Immunization
Tracey Goodman and Michel Zaffran, World Health Organization, Geneva, Switzerland
Bjorn Melgaard, Freelance Consultant, Denmark
Ó 2017 Elsevier Inc. All rights reserved.
This article is an updated version of the previous edition article by R. Lewis, M. Zaffran, B. Melgaard, volume 3, pp. 530–547, Ó 2008, Elsevier Inc.
Introduction
Immunization is widely recognized as one of the most
cost-effective public health interventions available. Edward Jen-
ner developed the technique to prevent smallpox in 1798 when
he vaccinated a young man with cowpox from the pustules of
a milkmaid. This eventually led to the eradication of smallpox
almost two centuries later (Fenner et al., 1988; Figure 1).
Following this historic achievement, the World Health
Organization (WHO) and the United Nations Children’s
Fund (UNICEF) spearheaded the creation of the Expanded Pro-
gramme on Immunization (EPI) which was established in
1974 by the World Health Assembly resolution WHA27.57.
This ushered in a strategic and systematic approach to immuni-
zation, and the benefits began to reach children in
resource-poor countries in the 1980s. A major milestone was
the declaration of Universal Childhood Immunization (UCI)
in 1990 (Grant, 1991). In the 15 years preceding the declara-
tion, the legendary leaders of UNICEF and WHO, James Grant
and Halfdan Mahler, had mobilized massive support from
heads of state around the world and placed immunization at
the top of the international health agenda.
In the decades since EPI was established to deliver six
vaccines against tuberculosis (TB), diphtheria (D), tetanus
Figure 1 The last person with confirmed smallpox: Ali Maow Maalin
in 1977 (upper left) and 2002. Source: Fenner, F., Henderson, D.A.,
Arita, I., Jezek, Z., Landnyl, I.D., 1988. Smallpox and Its Eradication.
World Health Organization, Geneva, Switzerland.
182 International Encyclopedia of Public Health, 2nd edition, Volume 4
(T), pertussis (P), oral polio, and measles, the schedule recom-
mended by WHO has grown to target additional diseases,
Hepatitis B (HepB), Haemophilus influenzae type b (Hib), pneu-
mococcal, rotavirus, rubella, human papillomavirus (HPV),
and yellow fever, Japanese encephalitis, and meningococcal
vaccines (the last three specifically relevant for Africa, Asia,
and South America), and others for important diseases are
under development (Figure 2). Previously, political, financial,
and operational barriers made the uptake of these vaccines
around the world slow, if not impossible. Today, combination
pentavalent vaccines including DTP, Hib, and HepB are widely
used in almost all developing countries, and many have, or
have plans to add, vaccines against pneumococcus, rotavirus,
human papillomavirus, and other diseases that are major
causes of morbidity and mortality.
With the new millennium immunization has continued to
garner top attention and the imagination of both public and
private partners. The GAVI Alliance was created as a financing
mechanism in late 1999 with the aim of addressing the gross
inequality in access to new and underutilized vaccines. The
collective recognition of the full potential of immunization,
led the global health community to call for a Decade of Vaccines
(2011–20) with the vision of a world in which all individuals
and communities enjoy lives free from vaccine-preventable
diseases (VPD).
The Global Vaccine Action Plan (GVAP, 2013) is the frame-
work approved by the World Health Assembly in 2012 to
achieve the Decade of Vaccines vision. GVAP is the product
of the Decade of Vaccine Collaboration, an unprecedented
effort that brought together the development, health and
immunization experts, and stakeholders. The leadership of
the Bill & Melinda Gates Foundation, GAVI Alliance, UNICEF,
United States National Institute of Allergies and Infectious
Diseases, and WHO, along with all partners – governments
and elected officials, health professionals, academia, manufac-
turers, global agencies, development partners, civil society,
media, and the private sector – are committed to achieving
the ambitious goals of the GVAP.
GVAP aims to strengthen routine immunization to meet
vaccination coverage targets; accelerate control of VPD with
polio eradication as the first milestone; introduce new and
improved vaccines; and spur research and development for
the next generation of vaccines and technologies. It rallies tech-
nical agencies, countries, and donor agencies around six stra-
tegic objectives, and the actions to support their achievement,
as well as an initial estimate of resource requirements and
return on investment. It includes a monitoring and evaluation
framework that all partners have endorsed. It is, therefore
a roadmap, which everyone engaged in vaccines and immuni-
zation has gathered behind.
Vaccination prevents an estimated 2–3 million deaths from
VPD every year (WHO, 2014a), making a significant contribution
http://dx.doi.org/10.1016/B978-0-12-803678-5.00225-3
 Immunization 183

