 2 12-15
2 2 12-15 2 2
2 2
1
1 Hib vaccine
* Hib vaccine Hib vaccine

1 Hib vaccine 2
1,10
(Inactivated Influenza vaccine)

2
12
Cochrane reviews 200913

708

4
haemagglutination inhibition (HI) titer > 32
25-52

50-86
71-81
720
1 13
2,14
3-4
neutrophil lymphocyte 1000 /
..32
3-6 2,14
2
3 (remission)
1 lymphocyte > 700
/.. > 100,000 /..14

Centers for Disease Control and Prevention

immune memory 2
acute lymphoblastic leukemia

1 15 Esposito 14

14

hematopoietic
ablative therapy
graft versus host disease (GVHD)
16,17
18 19 S.pneumoniae20
21
1-10
autologous allogenic 22-25

26-29
56 721
4 14
MMR
2 3
3-6
VZV
2 3
(remission) 1
lymphocyte > 700/..
> 100,000/..;
maintenance 1
RV
OPV
IPV
DTP,
< 7 primary series (3
DTaP-IPV, 1 ) 2
Tdap-IPV
6 3
> 7 primary series (0, 1, 6 )
3
Tdap dT 2
3
Hib
primary series
3
Pneumococcal primary series PCV PS-23
vaccine (PCV 8 > 2
PS-23) 3
Inactivated 2 1
influenza
< 9 1
vaccine
HAV
2 6
HBV
3 (0,1, 6 )
Inactivated 3 (0,1,12 ) Live JEV

JEV
3
polymorphonuclear cells, monocytes natural killer

cells 2-3 lymphocyte
T-cell B-cell 30 B-cell
1-3
1
3-6
1 (remission)
1
lymphocyte > 700/..
> 100,000/..;
maintenance
1
IPV
1
3
1
3
1
3
1
1
2 3
3-12
rituximab B-cell
6 31
B-cell
722
T-cell B-cell
1-3 (CD4
< 200/..) T-cell
CD4+ T cell 18
CD4
200/.. 6-9
GVHD
GVHD 2
CD4 >200/.. T-cell
memory T-cell

nave T-cell
6-12
16
immunoglobulin
32
(autologous, allogenic, umbilical cord transplantation)

516
(inactivated
vaccine) 6

24 1,2,33
GVHD
6

GVHD

GVHD34
GVHD
12 32
(Solid Organ Transplantation; SOT

candidates and recipients)
35
71
36,37

35,38

38

6
graft dysfunction rejection

6
32,39

6
35,39
12-15
39
56 723
5 16,33
Pneumococcal vaccine1
3-6
3-4
Diphtheria, tetanus
Pertussis2
6-12
Hib3
IPV
HBV4
Inactivated influenza
vaccine5
MMR6
HAV
Inactivated JEV
Varicella vaccine7
BCG
OPV
Rotavirus vaccine
6-12
6-12
6-12
4-6
3
3
3
1-2
24
2
12
24
1-2
2
3
PCV13 0, 2, 4 PS-23
8 PCV 3
< 7 DTP/DTaP 0,
2,12 > 7 DTaP 0,
2,12
0, 2,12
0, 2,12
0, 2,12
0, 1
0, 6-12
0,1-2,12
PCV 3 3-6 8 (
4 ) PS-23 1 8 PCV 3
GVHD PCV 4 PS-23 16
2
DTaP DTP 3 > 7 DTaP

Tdap
autologous allogenic Tdap16
3
Hib 3 1 6
4
(Anti-HBS Antibody) 1 HBV 3
HBV 3 16
5
(inactivated influenza vaccine) 6

4 6 2
6 9 2
1 2,16
6
MMR 2 1 16
7
Varicella vaccine
24 16,17
724
6
(Solid Organ Transplantation; SOT candidates and recipients)38

(DTP/DTaP) 1
(HAV) 2
(HBV)
(Hib)
(PS-23)
(IPV)5
2
6
(BCG)

(MMR)
(VZV)
1 2 4
2 3 4
3 4 6
4 5 6
1 2 4
1 2 4
2 3 8
1 2 4
2 3 4
3 4 8
1 2 4
1 2 4
2 3 4
3 4 8
1 2 4
2 3 4
3 4 6
1 2 4
1 2 4
(Influenza)3 6
(PCV7)4 6

SOT
SOT
Td 10 38
2

6
38
3
9
2 4 1 38
4
PCV PS-23 1 2
PCV 8 PS-23 1 3-5
38
5
OPV 1
56 725

39

Recombinant human protein

tumor necrosis factor antagonist
( adalimumab, infliximab etanercept) antiB-lymphocyte monoclonal antibody ( rituximab)

2

40-42

1

1. National Center for Immunization and

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729
HIV-exposed babies

1.
2.
3.

4.
1:

( 1)
DNA Polymerase Chain Reaction (PCR)

1-2
4-6

57

(BCG)

1
730
1a :
17
Tuberculosis(1)
Hepatitis B(2)
Diphtheria, tetanus,
pertussis(3)
Polio(4)
1 2 4 6 9 12 18 2-2 4-6 11-12

BCG
HBV1
HBV2
(HBV)
HBV3
DTwP1 DTwP2 DTwP3

OPV1 OPV2 OPV3
or IPV1 or IPV2
Measles, mumps,
rubella(5)
Japanese
encephalitis(6)
Diphtheria, tetanus,
pertussis
( 4 ; DTaP,
4 ; Tdap)(3)
Japanese B
encephalitis(6)
Haemophilus influenza
type B(7)
Hepatitis A(8)
Varicella(9)
Influenza(10)
Pneumococcal (11)
(PCV PS23)
Human papilloma
virus(12)
or IPV3
DTwP5
OPV5
or IPV4
DTwP4
OPV4
MMR1, (MMR2)
dT
MMR2
JE1, JE2
4
JE3

DTaP1 DTaP2 DTaP3
DTaP4
DTaP5
Tdap
JE4
(4-5
JE3)
Hib1
PCV1
Hib2
PCV2
DNA PCR 1-2
Hib3
(
PRP-T)
PCV3
Hib
HAV1, HAV2 6-12

VAR 2 3
Influenza vaccine 6
PCV4
12-15 PS23 2 3-5
HPV 3
0,1-2,6
9-26
2:
( 1)
1-5
57 HIV-exposed babies 731
1b : Hib 17
PRP-T, HbOC
PRP-OMP
2 - 6
0, 2, 4, Booster
0, 2, Booster
7 - 11
0, 2, Booster
0, 2, Booster
>12 - 59
Booster 12-18 2
1c : PCV 17
2-6
7-11
12-23
24-59
3 6-8
2 6-8
2 6-8
12-15
12-15
1
2 6-8
(1) BCG
(2) HBV DTP-HBV 2, 4, 6

(3) DTP DTwP DTaP (Tdap) 1
(4) Polio vaccine IPV OPV IPV
(5) MMR (clinical stage C CD4 15)

MMR2 1 MMR1 4-6
(6) JE 1 3 4-5
(7) Hib 2 1 12-18
2 1b
(8) HAV 1 2 6-12
(9) VAR 1 CD4 15 2 3
(10) Influenza vaccine
9 2 1
(11) PCV 2 3 2 12-15
( 1a 1c) PS23 2 PCV
2 PS23 1 5
(12) HPV 3 0, 1-2, 6 9 26
732

-- (MMR)

(CDC stage C WHO stage IV) CD4
156
BCG

BCG

BCG (systemic disseminated
BCG disease) 407-1,300 100,000
7

1

(IPV/
OPV)8-10

IPV 1
OPV
OPV
(Vaccine associated polio paralysis, VAPP)11, 12
13
14
(VAR) %CD4
15 2 3
8215

(PCV) polysaccharide 23
valent (PS23) 2

16

3:

14

( 2a 2b)

6
2a : 1-6
18
1
2
3
4
6
0
1
2
7
12
dT1, OPV/IPV1, MMR, BCG

HBV1, JE1
dT2, JE2, OPV/IPV2, HBV2
HBV3
dT3, OPV/IPV3, JE3
2b : 7-18
18
1
2
3
4
6
0
1
2
7
12
dT1, OPV/IPV1, MMR, BCG

HBV1, JE1
dT2, JE2, OPV/IPV2, HBV2
HBV3
dT3, OPV/IPV3, JE3
2 1
CD4 15

19-26
27
4: 4:
14

14
CD4 15

CD4 25
CD4 350 /.. ( > 5 )
6 19-24 CD4 15
viral suppression 400 copies/. 1
T cell B cell 3

CD4 CD4
734
3
CD4 1514
1
2
6
HBV vaccine
HBV1
HBV2
HBV3
3
JE vaccine*
JE1
JE2
2
Measles vaccine** MMR1
1
dT vaccine
>7 10
*
** MMR
2. Chokephaibulkit K, Plipat N, Yoksan S,

Phongsamart W, Lappra K, Chearskul P, et al. A comparative study of the serological response to Japanese
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16:479-83.
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28
(TIG) (RIG)
6. Measles immunization in HIV-infected

