Vaccine Immunology

JIASHING YU 游佳欣 9.12.2023

Innate vs adaptive immunity
immunity is made up of both innate and adaptive arms. Innate immunity, also known as natural
or genetic immunity, is something an organism is born with, encoded in their genes and protects
them throughout their life. Innate immunity consists of:

External defenses: Known as the first line of defense, external defenses work to protect an
organism from pathogen exposure and include things like the skin, tears and stomach acid.
Internal defenses: Known as the second line of defense, internal defenses address a pathogen
once it has entered the body and include things like inflammation and fevers and the chemical
and cellular components that make up the innate immune system.
Adaptive Immunity
Adaptive immunity, also known as acquired immunity, is the third
line of defense and, whilst slower to act, protects an organism from
specific pathogens. Adaptive immunity can be further classified into
two subgroups: active immunity and passive immunity. In this article,
we will explore active and passive immunity.

Adaptive immunity can be further classified into two subgroups: active immunity and
passive immunity
What is active immunity?

Active immunity is defined as immunity to a pathogen that occurs

following exposure to all or part of that pathogen.

When the body is exposed to a novel disease agent, a cascade of signaling molecules
and action from the innate immune system results in activation of the adaptive immune
system. Production of large numbers of T cells and B cells specific to the pathogen are
promoted. Subsets of T cells kill the pathogen directly while others help to stimulate B
cell production. B cells, a type of white blood cell, produce antibodies that assist in
destroying or neutralizing the disease agent. Antibodies are y-shaped proteins capable
of binding to sites on toxins or pathogens called antigens.
 A host’s immune response
• Passive Immunity :temporary protection against infectionand
clearance oftoxins
• Active immunity :vaccination
 Passively acquired immunity
• Passively administered antibody
• Maternally acquired antibody
• Intravenous immunoglobulin
• Adoptive transfer of cytotoxic T‐cells
 Passively administered antibody
• Temporary protection against infection and clearance of toxins
can be achieved by giving antibody isolated from the plasma of
an individual having a high antibody titer to the pathogen or a
hyperimmunized animal.
Monoclonal Ab

B lymphocyte

Myeloma cellline Sensitized B Cell

• Tumor of plasmacell
• Immortal
• Lack o HGPRT
 HAT (hypoxanthine-aminopterin-thymidine) medium

• Aminopterin : blocks de novopathway

• Hypoxanthine and Thymidine: allow
growth via salvage pathway
• Enzyme HGPRT (hypoxanthine-
guanine- phosphoribosyl transferase)
Hybridoma cell is requiredfor salvage pathway
 Vaccination