HIV/AIDS

Future TB
Malaria

Dengue
Mening (conj)
HPV
Rotavirus
Pneumo (conj)
Cholera
Underutilized
vaccines Typhoid
Hib (conj)
HepB
YF Influenza Rubella
JE

Measles

Traditional EPI Tetanus

Polio
Pertussis

Diphtheria
// //
1960 1980 2000
Vaccine development pipeline

Figure 2 The vaccine pipeline. Shaded area is proportional to number of deaths prevented by vaccination. conj, conjugate; EPI, Expanded Program
on Immunization; Hep B, hepatitis B; Hib, Haemophilus influenzae type b; HPV, human papillomavirus; JE, Japanese encephalitis; YF, yellow fever.
World Health Organization, Department of Immunization Vaccines and Biologicals. Source: World Health Organization, 2002. Distribution of the Esti-
mated Deaths from Diseases that Are Preventable by Vaccination. World Health Organization, Geneva, Switzerland.

Figure 3 Percentage of deaths from vaccine-preventable diseases (VPDs) among children under 5 years of age worldwide, 2008. Source: Black,
R.E., Cousens, S., Johnson, H.L., Lawn, J., et al., June 5, 2010. Global, regional, and national causes of child mortality in 2008: a systematic anal-
ysis. Lancet 375 (9730), 1969–1987. Epub 2010 May 11. * WHO/IVB estimates, March 2012.