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on Infectious Diseases and Committee on Pediatric
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Human immunodeficiency virus infection and routine
childhood immunisation. Lancet. 1987;2:669-72.
11. Chitsike I, van Furth R. Paralytic poliomyelitis associated with live oral poliomyelitis vaccine in
child with HIV infection in Zimbabwe: case report. Bmj.
1999;318:841-3.
12. Ion-Nedelcu N, Dobrescu A, Strebel PM,
Sutter RW. Vaccine-associated paralytic poliomyelitis
and HIV infection. Lancet. 1994;343:51-2.
13. Pavlov DN, Van Zyl WB, Van Heerden J,
Kruger M, Blignaut L, Grabow WO, et al. Prevalence
of vaccine-derived polioviruses in stools of immunodeficient children in South Africa. J Appl Microbiol.
2006;101:1367-79.
14.
2553.
:
; 2553.
15. Son M, Shapiro ED, LaRussa P, Neu N,
Michalik DE, Meglin M, et al. Effectiveness of varicella
vaccine in children infected with HIV. J Infect Dis.
2010;201:1806-10.
16. Steele AD, Cunliffe N, Tumbo J, Madhi
SA, De Vos B, Bouckenooghe A. A review of rotavirus
infection in and vaccination of human immunodeficiency virus-infected children. J Infect Dis. 2009;200
(Suppl 1):S57-62.
17. , ,
, . Update on pediatric infectious disease 2010. :
; 2553.
18.
.
1
1-6 6
7 . :
, ,
,
, .
.. 2550.
; 2550. . 69-70.
19. Siriaksorn S, Puthanakit T, Sirisanthana
T, Sirisanthana V. Prevalence of protective antibody
against hepatitis B virus in HIV-infected children with
immune recovery after highly active antiretroviral
therapy. Vaccine. 2006;24:3095-9.
20. Lao-araya M, Puthanakit T, Aurpibul L,
Sirisanthana T, Sirisanthana V. Antibody response to
hepatitis B re-vaccination in HIV-infected children with
immune recovery on highly active antiretroviral therapy.
736
Vaccine. 2007;25:5324-9.
21. Puthanakit T, Aurpibul L, Yoksan S,
Sirisanthana T, Sirisanthana V. Japanese encephalitis vaccination in HIV-infected children with immune
recovery after highly active antiretroviral therapy. Vaccine. 2007;25:8257-61.
22. Aurpibul L, Puthanakit T, Siriaksorn S,
Sirisanthana T, Sirisanthana V. Prevalence of protective antibody against measles in HIV-infected children
with immune recovery after highly active antiretroviral
therapy. HIV Med. 2006;7:467-70.
23. Aurpibul L, Puthanakit T, Sirisanthana T,
Sirisanthana V. Response to measles, mumps, and
rubella revaccination in HIV-infected children with immune recovery after highly active antiretroviral therapy.
24. Melvin AJ, Mohan KM. Response to immunization with measles, tetanus, and Haemophilus
influenzae type b vaccines in children who have human
immunodeficiency virus type 1 infection and are treated
with highly active antiretroviral therapy. Pediatrics.
2003;111:e641-4.
25. Tejiokem MC, Gouandjika I, Beniguel
L, Zanga MC, Tene G, Gody JC, et al. HIV-infected
children living in Central Africa have low persistence of
antibodies to vaccines used in the Expanded Program
on Immunization. PLoS One. 2007;2:e1260.
26. Rainwater-Lovett K, Moss WJ. The urgent
need for recommendations on revaccination of HIVinfected children after successful antiretroviral therapy.
27. Weinberg A, Huang S, Fenton T, Patterson-Bartlett J, Gona P, Read JS, et al. Virologic and
immunologic correlates with the magnitude of antibody
responses to the hepatitis A vaccine in HIV-infected
children on highly active antiretroviral treatment. J

Acquir Immune Defic Syndr. 2009;52:17-24.
28. Pancharoen C, Thisyakorn U, Tantawichien
T, Jaijaroensup W, Khawplod P, Wilde H. Failure of
pre- and postexposure rabies vaccinations in a child
infected with HIV. Scand J Infect Dis. 2001;33:390-1.
737
1-51

40
2-3

10

58

4,5
( 1)

active immunization
(antibody)

severe
immunocompromised host

738
1
Category
Assessing the health of
the traveler
Assessing the health risk of
travel Itinerary
Preventive advice
Vaccination
Post-travel assessment
Elements
Assessment of underlying medical conditions such as
pregnancy, immunocompromised condition,
medication, and allergies
Assessment of immunization history
Season of travel
Duration
Reason for travel
Style of travel, rural or urban
Planned activities
Risks of exposure
Vaccine-preventable illness
Travelers diarrhea prevention and self-treatment
Malaria prevention
Insect avoidance measures
Other vector-borne and water-borne illness
Personal safety, behavior, and sexual health
Educate on sexual transmitted diseases, bloodborne diseases
Environmental illness (related to altitude, heat, cold, swimming, and diving)
Motion sickness and jet lag
Animal bites and rabies avoidance
Long-term travelers, expatriates, and business travelers
Special needs travelers (e.g., pregnant women, patients with diabetes,
immunocompromised patients, and transplant recipients)
Travel health resources (e.g., traveler-oriented Web sites)
Travel medical kits
Travel health and medical evacuation insurance
Access to medical care overseas
Update routine vaccine profile
Routine, required and recommended vaccines
Access illnesses after trevelling (such as returning fever)
(last minute travelers)

58 739
1.

2. (destination)

3.

website
4.
( / )

2
Routine vaccines

(risk-benefit)

3
( 2)
1.
(mandatory or required vaccines for
certain destination)

(yellow fever vaccine)
(meningococcal vaccine)

2
Mandatory or required vaccines
for certain destinations
before entering
Yellow fever
Meningococcal*
Recommended vaccines
for persons with
risks of exposure
Hepatitis A
Typhoid
Rabies
Meningococcal
Japanese B encephalitis
Tick-borne encephalitis
Cholera
Tetanus-diphtheria
Pertussis
Varicella-zoster
Polio
Influenza
Pneumococcus
Hepatitis B
Haemophilus influenzae type B
Measles, mumps, Rubella
*The tetravalent vaccine (A, C, Y, W-135) is required by Saudi Arabia for Hajj and Umrah pilgrims
740

(
15 ) (
www.cdc.gov/
travel/index.htm)

Aedes () Culex Haemagogus ()

1:300-1:2,000

live-attenuated
vaccine
9 10
95
10 10 6,7
the Official International Certificate of Vaccination
against Yellow Fever (yellow book)
6

6-12

(endemic hyperendemic area)

subsahara

(-)

quadrivalent vaccine Neisseria meningitidis
A, C, Y W-135 (
serogroup B)
70 meningococcal serogroup
B meningococcal
vaccine 8-10
2. (routine vaccines)

58 741

(national program
for immunization)

dT
10

polysaccharide pneumococcal
vaccine
Knowledge, Attitudes and Practices among foreign

backpackers towards malaria risk in Southeast Asia.
J Travel Med. 2009;16:101-6.
4. Boapimp P, Comarmond C. Assessment
and counseling of international travelers: A guide for
practicing physicians. J Infect Dis Antimicrob Agent.
2005;22:133-49.
5. World Health Organization. International
travel and health 2009. WHO Press, Geneva,
Swtizerland; 2007. p.193-218.
6. Barnath ED. Yellow Fever: Epidemiology
and Prevention. Clin Infect Dis 2007;44:850-6.
3.
7. Centers for Disease Control and Prevention.
(recommended vaccines for person with risks of ex- Yellow fever vaccine. Recommendations of the Advisory
posure)
Committee on Immunization Practices (ACIP). MMWR.
2002;51:1-10.

8. Prevention and control of meningococcal
disease. Recommendations of the Advisory Com mittee on Immunization Practices (ACIP). MMWR
Recomm Rep. 2000;49:1-10.
9. Recommendation of the Advisory Com

mittee on Immunization Practices (ACIP). Revised
recommendations of the Advisory Committee on Immunization Practices to vaccinate all persons aged
1118 years with meningococcal conjugate vaccine.
MMWR. 2007; 56:765-6.

1. Steffen R. Epidemiology: Morbidity and
10. Harrison LH. Prospective for vaccine
mortality in travelers. In: Keystone JS, Kozarsky PE, prevention of meningococcal infection. Clin Microbiol
Freedman DO, et al. Travel Medicine 2nd Edition. Rev. 2006;19:142-64.
Mosby an imprint of Elsevier Limited; 2008. p.1-11.
2. Hamer DH, Conner BA. Travel health knowledge, attitudes and practices among United States
travelers. J Travel Med. 2004;11:23-6.
3. Piyaphanee W, Wattanagoon Y, Silachamroon U, Meansanguan C, Wichianprasat P, Walker E.
742
743

(
)
59
( )1,2

3-5
1.

2.

3.
4.

5.

1
744
serology

(Tdap)
2 0.5 .
1
SC
2 0.5 .
1
1 0.5 .
2 0.5 .
4-8 13
SC
3 1.0 . 0, 1
6
IM
1 0.5 .
(LAIV)
1 0.5 .
2 1 . 6-12
IM IM
IM IM
IM IM
SC
SC
SC SC
SC
SC
IM
: IM = intramuscular; SC = subcutaneous
3 0, 1
6 anti-HBs
1-2 36
anti-HBs
10 mlU/.

anti-HBs 10 mlU/.

3 (0, 1, 6 ) anti-HBs 1-2
3 anti-HBs
10 mlU/.

hepatitis B immunoglobulin (HBIG)

anti-HBs ( 10 mlU/.)
HBIG 0.06 ./.
1
HBIG
2 3
(known nonresponder) HBIG
2 1 2
59 745
2 HBsAg

(anti-HBs)
HBsAg
HBsAg
HBIG 1
HepB 3 a
HepB 3 HepB 3
HBIG 2
1 HBIG
1
3 b
anti-HBs

- 10 mIU/.
- < 10 mIU/.
HBIG 1
HepB c
HBsAg
anti-HBs
- < 10 mIU/.
HepB
- 10 mIU/.
: HBIG = hepatitis B immune globulin; HepB= hepatitis b

a HBIG 0.06 ./. 3 0, 1-2, 6
b HepB 2 (6 ) (nonresponder) HBIG (0.06 ./.)
2 1
c anti-HBs HepB 1-2 HBIG
HBIG 4-6 anti-HBs (< 10 mIU/.) 2 3
( 7)

8-10 .. 25522553
(H1N1) 2009
11

(H1N1) 2009
746
0.5 .