A Vaccine is a biological product that can be used to safely

induce an immune response that confers protection against
infection and/or disease on subsequent exposure to a pathogen.
The birth of immunology as a science dates from Edward Jenner’s
successful vaccination against smallpox in 1796.
 How vaccines work
• Vaccines areeffectivebecause ofadaptive immunity and immune memory.
• Antibody is the most important mechanism of vaccine‐induced resistance to
disease.
• Thebest vaccines arethose that stimulatethe development oflong- lived plasma
cells that produce high-affinity antibodies as well as memory Bcells.
 The generation of an immune response toa
vaccine
• The vaccine is injected into muscle and the protein antigen is taken up by dendritic cells, whichareactivated throughpattern
recognition receptors(PRRs) bydanger signals inthe adjuvantand then traffickedto thedraining lymph node.
• Thepresentation ofpeptides ofthevaccineprotein antigen byMHC molecules on the dendritic cell activates Tcells
through their Tcell receptor(TCR).
• In combination with signalling (bysoluble antigen)through the B cellreceptor (BCR),the Tcells drive B cell development in the
lymph node. Here, the Tcell-dependent B cell development results in maturation of the antibody response to increase
antibodyaffinity and induce different antibodyisotypes.
• Theproductionof short-lived plasma cells,which actively secrete antibodies specificfor
the vaccineprotein,produces arapidrise in serum antibody levels over thenext 2weeks.
• Memory B cellsarealso produced,whichmediate immune memory.
• Long-livedplasma cells thatcancontinue to produce antibodies fordecades travelto reside in bone marrowniches.
• CD8+ memory Tcells canproliferate rapidlywhen theyencounter apathogen,andCD8+ effector Tcells are important for the
elimination ofinfected cells.
• During primary viral infection, antiviral T‐cell responsesare critical
for reducing viral replication in addition to contributing to the
development of an effective antibody response.
• Following recovery from primary infection (or after vaccination),
persisting virus‐specific antibodyrepresents the first line of
defense against secondaryinfection.
• Memory B‐cells are highly efficient at presentingspecific
antigen and therefore may also be involved with more rapid
and efficient presentation to T‐cells aswell.
• Pre‐existing T‐cell memory will also play a role in protection against
secondary infection. However, even if T‐cell memory has declined
or is lost, the long‐term maintenance of antiviral antibody
responses will suppress virus replicationuntilanew virus‐specific
T‐cellresponse is mounted from the naiverepertoire.
Effector Mechanisms Triggered byVaccines
• Antibodies prevent orreduce infections by clearing extracellular
pathogens through:
–Binding to the enzymatic activesites of toxins or preventing their diffusion
–Neutralizing viral replication (e.g., preventing viral binding andentry into cells)
–Promoting opsonophagocytosis of extracellular bacteria (i.e.,enhancing their
clearance by macrophages andneutrophils)
– Activating the complementcascade
 Effector Mechanisms Triggered byVaccines
• CD8 + Tcellsdo not prevent infectionbut reduce, control, and clear
intracellular pathogens by:
– Directly killing infected cells (release of perforin, granzyme,etc.)
– Indirectly killing infected cells through antimicrobial cytokinerelease
 Effector Mechanisms Triggered byVaccines
• CD4+ T cells do not prevent infection but participate in the reduction, control, and
clearance of extracellular and intracellular pathogens by their homing and cytokine-
production capacities. Their main subsetsinclude:
–FollicularT-helper (Tfh)cellsproducing mainly interleukin(IL)-21and providing B- cellhelp
–T-helper 1 (Th1) effectorcellsproducing interferon (IFN)-γ,tumor necrosis factor (TNF)-
α/TNF-β ,IL-2, and mainly involved in protection against intracellular pathogens (viruses,
Mycobacteriumtuberculosis)
–Th2 effectorcellsproducing IL-4,IL-5,IL-13,and responding to extracellular pathogens
(bacteria andhelminths)
– Th9 effectorcellsproducing IL-9 and also responding to extracellularpathogens