toward the Millennium Development Goal of reducing mortality
in children less than 5 years of age (Figure 3).
Despite many successes, immense challenges remain. With
increasing birth cohorts, global immunization coverage has
been holding steady at around 80% for the past few years but
this is insufficient for control of some diseases (e.g., measles)
and also masks huge variations in coverage among and within
countries. An estimated 22.6 million infants worldwide, or one
in five, are still missing out on basic vaccines (WHO, 2013a).
Many more fail to finish the schedule (‘drop out’) and are
incompletely vaccinated.
Immunization in Public Health
Social Policy and Immunization
The benefits of immunization are public goods that foster
survival and productivity, such that investment commensurate
184 Immunization
with potential gains enhances social and economic develop-
ment. A cornerstone of primary health care, immunization
also helps governments deliver key elements of healthy public
policy such as creating a safe and enabling environment, and
promoting equity across socioeconomic strata. As such, immu-
nization policy and objectives should be articulated as
a component of wider social policy and public health strategy.
The primary objective for a given immunization program may
be to save lives, prevent premature death and disability,
improve ability of children to learn, reduce health sector costs
for hospital care or economic loss to society from absenteeism,
or any combination of these and other possible objectives,
according to the burden of disease and vaccine in question.
In most countries, vaccines and immunization policy is gov-
erned by legislation and regulatory authorities that monitor
vaccine quality and adherence to national and international stan-
dards. Today, numerous civil society organizations advocate for
and against vaccines. As such, immunization is both a hard-nosed
science and a source of passionate debate in society. For successful
collaboration, it is therefore critical for policy makers and immu-
nization program managers to share a clear vision of purpose.
Immunization and Public Health Practice
Vaccination is a classic example of primary disease prevention,
and immunization programs encompass other elements of
public health practice including health protection and promo-
tion, planning, monitoring and evaluation, and surveillance. A
reliable supply of high-quality vaccines must be ensured for the
populations that need them and demand must be sustained.
Immunization programs throughout the world are the
backbone of preventive health services, especially for children
and women. This contact between an individual and the health
system provides an opportunity to offer health education and
other services. In industrialized countries, immunization is
often provided by a family physician or a public health nurse
at which time a range of health issues can be discussed. In
developing countries, immunization services are increasingly
packaged with other preventive health measures, such as provi-
sion of vitamin A supplementation or insecticide-treated bed
nets for malaria prevention, antenatal care or family planning
services for women, or deworming tablets for school children.
Planning for Immunization
For a successful national immunization program, vaccines
must be identified as a desirable public health good, planned
for, financed, procured, purchased, transported, stored appro-
priately, and administered safely in good condition to an
informed and knowledgeable population by trained and
competent health workers. To inform priority setting and plan-
ning, decision makers must have knowledge of the epidemi-
ology of VPDs and their contribution to morbidity and
mortality. Some populations may be at higher risk due to
age, gender, socioeconomic status, occupation, ethnic back-
ground, or other factors. Therefore, to determine need for
a vaccine and monitor its impact following introduction,
health information systems must be in place to collect data,
track key process and performance indicators, and guide
program strategies and management.
Vaccine product options include oral or injectable formula-
tions, monovalent or combination vaccines, and single- or
multi-dose vials. Vaccines may be liquid or freeze-dried. Other
product characteristics to consider include temperature stability
(and in case of the presence of a vaccine vial monitor (VVM), its
type), type of preservative used, package size, and space
requirements for cold storage and delivery.
Vaccines are delicate products which must generally be
stored at between 2  C and 8  C (Figure 4), and they lose their
potency if handled incorrectly.
There must therefore be an adequate ‘supply chain’ from
point of manufacture to point of administration. This involves
people, equipment (such as cold rooms freezers, vehicles, ‘cold
boxes,’ vaccine carriers, and ice packs), and a set of standard
operating procedures. Temperature monitoring technology
exists to help ensure vaccine potency, such as electronic temper-
ature recorders, that indicate exposures below 0  C or above
10  C, and VVMs, a heat-sensitive label affixed on the indi-
vidual vaccine vial that changes color when a product has
been exposed to high temperatures during a period of time
likely to have altered its potency (WHO, 2007; Figure 5).
Vaccine management spans a spectrum of activities from the
manufacturer to the end-user, so that the ‘six rights of a well-
performing supply chain’ are complied with: the right product,
in the right quantities, at the right time, in the right place, in the
right condition, and at the right price. With the rising cost of
vaccines and the greater storage capacity now required at every
level of the cold chain, countries must accurately forecast
vaccine requirements, maintain lower stock inventories, reduce
wastage, and prevent equipment breakdowns. This requires
a consistently high standard of supply chain management,
which can only be achieved if all the links in the supply chain
comply with current standards for storage and distribution. The
Effective Vaccine Management (EVM) process recommended
by WHO and UNICEF (WHO, 2014e) and now broadly imple-
mented in low and lower middle-income countries consists of
a set of materials and tools needed to monitor and assess
vaccine supply chains and provide guidance for their
improvement (Figure 6).
Delivering a Successful Immunization Program
A successful immunization program has the support of politi-
cians, physicians, and other professionals; the general public;
and the media. Program managers must be able to advocate
and raise awareness, manage rumors, and engage stakeholders.
Involving health workers and the public in designing commu-
nication materials and messages will improve their appropri-
ateness and acceptability in the local context (Figure 7).
Health worker competence is paramount to safe administra-
tion of the right vaccine to the right person, at the right time,
and in the right manner. Maintaining the curricula in nursing,
midwifery, and medical schools is therefore essential. However,
in the rapidly changing world of vaccines and immunization,
in-service training and health services management education
are also necessary.
Usually a mix of immunization strategies (fixed site, outreach,
campaign) provides the optimal balance to achieve disease
control targets and strengthen health systems. Routine infant
vaccination is the primary building block for control of VPDs;
 Immunization 185

Figures 4 and 5 Vaccine vial monitors.

186 Immunization

Today’s vaccine A network of people and equipment

supply chain and well established procedures
Manufacturer

Request
for supply

on Annual statistics
mati
and estimates
Infor

Analysis Airport

Monthly report/
checking Central store

Daily
record District/ s
lie
regional store upp
ds
an
ines
cc
Health centre Va
Simple, precise
Vaccinator/ and standardized
mother and child

Figure 6 Vaccine supply chain. Source: Project Optimize, World Health Organization, Geneva, Switzerland.