2-49

13
0.5 .
2 4-8
2
99
( Pre-exposure prophylaxis )

2 MMR
0.5 . 2 4 12 negative
pressure airborne
(Post-exposure prophylaxis) precaution contact precaution14

MMR 72

varicella lgG varicella lgG

()
1.
3
(Pre-exposure prophylaxis) 5 15-17

2.

2
VZIG 96 VZIG
IVIG acyclovir 7-10
59 747
7 VZIG
125 /10 . ( 625 )
3. acyclovir
10 ./. ( 400 .) 4
7 7

10-21 18

1 .
2 6-12

0.02 ./.
19-21

22-26
CDC
Tdap 1 27
Td
10

2
40

1
748

Salmonella typhi

Tdap 1

1. Nichol KL, Hauge M. Influenza vaccination

of healthcare workers. Infect Control Hosp Epidemiol.
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viral hepatitis. N Engl J Med. 1997;336:196-204.
7. , ,
, , ,
. 2010-2011.
; 2553.
8. Balkovic ES, Goodman RA, Rose FB, Borel
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Nosocomial influenza B virus infection in the elderly.
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11. , ,
, , ,
.
(H1N1)
2553.
59 749
. 2553;41:409-15.
12. Bolyard EA, Tablan OC, Williams WW,
Pearson ML, Shapiro CN, Deitchmann SD. Guideline
for infection control in healthcare personnel, 1998.
Hospital Infection Control Practices Advisory Committee.
Infect Control Hosp Epidemiol. 1998;19:407-63.
13. Nettleman MD, Schmid M. Controlling
varicella in the healthcare setting: the cost effectiveness
of using varicella vaccine in healthcare workers. Infect
Control Hosp Epidemiol. 1997;18:504-8.
14. Garner JS. Guideline for isolation
precautions in hospitals. The Hospital Infection Control
Practices Advisory Committee. Infect Control Hosp
Epidemiol. 1996;17:53-8.
15. Asano Y, Nakayama H, Yazaki T, Kato R,
Hirose S. Protection against varicella in family contacts by
immediate inoculation with live varicella vaccine.
Pediatrics. 1977; 59:3-7.
16. Arbeter AM, Starr SE, Plotkin SA. Varicella
vaccine studies in healthy children and adults.
Pediatrics. 1986;78:748-56.
17. Salzman MB, Garcia C. Postexposure
varicella vaccination in siblings of children with active
varicella. Pediatr Infect Dis J. 1998;17:256-7.
18. American Academy of Pediatrics. Varicella
zoster infections. In: Red Book: 2009 Report of the
Committee on Infectious Diseases, 28th ed, Pickering,
LK (Ed), American Academy of Pediatrics, Elk Grove
Village, IL; 2009. p.714-27.
19. Mink CM, Cherry JD, Christenson P, Lewis
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20. RosenthalS,StrebelP,CassidayP, SandenG,
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21. Wright SW, Edwards KM, Decker MD,
Zeldin MH. Pertussis infection in adults with persistent
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22. Steketee RW, Wassilak SG, Adkins WN Jr,
Burstyn DG, Manclark CR, Berg J, et al. Evidence for a high
attack rate and efficacy of erythromycin prophylaxis in a
pertussis outbreak in a facility for the developmentally
disabled. J Infect Dis. 1988; 157:434-40.
23. Fisher MC, Long SS, McGowan KL, Kaselis E,
Smith DG. Outbreak of pertussis in a residential facility
for handicapped people. J Pediatr .1989;114:934-9.
24. Addiss DG, Davis JP, Meade BD, Burstyn DG,
Meissner M, Zastrow JA. A pertussis outbreak in a
Wisconsin nursing home. J Infect Dis. 1991;164:704-10.
25. Christie CD, Glover AM, Willke MJ, Marx ML,
Reising SF, Hutchinson NM. Containment of pertussis in th,
e regional pediatric hospital during the Greater Cincinnati
epidemic of 1993. Infect Control Hosp Epidemiol.
1995;16:556-63.
26. Calugar A, Ortega-Snchez IR, Tiwari T,
Oakes L, Jahre JA, Murphy TV. Nosocomial pertussis:
costs of an outbreak and benefits of vaccinating health
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27. Mast EE, Weinbaum CM, Fiore AE, Alter MJ,
Bell BP, Finelli L, et al; Advisory Committee on Immunization
Practices (ACIP) Centers for Disease Control and Prevention
(CDC). A comprehensive immunization strategy to eliminate
transmission of hepatitis B virus infection in the United
States: recommendations of the Advisory Committee on
Immunization Practices (ACIP) Part II: immunization of
adults. MMWR Recomm Rep. 2006;55:1-33.
750
751
60

1 2

(Tetanus vaccine)
752

3
10
()
3

1
30-60
10

.. 2541-25422 88-98
anti-tetanus toxin
antibody 0.15 IU/.

15-30
tetanus toxoids
(TT)

diphtheria-tetanus toxoids (dT) tetanus toxoid
(TT) 10
60 753
3 (primary immunization) 3 0,
4-8 6-12 1 (
)
1 dT 2
1 2
dT 1
3 5 dT
1
5

1 4
1
tetanus immune globulin

(TIG)
TIG
3
Tetanus immune globulin (TIG)
TT dT
TT dT 1

81-94
TIG
1
(Diphtheria vaccine)

(epidemic)
4 100,000 0.1
100,000
5-14
15 ( 21.7 ..
2533-2542)
3 .. 2533-2537
10-100
40-49
1 (TIG)
(completed primary immunization) 7
- dT TT 11-16 10
/
- dT TT 2 4-8 1 6-12
- dT TT 3 10
- /
(clean wounds) - dT TT 2 4-8
1 6-12
(contaminated wounds) - dT TT 2 4-8
1 6-12 TIG
- ( tetanus toxoid 3 )
(clean wounds) - dT TT 1 10
(contaminated wounds) - dT TT 1
5
754

3 92
72

4,5
( 20-60
)6
7 .. 2537
17
5-14
15 15
2
85
(anti-diphtheria toxin antibody 0.1
IU/.)

dT
TT dT
TT
10
dT TT

dT 1
81-90
7,8
(Acellular pertussis
vaccine)

2-3

(classic pertussis)

9-12
--
.. 2520

7.25 3.52
.. 2520 .. 2529
0.02 ..
2549

60 755

5-8

3
serologic tests
10-25 ( PCR 2-10)
80
2-3
50
6
whooping cough
8-40
( 22)

CDC
6
5
90 2
13,14

acellular pertussis vaccine
effectiveness 70-90

Tdap (diphtheria-tetanusacellular pertussis vaccine)
Tdap 1
Tdap
dT 1

Tdap

Streptococcus
pneumoniae (23-valent polysaccharide
pneumococcal vaccine; PS-23)
S.pneumoniae
756

(invasive pneumococcal infection)
( 70 )

5
( 65 ) 90 S.pneumoniae
PS-23 (
1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A,
12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F
33F) S. pneumoniae
1, 3, 19F, 6B, 19A, 5, 23F

PS-2315
S. pneumoniae
PS-23

( 65-74 )
5
71 75-84
67 nonbacteremic pneumococcal pneumonia
S.pneumoniae

( 65 )
16
(cost-effectiveness)

65
2
PS-23 influenza vaccine

15,18-20
(pandemic influenza)
S.pneumoniae

(pandemic influenza
H1N1:1918-19)
PS-23
215,17
(revaccination) 2

primary vaccination

PS-23
( 3050)
1-3

60 757
2 23-valent polysaccharide pneumococcal vaccine15,17
(revaccination)
65
5
65
2 - 65
- (asplenia)
3-5
-
cardiomyopathy (COPD)
- (CSF)
19 - 64 ()
-
2 - 65
- HIV
-
5
-
- (chronic renal failure)
-
2
(inactivated vaccine) split
virion vaccine
surface antigen external antigen (H N) internal antigen
subunit vaccine external
antigen
(Influenza vaccine)
()
3-5
2-49
antigenic drift
(COPD, asthma, cystic
fibrosis)

(seasonal influenza) inactivated influ 7-valent
pneumococcal conjugated vaccine 13-valent
pneumococcal conjugated vaccine

758
enza vaccine
(
)

21-25
1.
65
(COPD)

2
3
(6 - 18 )
(
Reyes syndrome
2.
( 1)
3.

(Rabies vaccination for pre-exposure

prophylaxis)
(bite prevention)

20 (
300,000 )
(pre-exposure prophylaxis)

()

(rabies
immune globulin)
60 759

1
(
)
25,26

27-30

1
( 0.1 .)
0, 7 21 28 (
)25

(neutralizing antibody; Nab) 0.5
IU/.
Nab titer
6 Nab titer 0.5
IU/. 1
0.1 . 1
1

Nab titer 1-2

Nab titer 0.5 IU/.