–Th17 effectorcellsproducing IL-17, IL-22, and IL-26 and contributing tomucosal defense
(Streptococcus pneumoniae, Bordetella pertussis, Mycobacterium tuberculosis
The memory response may be
sufficient to protect against
disease if there is a long
incubation period between
pathogen exposure and the
onset of symptomsto allowfor
the 3–4 days required for
memory B cells to generate
antibody titres above the
protectivethreshold.
The memory response
may not be sufficientto
protect against disease if
the pathogen has a short
incubationperiod
and thereis rapid onset of
symptoms before antibody
levels have reached the
protective threshold.
In some cases, antibody
levels after primary
vaccination remainabove
the protective threshold
and can provide lifelong
immunity.
 Immune memory
Thewaning of antibody levelsvaries depending on the
• Age of the vaccinerecipient (being very rapid in infants as a result of the lack
of bone marrow niches forB cellsurvival)
• The nature of theantigen
• The number of booster dosesadministered
• One solution to this is the provision of booster doses of vaccine through
childhood :diphtheria, tetanus, pertussis and poliovaccines
• Lifelongprotection seems to be the rule following a single dose with some
of the live attenuated viral vaccines, such as yellow fever vaccine.
 Typesof vaccines
• Killed/inactivated organisms
• Live attenuatedvaccines
• Purified subunit vaccine
• Recombinant protein subunitvaccine
 Killed/inactivated vaccines
• Thesimplestway to destroytheability of microbesto causedisease yet maintain their
antigenic constitution is to prevent their replication by killing in an appropriatemanner.
• Inactivation withheat/chemicals
• Inactivated vaccines>> do not replicatein the host
• The inactivated microorganisms have provided a number of safe antigens for
immunization.
• Requires multipledoses
◦ 1st dose: “primes” immunesystem
◦ Subsequent doses: protectivedose
◦ Mostly humoral immuneresponse
◦ Little or nocellular immune response
 Killed/inactivated vaccines
• Influenza vaccine
• Cholera vaccine
• Inactivated poliovaccine
 Live attenuated vaccines
• The objective of attenuation is to produce a modified organism that mimics
the natural behavior of the original microbe without causing significant
disease.
• Thereplicationof the living microbes confronts the host with a larger and
more sustained dose of antigen and that, with budding viruses, infected cells
are required for the establishment of good cytotoxic T‐cellmemory.
• Significant advantage of using liveorganisms is that the immune
response takesplacelargelyatthe siteof the natural infection.
 Live attenuated vaccines
Methods of attenuation
• Theobjectiveof attenuation thatof producingan organism thatcauses only a very mild form of the natural
disease.
• Using cross-speciesvaccination
:using cowpox to protect against smallpox 天花 (EdwardJenner)
• Mycobacterium tuberculosis 結核菌
:culturewith bilefor 13 years >> strain remained avirulent:BCG (bacilliCalmette-Guerin)
• Attenuation by coldadaptationhas been appliedto influenzaandother respiratoryviruses
:Theorganism cangrow atthe lower temperatures (32–34°C) of the upper
respiratorytract,but failsto produce clinicaldisease because of its
inabilityto replicatein the lower respiratorytract(37°C).
• Attenuation by recombinant DNAtechnology
 Live attenuated vaccines
Constraints on the use of attenuated vaccines
• Live viral vaccines there is a possibility that the nucleic acid might be
incorporated into the host’s genome or that there may be reversion to a
virulent form.
• Difficulty and expense of maintaining appropriate cold‐storage
facilities, especially in out‐of‐the‐way places.
• In diseases such as viral hepatitis, AIDS, and cancer, the dangers
associated with live vaccines are daunting.
• In immunodeficienthosts : children (BCG), on steroids, immunosuppressive
drugs,radiotherapy, hematologic malignant conditions
 Live attenuated vaccines
• Measles, Mumps, Rubellavaccine
• Rotavirus vaccine
• Oral poliovaccine
• The Mycobacterium bovis bacillus Calmette–Guérin (BCG)卡介苗vaccine
• Live attenuated influenzavaccine