important due to risk of perinatal transmission, for the

Figure 7 Delivering oral polio vaccines. Source: World Health Organi-
zation Polio Eradication Programme.
coverage well above 90% (proportion of the target population
vaccinated) protects individuals and reduces disease transmis-
sion. Most vaccines are first given in infancy and national
vaccination schedules vary depending on the local epidemiology
of the disease, the vaccine products used, and the health contact
opportunities. For example, a birth dose of hepatitis B vaccine is
primary series of the subsequent six to eight antigens many indus-
trialized countries follow 2, 4, and 6 months, whereas
resource-poor countries opt for an earlier 6, 10, and 14 weeks of
age schedule as the pressure of infection is higher and
younger infants are at greater risk. For similar reasons, the two
doses of measles vaccine are given at 9 and 15–18 months in
most developing countries, but at 12 and 18 months or older
elsewhere. WHO provides up-to-date recommendations on the
number of doses, optimal timing, an interval between doses to
assist countries in determining the appropriate immunization
schedule for their context (see Relevant Websites).
Conjugate vaccines such as Haemophilus influenzae type
b are so effective at preventing not only invasive disease but
also nasopharyngeal carriage of the pathogen, that even
moderate immunization coverage results in indirect protec-
tion (herd immunity) (WHO, 2013b). Nonetheless, for
certain antigens, booster doses are needed at school entry,
in adolescence and/or adulthood, as vaccine-induced immu-
nity can wane over time, especially in the absence of natural
boosting. The routine schedule is often complemented with
antenatal screening for rubella and hepatitis B, school-based
screening and immunization, voluntary or mandatory health
worker vaccination, and programs for university students,
military recruits, travelers, and other groups at risk. In coun-
tries where infant immunization coverage has been low,
women of childbearing age are offered tetanus toxoid to
prevent maternal and neonatal tetanus, and likewise where
it has been introduced, rubella vaccine against congenital
rubella syndrome. Other countries provide vaccines for the
elderly and persons with chronic conditions, for example,
the 23-valent pneumococcal polysaccharide vaccine, or the
seasonal influenza vaccine for priority groups at risk. Beyond
 Immunization 187