(
)
Nab titer

WHO
category 2 3
27

(Measles-mumps-rubella vaccine)

31
32,33
12 15
95 98
16 34
97

75-93 30
35
98
12 12
16 36
--
9-12
760
85-95 63-95
96-9937,38

(primary vaccine failure)

(secondary vaccine failure)
39
2
2 4-6 40
.. 2500

.. 2500

-- 1
1 4
1.
2. .. 2506-2510
3.
4.
5.
.. 2500
- 1 41
(Varicella and zoster vaccine)

70- 90 95
42,43
13
78-82 2
9944,45 breakthrough
1-4
46 breakthrough

47
60 761

48

2 4

anaphylaxis
(postexposure varicella immunization)

90 3

5

49

50

post-herpetic neuralgia (PHN)
10-15
PNH
Zostavax
Oka
0.65
. 1
zoster vaccine
1-3 3

51.3
PHN 66.5

60-69 50,51
(Human papillomavirus vaccine)

1

6,300 17
(persistent infection) 0.5

10-20 52-55
16
18, 45, 31 33
762
70 16 18

L1-VLP
2
1) HPV 4 (quadrivalent) 6,
11, 16 18 amorphous aluminium
hydroxyphosphate sulfate
L1 L1
MSD (HPV 16, 18)
(HPV 6, 11)
0, 2, 6 2) HPV 2 (bivalent)
16 18 L1
L1
ASO4 ( aluminium hydroxide
3-deacylated monophosphoryl lipid A)
GSK 0, 1, 6
2
5-7

(persistent
infection) 90-96
(
31, 45)
2
3 quadrivalent
16-24
CIN2 CIN3 AIS HPV 16
18 98 3
56,57 3 bivalent
15-25 18,644 14
1,852
34.9
CIN2 CIN2+
HPV 16 18 98.1
CIN2 CIN2+
HPV 31, 33, 45 58
67.4, 49.8, 100
49.6
58,59

11-26
11-12

CIN 2 3 adenocarcinoma in situ (AIS)

26
HPV

(
)
60 763
1. Wassilak SGF, Murphy TV, Roper MH,

Orenstein WA. Tetanus toxoid. In Plotkin SA, Orenstein WA. Vaccine. 4th ed. Philadelphia: WB Saunders;
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frequent cause of prolonged cough illness in adults
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10. Vincent JM, Cherry JD, Nauschuetz WF,
Lipton A, Ono CM, Costello CN, et al. Prolonged afebrile nonproductive cough illness in American soldiers
in Korea. Clin Infect Dis. 2000;30:534-9.
11. Birkebaek NH, Kristiansen M, Seefeldt
T, Degn J, Moller A, Heron I, et al. Bordetella pertussis and chronic cough in adults. Clin Infect Dis.
1999;29:1239-42.
12. Jackson LA, Cherry JD, Wang SP,
Grayston JT. Frequency of serological evidence of
bordetella infection and mixed infections with other
respiratory pathogens in university students with cough
illnesses. Clin Infect Dis. 2000;31:3-6.
13. Turnbull FM, Heath TC, Jalaludin BB,
Burgess MA, Ramalho AC. A randomized trial of
two acellular pertussis vaccines (dTpa and pa) and
a licensed diphtheria-tetanus vaccine (DT) in adults.
Vaccine. 2001;19:628-36.
14. Halperin SA, Smith B, Russell M, Scheifele
D, Mills E, Hasselback P, et al. Adult formulation of a
five component acellular pertussis vaccine combined
with diphtheria and tetanus toxoids and inactivated
poliovirus vaccine is safe and immunogenic in adolescents and adults. Pediatr Infect Dis J. 2000;19:276-83.
15. Prevention of pneumococcal disease:
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16. Whitney CG, Schaffner W, Butler JC.
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17. Recommended adult immunization
764
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18. Mangtani P, Cutts F, Hall AJ. Efficacy of
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more developed countries: the state of the evidence.
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19. Jackson LA, Neuzil KM, Yu O, Benson
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20. Christenson B, Lundbergh P, Hedlund
J, Ortgvist A. Effects of a large-scale intervention
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21. Recommendations of Advisory Committee on Immunization Practices (ACIP) 2005-2006.
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22. Influenza vaccine supply and recommendation for prioritization during 2005-2006. MMWR.
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23. Monto AS. The risk of seasonal and
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31.
.
..2520-2537 : ; 2538.
32.
. . :
; 2544. .292-5.
33.
:
; 2544. .219-26.
34. -
- :

: ; 2548, .91-100.
35. Centers for Disease Control and Prevention (CDC). Recommended childhood immunization
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36. Chu SY, Bernier RH, Stewart JA, Herrmann KL, Greenspan JR, Henderson AK, et al.
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Sixteen-year follow-up in the Hawaiian Islands. JAMA.
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37. , ,
, , ,
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2
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42. Chu SY, Bernier RH, Stewart JA, Herrmann
KL, Greenspan JR, Henderson AK, et al. Oka/Merck
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43. Weibel RE, Neff BJ, Kuter BJ, Guess HA,
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Engl J Med. 1992;327:1272-8.
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2006;20:1-15.
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anogenital diseases. N Engl J Med. 2007;356:1928-43.
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high-grade cervical lesions. N Engl J Med. 2007;356:
1915-27.
58. Harper DM. Sustained immunogenicity
and high efficacy against HPV 16/18 related cervical
neoplasia:long-term follow up through 6.4 years in
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CM, Chow SN, Apter D, et al. Efficacy of human
papillomavirus (HPV)-16/18 AS04-adjuvanted
vaccine against cervical infection and precancer
caused by oncogenic HPV types (PATRICIA): final
analysis of a double-blind, randomised study in young
women. Lancet. 2009;374:301-14.
767
61

6 - 12

( 1)

(Congenital
(killed vaccine) rubella syndrome, CRS)
(live attenuated vaccine)
85
1 16

,,
768
1 Vaccination in pregnancy : Live attenuated vaccines

Bacteria
Virus
Vaccines
BCG
Oral typhoid vaccine
Influenza
MMR
Smallpox
Varicella
Yellow fever
Zoster
( 15)
Recommendation
Contraindicated
Contraindicated
Contraindicated
Contraindicated
Contraindicated
Contraindicated
Contraindicated
Contraindicated

progressive encephalopathy
CRS
.. 2010 ..
20151

CRS

.. 1971-1989
1-2
CRS 321
(RA 2713)
2
Comments
Inactivated typhoid Vi polysaccharide
vaccine is preferred.
Should receive inactivated influenza vaccine
Has been reported to cause fetal infection
Unless travelling to yellow fever endemic area
anti-Rho (D)
28 198
16 3
1 cerebral
cortical atrophy, mental retardation
4
5
2
61 769

17-30 315

1
2
4-8 1

362 .. 1995-2000
6

varicella zoster immunoglobulin 96
125 10
( 625 )

1

4

304

( 2, 3)

8,9

4 10
(
)

252
26.1 11,12

770
2 Vaccination in pregnancy : Inactivated vaccines

Bacteria
Virus
Vaccines
Cholera (oral)
Meningococcal
polysaccharide
vaccine (MPSV4)
Recommendation
Not recommended
Recommended for
women at increased
risk
Comments
Inadequate safety information
No documented adverse events in either pregnant
women or their newborns, but the number
of vaccinees reported is small.
Pneumococcal
polysaccharide
vaccine (23 v PPV)
Tdap
Recommended for
women at increased
risk
Recommended for
women who work in
close contact with
infants
Travelling to
endemic countries
Data are limited to clinical trials and deferral

of vaccine unless there is an increased
risk of IPD.
If not given before pregnancy, it should be
given as soon as possible after delivery.
Typhoid Vi
polysaccharide
vaccine
Hepatitis A
Hepatitis B
Human papilloma
virus (HPV)
Influenza
Japanese
encephalitis (JE)
Polio (IPV)
Rabies
( 15)
No evidence of risk to the fetus
Recommended for
susceptible pregnant
women
Recommended for
women
Not recommended
Recommended
Recommended for
women at risk
Recommended for
women at risk
Recommended
No evidence of congenital defects on

the fetus.
No adverse effects on pregnancy, whereas
JE infection is associated with miscarriage.
Vaccination of pregnant women should be
avoided on theoretical grounds
3 Vaccination in pregnancy : Toxoids and Immumoglobulins

Toxoids and Immumoglobulins
Tetanus/diphtheria
Hyperimmune globulins
( 15)
Recommendation
Recommended
Recommended for
women exposure to
measles, hepatitis A,
hepatitis B, rabies,
varicella and tetanus
Comments
Toxoids are safe in pregnancy
No known risk to the fetus from passive
immunization of pregnant women with
immune globulins.
61 771
13
(Td)
Td
10 1

3
Td 2
Td 2
4 Tdap 1 Td
6

2

Tdap Td
Catch-up

<12

6

12
772

14
1.
2.
3.
4.
5.
6.
7.

40.
8. anaphylaxis neomycin streptomycin
9.
10.
2

61 773

Prevention(CDC). Progress Toward Control of Rubella
and Prevention of Congenital Rubella Syndrome--Worldwide, 2009. MMWR Morb Mortal Wkly Rep.
2010;59:1307-10.
Reef S, Phillips L. Centers for Disease Control and
Prevention. Measles, mumps and rubella vaccine
use and strategies for elimination of measles,
rubella, and congenital rubella syndrome and
control of mumps: recommendations for the advisory
committee on immunization practices (ACIP). MMWR
Recomm Rep.1998;47(RR-8):1-57.
3. Gershon AA. Chicken pox, measles and
mumps. In: Remington JS, Klein JO, eds. Infectious
diseases of the fetus and newborn infant. Philadelphia:
WB Saunders; 2001. p. 683.
4. Hargar JH, Ernest JM, Thurnau GR,
Moawad A, Thom E, Landon MB, et al. Frequency
of congenital varicella syndrome in a prospective
cohort of 347 pregnant women. Obstet Gynecol.
2002;100:260-5.
5. Denicola LK, Hanshaw JB. Congenital and
neonatal varicella. J Pediatr .1979;94:175-6.
6. Shields KE, Galil K, Seward J, Sharrar
RG, Cordero JE, Slater E. Varicella vaccine exposure
during pregnancy: data from the first 5 years of the
pregnancy registry. Obstet Gynecol. 2001;98:14-9.
7. Cavalcanti DP, Salomo MA, JopezCamelo J, Pessoto MA. Campinas Group of Yellow
1.
2.
3.

4.

5.

4
6.

7.
8.