• Live attenuated vaccines may induce some milddisease

• 5% of children willdevelop arash and up to 15% fever aftermeasles
vaccination.
 Purified subunitvaccine
• A whole pathogen usually contains many antigens that are not
concerned in the protective response of the host but may give rise
to problems by suppressing the response to protective
antigens or by provoking hypersensitivity.
• Vaccination with the isolated protective antigens may avoid
these complications.
 Purified subunit vaccine
Hepatitis B virus (HBV)
• “Australiaantigen” was subsequently shown to be a particle formed from
the surfaceantigen of hepatitis B virus.
• Initially, antigen particles were isolated from the plasma of HBV carriers
and inactivatedand used as a vaccine.Later,the particles were prepared
inyeast.
• TheHBV subunit vaccinewas a milestone in vaccinology as itwas the first
manufactured using recombinant DNAtechnology.
 Purified subunit vaccine
Carbohydrate vaccines /Polysaccharide vaccine
• Glycans tend to be poorlyimmunogenic.
• They should be coupled to acarrierprotein to provide asource of CD4+ T‐cellhelp.
• Anti‐glycan antibodies typically have low affinities relative toanti‐protein
antibodies.
• Licensed carbohydrate vaccines include those against Haemophilus
influenzaetype b (Hib), Neisseria meningitidis, Salmonella typhi,and
Streptococcus pneumoniae.
 Purified subunit vaccine
Carbohydrate vaccine/Polysaccharide vaccine
• Purepolysaccharide vaccines:T-cellindependentB cellstimulation
◦ Repeateddoses do not causea booster response
◦ Predominant response :IgM
• Conjugated polysaccharide vaccines :polysaccharide combined with protein : mostly
tetanustoxoid,or diphtheriatoxoid or a mutant protein derivedfrom it, known asCRM
◦ T-celldependent
◦ Increasedimmunogenicityin infantsand antibody booster
response to multipledoses of vaccine
◦ Inducesboth higher-affinity antibody and immune memory
Immune responses to polysaccharidevaccines
Immune responses to protein–polysaccharide conjugate vaccines
 Purified subunit vaccine
DNA vaccine (genetic immunization)
◦ J.Wolffand P.Felgner:development of genetherapy
◦Finding :controls injected with DNA without lipids showedhigher uptakeofDNA and
expression ofproteinencoded
◦ Transcriptionunit:cDNA + polyA terminator+ promoter(inavector)
+ CpG bacterial sequence(adjuvant)
◦ The CpG immunostimulatory sequences engage Toll‐like receptor 9 (TLR9) and thereby
provoke the synthesis of IFNα and β, IL‐12, and IL‐18, which promote the formation of
T‐helper(Th)1cells
◦ Not successful inhumans/nonhuman primatesasinmice
 Purified subunit vaccine
RNA vaccines
• RNA needs only to be delivered into the cytoplasm of the host cell to be translated into
protein, whereas DNA must first be transcribed into mRNA in the nucleus, before back into
thecytoplasmfortranslation.
• The safety concerns associated with potential integration of DNA into host chromosomes is
absent forRNA.
• RNA can have a very strong adjuvant effect by triggering innate responses that can
lead eventually to more effectiveadaptive immune responses.
• Very low stabilitycompared toDNA.
 Adjuvants
• Adjunant is a substance incorporated into or injected simultaneously with antigen that
potentiates the immuneresponse.
• Non-live vaccines are often combined with an adjuvantto improve their abilityto induce an
immune response (immunogenicity)
• Two types ofaction
• Immunostimulation
:Results from the action of molecules to directly enhance immune responses.
: Included Toll‐like receptor (TLR) agonists, cytokines, and bacterialexotoxins.
• Antigen delivery
:Antigen delivery vehicles serve to optimally present antigens to the immune system by
preventing dispersal of antigen and promoting slow release of antigen (“depot effects”)
 Alum
• Themostwidelyused adjuvantsin humans arebasedon gelsformedby aluminum
saltsand arereferredtocollectivelyas “alum”adjuvants.
• Antigensareadsorbed on thealuminumparticlesand theappropriate adjuvant
formulation selected based onimmunogenicity.
• Theactivityof alumis ascribedtodepot effectsandimmunostimulatory effectsbasedon
particleformationand inductionof inflammation.
• Alum is used in several licensed vaccines, including hepatitis A, human papillomavirus
(HPV), diphtheria–pertussis–tetanus (DPT),Haemophilus influenzae b, and inactivated
polio.
Vaccines contain other components thatfunction
• Preservatives
• Emulsifiers :polysorbate 80
• Stabilizers :gelatine or sorbitol
• Antibiotics, egg or yeast proteins, latex, formaldehyde and/or
gluteraldehyde and acidityregulators (such as potassium or sodium salts)
Impact of vaccination/immunization
Herd immunity
 Reference
• Roitt’s Essential Immunology. 13th edition.2017
• Cellular and Molecular Immunology. 8th edition.2019
• Pollard, A.J.,Bijker, E.M. A guide to vaccinology: from basicprinciples to new
developments. Nat Rev Immunol 21, 83–100(2021).
• Siegrist CA. Chapter 2 Vaccine immunology.WHO.
• http://guruvaccine.com
HW week3

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