adopting a life-course approach to vaccination, the fact that Table 1 Distinguishing characteristics of routine/supplemental
some vaccines available are not able to fully protect against immunization and doses
all causes of the disease (for example, pneumococcal conju-
Routine Immunization/ Supplementary
gate vaccines (PCV), rotavirus, and HPV vaccines) compels
Doses Immunization/Doses
modern immunization programs to collaborate with others
to ensure that a comprehensive approach to disease control To provide ongoing Purpose To provide broad scale,
includes the provision of other interventions such as treat- vaccination according synchronized, selected
ment and screening. to the National vaccines according to
There are situations where the routine immunization Immunization Schedule a specific accelerated
schedule is not sufficient to achieve adequate disease control. in order to ensure a fully disease control
immunized child. objective.
For instance, to reach geographically remote populations or
Individual protection to Goal Boost population level
insecure areas, outreach and pulse immunization strategies
reduce mortality and immunity to reduce/
have proven very effective, whereby health workers visit such morbidity from VPD interrupt transmission
communities monthly or even less often to offer vaccination. through high coverage of selected diseases
These strategies, often called Periodic Intensification of with all antigens (90% often with the goal of
Routine Immunization or ‘PIRI’ (WHO, 2009a), can offer an in all districts). elimination or
opportunity to integrate child health, reproductive health, eradication.
and antenatal services such as intermittent preventive treat- Children under 1–2 years Target groups Expanded to children of
ment in pregnancy for malaria, and curative care, if personnel and pregnant women other age groups up to
and resources allow. Many countries now have national (although older age 5–15 yrs generally;
groups for boosters and women of childbearing
‘immunization weeks’ or ‘child health days’ to raise public
other vaccines e.g., HPV age; entire populations
awareness and mobilize communities for routine or supple-
vaccine are also in high-risk areas.
mentary immunization services. Previously unimmunized increasingly seen as
population groups can be reached in such ‘catch-up’ activities. important to include).
Since 2012, the last week of April has been designated as Continuous and Frequency Intermittent defined by
‘World Immunization Week,’ and the intense focus of activi- predicable: daily, disease epidemiology
ties around the world to raise awareness about vaccination weekly, monthly, and level of susceptibles
and increase coverage. quarterly, etc. in population.
Fixed, outreach, mobile, Service delivery Fixed, outreach, door-to-
school-based, strategy door, extra posts,
campaigns, PIRI. mobile, school-based,
Epidemic Prevention and Control of VPDs
campaigns
Yes, for age and Screening and Screen only for age
Epidemic prevention and control programs aim to detect infec- vaccination/AEFI history decision to eligibility and previous
tious disease outbreaks early and institute control measures, (obtained from card/ vaccinate AEFI. Prior vaccination
such as vaccination, as rapidly as possible. For some diseases caregiver); ‘routine’ history not important.
such as measles, the virus is so contagious that even with dose is given only if due ‘Supplemental’ dose is
high routine immunization coverage, eventually the pool of according to the given to all of eligible
unvaccinated individuals (and those with an inadequate national schedule and age irrespective of
primary immune response to the vaccine) accumulates suffi- child is of eligible age. vaccination history.
ciently for transmission to be reestablished and outbreaks to Child health/immunization Recording Tally sheet disaggregated
card, tally sheet, health by age (generally not
occur.
facility register, monthly recorded on child health
To accelerate disease control and dramatically reduce death
summary. card but if included
and disability, supplemental immunization activities (Table 1) must be in section
have proven invaluable to raise population immunity and marked
reduce the accumulation of susceptibles. Most countries in ‘Supplemental’). These
the Americas, Asia, and Africa have carried out national ‘additional or extra’
campaigns over days or weeks to offer supplemental doses of doses are not counted
polio and measles vaccines to children. Many others have at toward completion of
one time or another carried out similar activities for adults or the routine schedule.
the whole population for polio, measles, diphtheria, yellow Routine doses would be Reporting Supplementary doses
included in should not be included
fever, meningococcal meningitis, Japanese encephalitis, and
administrative data in the routine
even anthrax for groups at high risk.
collection systems, and administrative data
Outbreak prevention and control activities are highly orga- included in the collection systems, but
nized enterprises to reach the target population with available ‘Administrative should be reported
resources and in tune with the local context. Since these activ- Coverage’ section of the separately. In the WHO/
ities typically deliver a high volume of vaccines in a short WHO/UNICEF Joint UNICEF Joint Reporting
period of time, adequate vaccine supply and logistics, human Reporting Form. Form, they should be
resources, cold chain materials, and communication become included in the section
essential. Campaigns have been much maligned for detracting ‘Supplemental
from routine immunization services. There are as many Activities.’
188 Immunization
examples, however, of campaign activities strengthening inter-
sectoral collaboration, planning, and cold chain capacity;
health worker competence; and public acceptance, thereby
strengthening the health system and immunization