774
Fever Immunization During Pregnancy. Early exposure
to yellow fever vaccine during pregnancy. Trop Med
Int Health. 2007;12:833-7.
8. Harris JW. Influenza occurring in pregnant
women: a statistical study of thirteen hundred and fifty
case. JAMA. 1919;72:978-80.
9. Freeman DW, Barno A. Deaths from Asian
influenza associated with pregnancy. Am J Obstet
Gynecol. 1959;78:1172-5.
10. Neuzil KM, Reed GW, Mitchel EF,
Simonsen L, Griffen MR. Impact of influenza on acute
cardiopulmonary hospitalizations in pregnant women.
Am J Epidemiol. 1998;148:1094-102.
11. Munoz FM, Greisinger AJ, Wehmanane
OA, Mouzoon ME, Hoyle JC, Smith FA, et al. Safety of
influenza vaccination during pregnancy. Am J Obstet
Gynecol. 2005;192:1098-106.
12. Fiore AE, Uyeki TM, Broder K, Finelli L,
Euler GL, Singleton JA, et al. Prevention and control of
influenza with vaccines: recommendations of the
Advisory Committee on Immunization Practices (ACIP),
MMWR Recomm Rep. 2010;59(RR-8):1-62.
Prevention. Seasonal Influenza and 2009 H1N1
Influenza Vaccination Coverage Among Pregnant
Women---10 States, 2009--10 Influenza Season.
MMWR Morb Mortal Wkly Rep.;59(47):1541-5.
14. Rotz LD, Dotson DA, Damon IK, Becher
JA; Advisory Committee on Immunization Practices.
Vaccinia (smallpox) vaccine: recommendations of
(ACIP). MMWR Recomm Rep. 2001;50(RR-10):1-25.
15. Gruslin A, Steben M, Halperin S, Money
DM, Yudin MH. Immunization in pregnancy. J Obstet
Gynaecol Can. 2008;30:1149-54.
775
Community immunity

1.
Community immunity
6
smallpox inoculations variolation

Lady Mary, Wortley Montagu

Edward Jenner (..1749-1823)

..1853

..1980
(World Health Organization: WHO)

polio
1,2
..1807-1883 William Farr

3
(disease agents) (human hosts)
(environmental conditions)
62
3
community (herd)
immunity ..1923 Topley
Wilson The spread of bacterial infection: the problem of herd immunity4

5

Bacillus enteritidis

Wilson
herd immunity Greenwood
Epidemics and Crowd Diseases
..19355,6
20
smallpox
..1974
WHO Expanded Program on
776
Immunization (EPI)

neonatal tetanus measles5,7

community

..
1933 Hedrich

..1900-1931

68

herd immunity

68

8
..1924
Pittsburgh
Voux

Pittsburgh 9 ( ..
1915-1924)
22 112 9
.. 1947-1974
10 94
.. 2002

3

9
.. 2006
245 Iova

10

community (herd) immunity
community
(herd) immunity
2. Community (herd) immunity

community immunity herd immunity

(immunity)
(community herd)

5,11 1
1. Herd immunity
12
2. Herd immunity

62 Community immunity 777
13
3. Herd immunity
14

(Community Herd immunity)

herd
protective/immunity effects5,11
immunity

(state
of protection)
(immunity)
2 11
community
immunity

5,11
3.
(Nave populations)
basic reproduction number (R0)
Basic reproduction number (R0)
herd
immunity (susceptible
to infection)
. A
A
A (susceptible
to infection) . A
. 2
. R0 A
2 R0

1 Community (herd) immunity

( 2)
778
2 (No herd immunity)

( 17)
1 R0
Infection

Diphtheria
6-7
1
Influenza
1.4-4
2
Measles
12-18
Mumps
4-7
Pertussis
12-17
3
Polio
2-15
Rubella
6-7
Smallpox
5-7
Tetanus
Not applicable
4
Tuberculosis
?
5
Varicella
8-10?
Pandemic influenza (H1N1)
1.6?
( 15 ,16)

5,11 2
R0
herd immunity R0 1
4.
(some are immune/herd immunity)
indirect protection and the effective
reproduction number (R)
Effective reproduction number (R)

B .
A 2
50


R = (1-P)* R0
R 1
P 1-1/ R0
5. The herd immunity threshold5,11
B R0 = 5 ( 5

principal reservoir ) P = (1-1/5)
= 0.8 80
effective reproduction number (R) 1
1

P herd immunity
threshold
(R) R0
(population: P) herd immunity threshold
2

(R) 1
3
3 (some are immune/herd immunity)

( 17)
2 Basic reproduction number (R0) Herd immunity threshold, P

Infection
Diphtheria
6-7
Influenza
1.4-4
Measles
12-18
Mumps
4-7
Pertussis
12-17
Polio
2-15
Rubella
6-7
Smallpox
5-7
Tetanus
Not applicable
Tuberculosis
?
Varicella
8-10?
Pandemic influenza (H1N1)
1.6?
( 5,15)
Herd immunity threshold, P (%)

85
30-75
92-94
75-86
92-94
50-93
83-85
80-85
Not applicable
?
?
~40%
780
R0
1.6
40-50

P

80-90

(social network) 5,11
6. Infection elimination and eradication17

elimination
eradication

Elimination of infections

Eradication
7. direct indirect effects

17

(direct effects)

herd effects (indirect effects)

1.
herd effects
2.
herd effects
vaccine
coverage

3.
herd effects

herd effects

(population 1)
(population 2)

4 direct indirect effects
( 17)

4
1. Direct protective effect
(incidence)
1
2. Indirect protective effect
(incidence)
1
2
3. Overall protective effect (
direct indirect effect)
(incidence)
1 2
4. Total protective effect
(incidence)
1
217

)

5,11,17
herd immunity

community immunity

8.
10
herd protection5,11,17
herd protection (
75 (
( 502 )5
782
incubation
period 7-19

native Alaskans
18
herd effects
community immunity

13
..1981
indirect effect
5, 19,20

com herd effects
waning munity immunity
major genetic (shift) minor genetic (drift)

4-5

(H5N1)

5
H1N1 2009

5

1 10
herd immunity effect
7-valent pneumococcal conjugate vaccine
.. 2000 21

type 16
18
11-26

indirect effect

sexual contact
multiple partners
indirect effect single partner

cost-benefit
herd
immunity

18-26
herd immunity

5,22-25
9. Herd effects
11
herd effects

herd effects
lymphatic filariasis
Ivermectin diethyl carbamazine

(early detection)

immunity

herd effects

intervention
intervention
intervention
11
10.
Community (herd) immunity

(immunity) community

immunity

784

immunity

community immunity

() (
)
of bacterial infection: the problem of herd immunity.

J Hyg. 1923; 21: 243-9.
5. Fine PEM, Mulholland K. Section 5: Public
health and regulatory issues. Community immunity.
In: Plotkin SA, Orenstein WA, and Offi PA, editors.
Vaccines. 5th ed. Saunders: US; 2008. p.1573-92.
6. Greenwood M, editor. Epidemics and
crowd diseases. London: Williams & Norgate Ltd, 1935.
7. Dowdle WR, Hopkins DR, editors. The
eradication of infectious diseases. Chichester, UK;
John Wiley, 1998.
8. Hedrich AW, editor. Monthly estimates of
the child population susceptible to measles, 19001931. American Journal of Epidemiology; Oxford
University Press, 1933.
9. Eleanor McBeans book, Vaccination condemned, Better Life Research, 1981.
10. Galil K, Lee B, Strine T, Carraher C,
Baughman AL, Eaton M, Montero J. et al. Outbreak
of varicella at a day care centre despite vaccination.

1. Microbiology awareness campaign (MAC) N Engl J Med. 2002;347:1909-15.
[Internet]. Vaccines & immunization. [cited 2011 Feb
11. Jacob John T, Samuel R. Herd immunity
17]. Available from URL: www.sgm.ac.uk.
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2. CDC. [Internet]. History and Epidemiology of Epidemiol. 2000;16:601-6.
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12. Saunders WB. Dorlands illustrated medical
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2011 Feb 20]. Available from URL: www.bt.cdc.gov/agent/
13. Keusch GT, Bart KJ. Immunization and
smallpox/training/overview
vaccine use. In: Fauci AS, Brawnwald E, Isselbacher
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com /public-health-encypedia/ epidemic-theroy-herd- Oxford Text Book of Medicine. 3rd Edn, Vol.1. Oxford:
Oxford University Press; 1996. p. 315-21.
immunity/pritnt.
15. Fine PE. Herd immunity: history, theory,
4. Topley WWC, Wilson GS. The spread
practice. Epidemiol Rev. 1993;15:265-302.

16. Anderson RM., May RM. Infectious
diseases of humans: dynamics and control. Oxford,
UK: Oxford University Press, 1991.
17. Smith PG. Concepts of herd protection
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18. Black FL. The role of herd immunity in
control of measles. YJBM. 1982;55:351-60.
19. Kyaw MH, Lynfield R, Schaffner W, Craig
AS, Hadler J, Reingold A, et al. Effect of introduction
of the pneumococcal vaccine on drug resistant Streptococcus disease. N Eng J Med. 2006;354:1455-63.
20. McIntosh EDG, Conway P, Willingham J,
Hollingsworth R, Lloyd A. Pneumococcal pneumonia
in the UK-how herd immunity affects the cost-effectiveness of 7-valent pneumococcal conjugate vaccine
(PCV). Vaccine. 2005;23:1739-45.
21. Armstrong GL, Billah K, Rein DB, Hicks
KA, Wirth KE, Bell WB. The economics of routine
childhood Hepatitis A immunization in the United
States: The impact of herd immunity. Pediatrics.
2007;119:e22-9.
22. Connor KO. Herd immunity. Australian
Family Physician. 2007;36:667.
23. ABC Radio National, PM, Calm urged
over gardasil vaccinations. Tuesday, 22 May, 2007.
24. FUTURE II Study Group. Quadrivalent
vaccine against human papillomavirus to prevent
high grade cervical lesions. N Engl J Med. 2007;356:
1915-27.
25. Klein R, Tankard Reist M. Why are we
experimenting with drugs on girls? The age, May 25,
2007.
786
787
63

(cell culture Vaccinia) Botulinum toxoids
(Tularemia vaccine)
(Q fever vaccine)
(VEE, Venezuelan equine encephalitis)
(EEE, Eastern equine encephalitis)
(WEE, Western
equine encephalitis)

() (vaccinia virus vaccine)
788

( 7
)

60
30

2
alum-
63 789
adsorbed
Bacillus anthracis
0, 2 4
6, 12 18

2
(protective factor)

recombinant
technology modern
adjuvant
2
Botulinum toxoids
pentavalent botulinum toxoid

.. 2504

(equine-derived botulinum antitoxin,
BAT) (human-derived botulinum
immunoglobulin, BIG)
1. Russell PK. Vaccines in Civilian Defense

Against Bioterrorism [Internet]. Special Issue:
Emerging Infectious Diseases Journal. National Center
and Prevention; 1999. Available from: http://www.cdc.
790
gov/ncidod/eid/vol5no4/russell.htm#Ref
2. CommitteeonR&DNeedsforImprovingCivilian
Medical Response to Chemical and Biological Terrorism
Incidents. Institute of Medicine, National Academy of
Sciences. Chemical and Biological Terrorism. Research
and Development to Improve Civilian Medical Response.
Washington: National Academy Press; 1999.
3. Zajtchtchuk R, Bellamy RF, editors.
Textbook of military medicine: medical aspects of
chemical and biological warfare. Office of the Surgeon
General, Department of the Army. Washington, D.C.;
1997.
4. Pomeratnsev AP, Startsin NA, Mockov YV,
Marnin LI. Expression of cereolysin AB genes in
Bacillus Anthracis vaccine strain ensures protection
against experimental hemolytic anthrax infection.
Vaccine. 1997;15:1846-50.
5. Office of Technology Transfer, National
Institutes of Health [Internet]. Botulinum Toxoid.
Available from: http://www.ott.nih.gov/Technologies/
abstractDetails.aspx?RefNo=1811
6. Keller JE. Characterization of new
formalin-detoxified botulinum neurotoxin toxoids.
Clin Vaccine Immunol.2008;15:1374-9.
795
, ,
64

.. 2553
(Expanded Program on Immunization
EPI) .. 2520 4
1 BCG
-- (DTP) 1
() 8
1 10 (

)
1 .. 2520 2, 3
2520-2524
BCG
DTP
OPV
T*
Ty
2525-2529
2530-2534
BCG
BCG
DTP
DTP
OPV
OPV
T*
T*
(M)
(M)
(R) (R)
dT**
dT**
JE
Ty
Ty
*
**
***
2535-2539
BCG
DTP
OPV
T*
(M)
(R)
dT**
JE
HB
2540-2544
BCG
DTP
OPV
T*
(M)
dT**
JE
HB
MMR
2545-2552
BCG
DTP
OPV
dT*
(M)
dT**
JE
HB
MMR
DTP-HB
***
-
2553
BCG
DTP
OPV
dT*
(M)
dT**
JE
HB
MMR
DTP-HB
***
-
796

(EPI)
1. BCG
.. 2525
1 .. 2535
4-6 (
1

.. 2546 . 1
BCG
2. -- (DTP)
2 4 ..
2525 6 . .
2534 1 -2
.. 2543
4-6 2
3.
--
.. 2520
..
2521 24
.. 25251

2 (national immunization day) 4-6
.. 2537

OPV
4. (M) .. 2527
912 .. 2539
1
.. 2540
1 -- (MMR)2
..2553
MMR Jeryl Lynn
9-12
5.
6 .. 2529
congenital rubella syndrome
.. 2536
1

1
6
6 ..
2541 2
6. (HB)
.. 2531
.. 25352 ..
2551 DTP-HB
7. JE (Inactivated Japanese encephalitis vaccine)
1 2 ..
2533

.. 2543

2 3
.. 25442
8.
2 ..
2536 .. 2548
-

9.
64 797

(
BCG, DTP, OPV
( BCG, M)
( JE)
(

1
6

congenital rubella syndrome)
( 1)
.. 2551
( JE)
90 ( 2)5

.. 2540

( 2-5)

(pandemic influenza)
. 2548

.. 2551 .. 2552-25534
H1N1 2009

7
( body mass index >35
100 )

2 65 (

HIV )
(65 )
( 6 2 )
10.
1-6 .. 2521

.. 25334
798
1 1 .. 2530-2551
( 30-Cluster survey )
2

.. 25515
BCG
DTP OPV 3
DTP OPV 4
DTP OPV 5
HB 3
M 1
JE 2
JE 3
T (2 )
99.9
98.7
96.5
79.4
98.3
98.1
94.6
89.3
96.7
( Cluster survey .. 2551)
64 799
.. 2530-2553
2 DTP 3 1 :
.. 2530-2553 ()
3 DTP 3 1 :
.. 2530-2553 ()
800
4 DTP 2 + :
.. 2530-2553 ()
5 1 :
.. 2530-2553 ()
-
-
EPI
3 3 0, 1, 6
4 10

5 6
64 801
BCG
HB
DTP**
OPV
dT
, 2 *, 6
2 , 4 , 6 , 18 , 4-6
2 , 4 , 6 , 18 , 4-6
- 12-16 (.6) 10
- 0, 1, 6 10
MMR
9-12 ( MMR ), 6-7 (.1)
JE
18 (2 4 ) 21/2 (1 )
* 1-2
** 2, 4, 6 DTP-HB DTP HB
1.
2. 1
1
* BCG
802
5 1
1-6
2
3
4
5
6
0
DTP1, OPV1
(
)
M MMR
BCG*
1
2
4
8
12
HB1, JE1
DTP2, OPV2, JE2
DTP3, OPV3. HB2
HB3
DTP4, OPV4, JE3
1.
2.
5 1 4 ( 12 )
1
1
* BCG
6 6
7
1
2
3
4
5
0
dT1, OPV1, MMR
( BCG*
)
1
HB1
JE1, JE2
2
dT2, OPV2, HB2
7
HB3
12
dT3, OPV3, JE3
1.
2.
2 2 **
6 1 4 ( 12 )
1
1
* BCG
**
64 803
- 1 2
0, 6 2
1 2
3 6 10
- 3
10 1
10
(EPI)

EPI

EPI

7 8
1. EPI

EPI
(acellular
pertussis) -
(DTaP) (Tdap)

-- (DTPIPV, DTaP-IPV, Tdap-IPV)

(SA14-14-2)
2.

3.

(23-Valent polysaccharide) (
)

4.
- (dT) 1020 --
(Tdap) dT
--
804
7
(EPI)
( .. 2554)
DTaP1
DTaP2
DTaP3
DTaP4
IPV1
IPV2
IPV3
IPV4
Hib1
Hib2
Hib3
PCV1
Rota1
PCV2
Rota2
PCV3
Rota3
(
pentavalent)
Live JE 2
3-12
IPV5
Tdap Tdap
DTaP5 dT
10
Hib4
HAV 2 6-12
VZV1
VZV2
Influenza 6 -18 ( 6-24)
2 4
PCV4
HPV
3
0,1-2,6
: : DTaP: -- , Tdap: --
, dT: -, IPV: , Live JE: , Hib: (Haemophilus
influenzae type b), HAV: , VZV: , Influenza: , PCV: , Rota:
, HPV: (human papilloma virus)
1. IPV DTaP
2. Hib PRP-T DTP
3. DTwP-HB, DTwP-HB-Hib, DTaP-IPV, DTaP-IPV-Hib, DTaP-IPV-Hib-HB
(Passive immunization)
5.


1.
congenital acquired B-lymphocyte defect
64 805
8
( .. 2554)
()
(Haemophilus
- 2 2
influenzae type b)
-
2
( PCV10,13)
- 2 5
- 2

/
2
23- valent

(PS23) /
-
1
- /

- (
CD4 >15%)
-
3-5
3 2, 4, 6
2

2
- 2-6 3
- 7-11 2
- 12-24 1
24
2 2
4 2, 4, 6, 12-15
3 2, 4, 12-15
( 2+1)
2
6-8
- 2-6 3
- 7-11 2
- 12-23 2
- 24-59
2
12-15
12

PS23
2 2 3-5
2 1 3-5
PCV
PCV 2 2
5
2 1 4-6
1 13
2
4
3

2 4-6
3
13 2
4-8
2 3
1
806
8 ()
( .. 2554)
()
-
-
0,7,21 ( 28)
0,3,7,14, 28

(
)
6
( 9
2 4 )

- 66
- 66

hemoglobinopathy

hemoglobinopathy
BMI
BMI>35
>35
, 2-3
>100
100
- 6 15
monovalent 2
2, 4
pentavalent 3
2, 4, 6

6-15
32
4
- 1
1 2 6-12
- 1

- 1-40
2
- 9-26 ( bivalent 3 0, 1-2, 6
quadrivalent)
- 9-18 (
quadrivalent)
-
-

64 807
2.