program simultaneously (Mogedal and Stenson, 2000; Giffiths
et al., 2011).
Surveillance, Monitoring, and Evaluation
The International Health Regulations (WHO, 2005) list the
diseases that must be reported to the World Health Organiza-
tion, and countries maintain their own lists of notifiable
diseases. High-quality surveillance is essential to detect cases
and outbreaks early, identify populations at risk, and monitor
vaccine impact.
Surveillance takes different forms according to the pathogen
and disease control objectives. Most ‘passive’ surveillance relies
on routine weekly or monthly reporting from physicians, labora-
tories, or health units. Conversely, active search of cases is usually
required for programs targeting eradication or elimination of
a disease, to prove that the pathogen can no longer be found.
An example is surveillance for acute flaccid paralysis for polio
eradication, whereby stool specimens are collected from every
person with this clinical syndrome and cultured to identify the
poliovirus. Another example is case-based surveillance of child-
hood rash and fever-requiring serological assay of a blood spec-
imen to confirm and differentiate between measles or rubella.
For some conditions, sentinel surveillance is adequate. In
the case of seasonal influenza, a few sites worldwide collect
specimens for detailed laboratory analysis to inform the
composition of influenza vaccine every year. Where resources
are severely constrained, sentinel sites can be useful to monitor
disease trends and vaccine impact in a region. Examples of this
are the African pediatric bacterial meningitis surveillance
network and the networks established for the surveillance of
invasive bacterial diseases and rotavirus diarrhea.
Immunization coverage assessment is essential to monitor
program performance. The number of children vaccinated with
given antigens is usually provided by administrative reports
from health units, physicians’ offices, and even parents in some
countries. Individual child health cards are used to record the
vaccines administered and remind about the date to return for
the next scheduled vaccination. New electronic communication
technologies are increasingly being used ranging from SMS
reminders to smart phone applications for immunization
records, and there are many efforts to strengthen health manage-
ment information systems (HMIS) and improve data quality.
Countries report immunization coverage data annually
through the WHO and UNICEF Joint Reporting Form (JRF)
and this data, plus calculated immunization coverage estimates,
are published each year as a time series (www.who.int/
immunization/monitoring_surveillance/routine/coverage/en/).
Special coverage surveys, either independent or part of Demo-
graphic and Health Surveys (DHS) or UNICEF Multi-Indicator
Cluster Surveys (MICS) provide additional data, as well as
information on the service provided, timing of vaccination,
and attitudes to immunization. It is best practice, that a review
of the national immunization program is conducted periodi-
cally to ensure the relevance and quality of the vaccines
offered, and the appropriateness and reach of immunization
service delivery.
Considerations for New Vaccine Introduction
New vaccines and reformulations of existing vaccines are being
made all the time. The decision to introduce a new vaccine in
a national public immunization program is a major one that
requires careful priority setting, planning, and stakeholder
consultation and support. Policy goals must be clearly articu-
lated, all aspects of the existing program must be reviewed to
accommodate the new product, and resources and personnel
must be made available (WHO, 2014b). Table 2 outlines
some of the elements and activities that need to be considered.
Vaccines for Communicable Diseases
Dozens of vaccines have been developed to date. Not all of
them are still in use and not all have the same degree of immu-
nogenicity, efficacy, and safety. Table 3 provides summary
information on some vaccines, and more details are provided
on the major ones in the following paragraphs.
Diphtheria
Diphtheria is a bacterial infection, transmitted through close
physical and respiratory contact, which once caused regular
epidemics. With the DTP vaccine in use since the 1940s,
epidemics gave way to sporadic cases and intermittent
outbreaks. DTP is given to infants and preschool-age children
for primary vaccination, while bivalent vaccine (DT) is used
for booster doses. From 7 years of age onward, the adult
form (Td) is used, containing one-tenth the diphtheria toxoid
to reduce the risk of sensitivity to the diphtheria component.
Pertussis
Pertussis (whooping cough) is a highly contagious disease and
an important cause of death of infants worldwide, and
continues to be a public health concern even in countries with
high vaccination coverage. It is estimated in 2008, 16 million
cases of pertussis occurred worldwide and that about 195 000
children died (WHO, 2010). Several decades of using inacti-
vated whole cell vaccines (wP) in immunization programs
dramatically reduced the occurrence of pertussis. Frequent,
mild, adverse reactions and a fear of rare neurological events
prompted development of acellular pertussis (aP) vaccines con-
taining one to five components of Bordetella pertussis. More
expensive, they compare favorably with wP vaccines but recent
evidence suggests that immunity wanes faster with aP perhaps
partially explaining the resurgence of pertussis in many industri-
alized countries. Pertussis vaccine is usually administered in
combination with diphtheria and tetanus toxoids (DTwP or
DTaP). Since local reactions tend to increase with age and the
number of injections, wP-containing vaccines are not used for
adolescents and adults. DTP-containing multi-antigen
vaccines (with Hep B, Hib, or IPV) are increasingly being used
in national immunization programs.
 Immunization 189