3.
botulism, diphtheria, tetanus, toxic shock syndrome
passive immunization Immune Globulin (IG)
IG (hyperimmune)
Immune Globulin
(IGIV) IG (hyperimmune)
( Botulism Immune Globulin, Cytomegalovirus Immune Globulin)
IG
monoclonal antibody
syphilis, hepatitis B,
hepatitis C, HIV-1, HIV-2, HTLV-1, HTLV-2
IG passive immnuniztion
1. IG
1,000

anterolateral
5 . 3 .
6

12 40 2

7
6 8

2. IG (IGIV)
15,000 60,000
FDA measle virus,

Corynebacterium diphtheriae, poliovirus, hepatitis B
virus 6

Varicella
Zoster Immune Globulin (VZIG)
96 9
Staphylococcal or streptococcal toxic shock
syndrome
Kawasaki disease
Chronic B-cell leukemia hypogammaglobulinemia
stem cell transplant
ganciclovir CMV pneumonia
Guillain-Barr syndrome
3. IG (hyperimmune globulin)

Hepatitis B Immune Globulin, Rabies Immune Globulin,
Diphtheria antitoxin, Tetanus Immune Globulin, Varicella Zoster Immune Globulin, CMV-IGIV, Botulism
Immune Globulin (
)
IG IGIV6
IG
IG
IGIV
IGIV

IG
808

epinephrine
IG
IgA deficiency
IgA IG

IgA deficiency IG
-
-

--

2-3 serum sickness
angiodema, glomerulonephritis, Guillain-Barre
syndrome, peripheral neuritis myocarditis
serum sickness 2-3
2
serum sickness
3
Anaphylaxis

angioedema
stridor

IG ()

IG Tetanus

Immune Globulin, Diphtheria antitoxin, Rabies Im-
mune Globulin, Botulism Immune Globulin
anaphylaxis
Ig E

6

scratch

(Intradermal test,
6
ID)
1. Acute febrile reactions

anaphylaxis
2. Serum sickness 7-10
3 scratch,
serum sickness prick, puncture ID 24
maculopapular ( . 48 .
90 )
64 809
scratch, prick puncture

1:100 1
scratch, prick puncture
positive control negative control
negative control 3 .
positive control
15-20
ID
Intradermal (ID)
1:1,000 0.02 .
positive
negative control
scratch
ID 1:100
ID 1:100
scratch
scratch test
negative control 3 .

Ig E

serum sickness
ID
anaphylaxis

desensitization

30

botulism

anaphylaxis
desensitization 6
desensitization
( 9)
(ID) (subcutaneous)
( 10)
desensitization
anaphylaxis
diphenhydramine
desensitization hydrocortisone
methylprednisolone
anaphylaxis aqueous
epinephrine desensitization

desensitization
810
9 desensitization
1
2
3
4
5
6
7
8
9
10
11
12
13
Dilution
1:1,000
1:1,000
1:1,000
1:100
1:100
1:100
1:10
1:10
1:10
(.)
0.1
0.3
0.6
0.1
0.3
0.6
0.1
0.3
0.6
0.1
0.3
0.6
1.0
* 15
10 desensitization
10
11
12
13
* 15
Dilution
1:1,000
1:1,000
1:1,000
1:100
1:100
1:100
1:10
1:10
1:10
(.)
0.1
0.3
0.6
0.1
0.3
0.6
0.1
0.3
0.6
0.1
0.3
0.6
1.0
64 811
1. , :
5 .. 2520-2524.
. 2526;9:121-34.
2. 2520-2545 :

.
3. 2546-2549 :

4.
; 2545. .52.
5.
..2546.

; 2547.
.19
6. American Academy of Pediatrics. Passive
Immunization. In: Pickering LK, Baker CJ, Kimberlin
p.55-67.
7. American Academy of Pediatrics. Hepatitis
A. In: Pickering LK, Baker CJ, Kimberlin DW, Long
SS, eds. Red Book: 2009 Report of the Committee
American Academy of Pediatrics; 2009. p 329-37.
8. American Academy of Pediatrics. Measles.
eds. Red Book: 2009 Report of the Committee on
9. American Academy of Pediatrics. Varicella-
Zoster Infectious. In: Pickering LK, Baker CJ, Kimberlin

p.714-27.
812
813
65

(Expanded Programme on Im-
munization)

(Inactivated
vaccine) (Live attenuated
vaccine) (Toxin)

(Recombinant vaccine)
(Regulations of vac-
814
cines: building on existing drug regulatory authorities)1
.. 1999

1.
(A published set of clear requirements for licensing of products and manufacturers)
2.
(Surveillance of vaccine field
performance safety and efficacy)
3. (System of lot
release)
4.
(Use of laboratory when needed)
5.
(Regular
inspections of manufacturers for GMP compliance)
6.
(Evaluation of clinical performance through authorized clinical trials)

1 3
1
6
2
3
(UN
Agencies)
2
(Assessment tool) (indicator)

(sub-indicator)
..
2007
(System to
regulate vaccines)
6
1. Marketing Authorization and Licensing activities
9
(critical) 7 ( 27
14 )

(GMP)
(variation)

65 815
1
Vaccine
Source
UN agency
Procure
Produce
Licensing
Surveillance
Lot release
Lab access
2. Post-marketing activities including surveillance of

Adverse Events Following Immunization (AEFI)

8
(critical) 7 ( 25
16 )
(monitor)

(

AEFI )

AEFI
GMP
inspections
Clinical
evaluation

GMP

4. Laboratory Access

10
(critical) 9 ( 36
26 )

3. NRA Lot release
(International profi ciency scheme) (collaborative
6 studies)
(critical) ( 24 (inter-laboratory comparisons)
12 )
816
5. Regulatory inspection
(GMP)
6 (critical) 5
( 24 13
) GMP

GMP
6. Regulatory oversight of clinical trials
6 ( 20 )
(Vaccine prequalification scheme)

..1996

(Vaccine
prequalification scheme)2
UNICEF PAHO ()
/

65 817
1.
(
)
GMP

1.
2.
1.
.. 2551

Prequalification scheme
.. 2553
-

2
23-29 .. 2539 Prequalification
list

13 (1) 13 (5) 1.
.. 25103

GMP 4

.. 2550

(
Prequalification list
818
)
(
)

2. (GMP)
(
)

..
2547

Pharmaceutical Inspec-
tion Cooperation Scheme (PIC/S)
5.

3.

(Good Clinical Practice: GCP)
(Good Laboratory Practice)
(Good Manufacturing Practice)

ISO/IEC 17025
4.
Prequalification scheme .. 2549

6.

65 819
.. 2541 2543
28 .. 2541 3
.. 2543 .. 2553
.. 2553

13 (1) (5)

5

(Summary production protocol)

(potency)

1. World Health Organization(WHO). Regulation of vaccines: building on existing drug regulatory authorities. Geneva: WHO;1999. Available from:
http://www.who.int/vaccines-documents/DocsPDF99/
www9918.pdf
2. World Health Organization(WHO). Procedures for assessing the acceptability of vaccines for
purchase by United Nations Agencies. Geneva: WHO;
1997. Available from: http://www.who.int/vaccinesdocuments/DocsPDF/www9715.pdf

3. .. 2510 Available from:
http://www2.fda.moph.go.th/law/sub default.
asp?producted=1
4. /
(Biological Products) ASEAN
Harmonization Available from : http://wwwappl.fda.
moph.gp.th/drug/zone service/ser016.asp#7
5.
.. 2553
127 66 ; 2553. .7
820
821

2483
5 1.
2.
3. 4.
5. 1
..
2510

( 5) .. 2530 3
2483

.. 2510

.. 2510
66
4 2

1. .. 2510
.. 2493
( 2) .. 2499 ( 3) .. 2499
( 4) .. 2500 ( 5) .. 2505
2. ( 2) .. 2518
3. ( 3) .. 2522

4. ( 4) .. 2527

5. ( 5) .. 2530

2483
822
.. 2510

(Lot release)

(1)
(2)

(3)

(4)

(1) (2) (4)

()
()

()

66 823
(1)
(2)

(3)

(eukaryotic cells)
(extraction of
substances from biological tissues including human,
animal and plant tissues (allergens))
(recombinant DNA or rDNA techniques)
(hybridoma techniques)
(propagation of
microorganisms in embryo or animals)
(derived from blood and plasma)

Human Rotavirus, Live
Attenuated

(Safety Monitoring Programme:
SMP) 2
3

SMP
SMP
4

.. 2510

(Lot release)

824

.. 2510

(1)
(2)
(3)
(4)
(5)
(6)
(7)

ASEAN Consultative Committee

on Standard and Quality/Pharmaceutical Product
Working Group (ACCSQ/PPWG)
ASEAN Common Technical Requirement (ACTR),
ASEAN Common Technical Dossier (ACTD),
Technical Guidelines Mutual Recognition
Arrangement (MRA)

31 2551

ASEAN Harmonization Product on Pharmaceutical
Registration5

ASEAN Harmonization
1 2522

(Biological product)
/
ASEAN Harmonization
ASEAN Harmonization
ICH (International Conference on
Harmonization of Technical Documents for Registration
of Pharmaceutical Products)
2
1.

.. 8

.. 8

2.
ASEAN Harmonization (ACTD: The ASEAN

Common Technical Dossier) ICH (ICH CTD:
ICH Common Technical Dossier)
..1 ( .1)
(1)
(Administrative data and product information)
66 825
(2)
(Quality documents)
(3)
(Safety: Non-clinical documents)
(4)
(Efficacy: Clinical documents)
/
ASEAN Harmonization
ASEAN Harmonization

7

480 (
1 )

(New
Drugs) (New Generic Drugs)

(Fast Track)
100-130
3 2547

1.

Guideline on Quality, Non-Clinical and Clinical
Assessment Regarding Marketing Authorizations
of Vaccines in Thailand6
2.
Drug substance(s) Drug Product

Non-Clinical
Clinical efficacy, 2
1.
Immunogenicity, Safety and Pharmacovigilance plan
Benefit-Risk

2.

826

72(1)

.. 2510 73
(1)
(2)

(3)
(4)

(5)

79
(Lot release)
(safety)

.. 25539

12

13 (1) (5)

14
(.. 2532)

(biological origin) 10

(potency)
66 827

(5)
(6)

1.
(7)

(8)

2. ...1
(9)

(1) (
(10)
)

(2) (
)
(3) (Investigator Brochure)
()
(4) (Patient Informa-

tion Sheet) ()
1.
(5) ()

(6) (
)
(7)
2. ...2
(8)

(Institutional Review Board: IRB Independent
Ethics Committee: IEC)
11
(1)

(2)
1.

(3)

(4)
828
2. ...3

Certificate of Free Sale
3.

1

1.

2. ...4

Certificate of Free Sale
3.

4.
1
7

() 60

1

1
.. 2510
( 3) .. 2522 ( 5)
.. 2530
88
(1)

(2)
(3)

(4)
(5)
(6)
(7)
(8)

77
(5) (6)
66 829
(1) (4) (5) (6)

(7) (8)

77
12
(1)
(2)
(3)
(4)
(5)
(6)

88

89

90
2 13
1.
2.

2 14
1.
1.1
1.1.1
1.1.2
830
(safety test)
1.1.3
1.1.4
1.1.5

1.1.6

1.2
1.2.1

1.2.2
1.2.3
1.2.4

2.

2.1

2.2 -
2.3

2.4

2.5

2
1.
2.
)

(
)
24
48
66 831

()
15
30
15

15
1. , , .
.. 2483

.
, , 2501.
2. , , .
.. 2510
[]. : http://www.ecombotthailand.com/porobo-drug.htm
3.
. : ; 2554. http://wwwapp1.
fda.moph.go.th/drug/zone_law/law020.asp
4.
. : ; 2554. http://wwwapp1.
fda.moph.go.th/drug/zone_law/law021.asp
5.
ASEAN
Harmonization Product on Pharmaceutical
Registration []. [] :
26 2551.
http://wwwapp1.fda.moph.go.th/drug/zone_law/files/
ASEAN.pdf
6. Guideline on Quality, Non-Clinical
and Clinical Assessment Regarding Marketing
Authorizations of Vaccines in Thailand, Bangkok:
Thai FDA; 2008.Available from: http://www.
app1.fda.moph.go.th/drug/zone_search/files/
Guideline_assessment_vaccines_12-12-08_final_revised.pdf
7.

..2552() 2 .
[]: ; 2552.
832
8.
(New Drugs)
(New Generic Drugs)
3 2552. []:
; 2552.
9. , , .

.. 2553. []: ; 2553.
10. 14
(.. 2532)
( 106 120
1 2532)
11.

22 2552. []:
; 2552.
12.

6 2520
[]. []: ; [2520].
13.
.. 2545
2 2545. [].
; 2545. http://wwwapp1.
fda.moph.go.th/drug/zone_service/files/ser001_04.asp
14. ,
. . []: ;
[2554]. http://wwwapp1.fda.moph.go.th/drug/
zone_gmp/gmp_book/c20.asp
15. 20 (.. 2525)
.. 2510. [] :
; 2510. http://www.jspherbalcenter.com/
archives/1143
67 833

1

30

67
2.
(Vaccine presentation)

(Supply availability)

(Programmatic strength)

2

2 (Policy 3, 4
issues) (Programmatic issues)2

1.
5
(Public health priority)
(Disease burden),
834

3
(Cost-benefit analysis: CBA)
(Cost-effectiveness analysis: CEA)
(Cost-utility analysis:
CUA)6,7
1

(Willingnessto-pay: WTP)

(Benefit : Cost
ratio) 1
(Cost-saving)
(Net benefit)

(Lives saved) (Life years)

1

(Qualityadjusted life year: QALY)

(Assumption)
CBA
CEA
CUA
(Quality-adjusted life
years: QALY)
()
- Net benefits
= Benefit-Cost*
- Benefit : Cost Ratio
- Cost-effectiveness ratio
= Net cost/cases prevented
- Cost-utility ratio
= Net costs/QALY
67 835
4
1.
2.
2

3. (Choosing study
design) randomized control
trial before and after without control group
(Prospective)
(Model) ( 3)
4. /

( 2)
5. /
/

6.

7. /
(Incremental cost
and benefit measuring)
8.
(Result analysis)
9. (Sensitivity analysis)
2
(Cost)
(Tangible cost)
- (Direct medical costs)
-
(Direct non-medical costs)
-
(Productivity losses)
(Intangible cost)
-

* (Quality-adjusted life year: QALY)

CBA CEA CUA
836
Prospective
Retrospective
-
- randomized clinical trials
Modeling

observer bias
selection bias

(Public goods)

5

1. (Transparency)
dynamic static model

dynamic model
(Assumption)

static model
dynamic model
static model

8,9
2. (Model)
3.
3.1 (Perspective)

(Societal perspective)
(Internal and external validation)

1
67 837
3.2 (Outcome measures)

(Quality-or disabilityadjusted life-years) (Onedimensional outcome) (Life-years
gained) /
3.3 (Comparators)

(Doing nothing)
3.4 (Time horizon/span)
1-100

3.5 (Costs)
3.6 (Joint
analysis)

3.7 (Discounting)
838

(Threshold analysis)
3.8 (Sensitivity analysis)
(Multivariate sensitivity analysis)

3.

4.

5.

11

10
1.
2.

(Acellular pertussis
vaccine) (Whole cell
pertussis vaccine)
67 839
12,13
25

(QALY)

14

12
(Advisory Committee on Immunization: ACIP)

(.)15
1. World Bank. World Development Report

1993: investing in Health. New York: Oxford University
Press; 1993.
2. World Health Organization. Vaccine Introduction Guidelines, Adding a vaccine to national
immunization program: decision and implementation.
Geneva: World Health Organization; 2005.
3. Johannesson M. Economic evaluation
of health care and policymaking. Health Policy.
1995;33:179-90.
4. World Health Organization, United Nations
International Drug Control Programme, United Nations
International Drug Control Programme. Workbook 8:
Economic Evaluations. 2000: : World Health Organiza-
840
tion; 2000.
5. Beutels P, Edmunds WJ, Antonanzas F, De
Wit GA, Evans D, Feilden R, et al. Economic evaluation of vaccination programmes: a consensus statement focusing on viral hepatitis. Pharmacoeconomics.
2002;20:1-7.
6. Richardson J. The Economic Framework
for Health Service Evaluation and the Role for Discretion, Working paper 105 Health Outcomes Conference
1999: Centre for Health Program Evaluation; 1999.
7. Meltzer MI. Introduction to health economics
for physicians. Lancet. 2001 ;358:993-8.
8. Edmunds WJ, Medley GF, Nokes DJ.
Evaluating the cost-effectiveness of vaccination
programmes: a dynamic perspective. Stat Med.
1999;18:3263-82.
9. Brisson M, Edmunds WJ. Economic evaluation of vaccination programs: the impact of herdimmunity. Med Decis Making. 2003;23:76-82.
10. Khaleghian P. Immunization Financing
and Sustainability: A Review of the Literature. Special
Initiatives Report No. 40. Bethesda, MD: Partnerships
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68

(Risk) 2

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International Conference on Harmonization

of Technical Requirements for the Registration of
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- ICH GCP Guidelines (1995)
- UNAIDS: Ethical consideration in HIV
preventive vaccine research (May 2000)
- WHO Guidelines for Ethical Review
Committees on Biomedical Research (2000)
- WHO Surveying and Evaluating Ethical
Practice (2002)
CIOMSs Guidelines
CIOMS (Council for International Organizations
Nuremberg Code
of Medical Sciences)
guideline UNESCO
war crime Helsinki declaration

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code CIOMSs Guidelines

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3

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2. do no harm (Benefi
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science science

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1. Caplan AL, Schwartz JL. Ethics. In: Plotkin

SA, Orenstein WA, Offit PA (editors). Vaccines 5th ed.
Philadelphia: Saunders; 2008. p.1677-83.
2. ,
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ethics : ,
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5. WHO. Ethical considerations arising from
vaccine trials conducted in paediatric populations with
high disease burden in developing countries. WHO/IVR
ethics meeting 26-28 November 2002. Accra, Ghana:
WHO; 2004. p.1-49.
851
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1. Plotkin SA, Orestein WA, Offit PA, Editors.

adaptive immune response

innate immune system

pattern-recognition receptor (PRR)

T cell B cell clone

B cell germinal center

2 T-cell independent B cell activation

3 T cell dependent B cell activation

T cell B cell immunogenicity

1. Moser M, Leo O. Key concepts in

subversion of pattern-recognition receptor signalling.

2.3.1 Vaccine Vial Monitor (VVM)

5 Vaccine Vial Monitor (VVM)

HB, DTP-HB, DTP, dT

8 Vaccine Cold Chain Monitor

Inactivated viral antigen

3. (-15 o. +20 o.)

1. Plotkin SA, Orestein WA, Offit PA, Editors.

(new delivery systems)

live attenuated pathogen

1 Highly purified antigens

naked pathogen-derived DNA

live vector attenuated live intracellular

(persistence of antigen) aluminium salt emulsion-based adjuvant

DTaP (paediatric diphtheria, tetanus and acellular pertussis)

endotoxin monophosphoryl lipid A (MPL) modified derivative of lipopolysaccharide (LPS) endotoxin

aluminium salt system

1.Bae KD, Choi JY, Jang YS, Ahn SJ, Hu BK.

ing upon nature. Gynecol Oncol. 2008;110(3 Suppl

Bacillus Calmette Guerin

: RV1= monovalent rotavirus; RV5 = pentavalent rotavirus

Bacillus Calmette Guerin

Recombinant viral antigen

Inactivated HepA antigen

(recommended interval) (minimum interval)