Table 2 Elements to assess the readiness of an immunization program to add a vaccine introduction

1. A strong decision making and accountability process that is transparent, coordinated, and integrated with the overall health sector:
l Vaccine introduction fits with the health priorities and plans.
l A functioning National Immunization Technical Advisory Group (NITAG) or equivalent technical committee to review the epidemiological, economic,
and other evidence and make recommendations about vaccine introduction.
l Plan for introduction is reviewed by the Health Sector Coordinating Committee or similar mechanism to ensure coordination of health programming
and funding requests.
l All key decision makers in relevant ministries are involved in the final decision.
2. A well-performing or improving immunization program to obtain the full benefit from existing vaccines:
l Immunization multiyear plan and annual work plan is in place, and policies are regularly updated.
l Coverage rates of existing vaccines meet national targets or reflect satisfactory improvement and have not fallen in the last 5 years.
l Dropout rates between vaccine doses have decreased in the past 5 years or are at acceptable levels.
l Differences in coverage rates between high- and low-performing districts and between the lowest and highest income groups (e.g., quintiles) are
decreasing or are at acceptable levels.
l Specific objectives are met or well underway for vaccines already in the program (e.g., catch-up campaigns, 2-dose measles schedule in place).
3. A sufficient or expanding, well-trained, and motivated health workforce:
l Analysis of adequacy of health workforce to provide current package of health services and addition of new vaccine.
l If additional personnel are needed, they are included in the multiyear plan and budget, and national health sector plan and budget.
l Appropriate preservice and in-service training and on-site supportive supervision.
l If staff turnover is a problem, there is a plan and budget to address this.
4. Functional vaccine management, cold chain, and logistics system:
l Updated cold chain equipment inventory and plan for maintenance and replacement.
l Cold chain system has adequate volume capacity and performance at all levels (central, provincial/regional, district, and facility) for vaccines already
in the program and the new vaccine.
l Sufficient dry storage space at all levels for injection materials.
l Infrequent vaccine stockouts at national or subnational levels in the last 5-years.
l 2–5 year forecasts for vaccine supply.
l Vaccine wastage is monitored, and levels of wastage are acceptable and do not compromise coverage targets.
5. Safe immunization practices, monitoring, and management of adverse events:
l All injectable vaccines are given with auto-disable syringes.
l Proper diluents and reconstitution methods are used for lyophilized vaccines.
l Capacity to procure, distribute, and properly dispose of additional injection materials for the new vaccine.
l Surveillance and reporting system for adverse events following immunization.
6. High-quality disease surveillance and immunization coverage monitoring:
l Appropriate surveillance to meet disease control objectives.
l Credible data on coverage of all vaccines.
l Vaccination coverage surveys conducted periodically to validate routinely collected data.
7. A financially sustainable program:
l Careful consideration of short- and long-term additional costs.
l Government commitment and budget allocations to finance the immunization program.
l Financing of new vaccine does not displace financing for other ongoing programs and activities.
l Multiyear plans include a secured budget linked to the national health budget.

Tetanus low levels that the disease is no longer a major public health
problem by 2015. Unlike polio and smallpox, tetanus cannot
Tetanus is a frequently fatal disease caused by a neurotoxin
be eradicated (tetanus spores are present in the environment
produced during growth of the bacterium Clostridium tetani in
worldwide). WHO estimates that in 2010 (the latest year for
dead tissues (dirty wounds, or in the umbilicus after birth).
which estimates are available), 58 000 newborns died from
Maternal and neonatal tetanus can be prevented by vaccination
NT, a 93% reduction from the situation in the late 1980s (Black
with tetanus toxoid and by observing clean delivery and
et al., 2010). While progress continues to be made, by
cord-care practices. Tetanus toxoid–containing vaccines (DTP,
December 2013, 25 countries have still not reached the MNT
DT, Td, TT) can be given as appropriate in infancy, childhood,
elimination status. Activities to achieve the goal are ongoing
and adulthood and in pregnancy to protect mother and child.
in these countries, with many likely to achieve MNT elimina-
A childhood immunization schedule of 5 doses, with the first
tion in the near future.
three doses administered as DTP or DTP-combination vaccines
before the age of 1 year, a booster dose of TT-containing
vaccine ideally at age 4–7 years, and another booster in
Measles
adolescence. An extra dose in adulthood provides assurance of
long-lasting, possibly life-long protection (WHO, 2006). Measles virus is highly infectious and during the prevaccine era,
There is a global Maternal and Neonatal Tetanus (MNT) measles affected almost every person before the age of 10 years.
Elimination Initiative that aims to reduce MNT cases to such Complications such as diarrhea, middle-ear infection, and
190 Immunization

Table 3 Main vaccines and their characteristics

Primary schedule and

Disease Vaccines route Booster doses Adverse reactions Comments

BCG Live bacterial, 1 dose (0.05 ml) at birth None Local abscess, regional Not to be given to
lyophilized vaccine or as soon as lymphadenitis HIV-infected infants.
possible, ID Many countries have
discontinued BCG
due to limited
efficacy
Cholera Monovalent inactivated 2–3 doses, 7 days to Every 6 months or 2 Mild local or systemic Not given to infants.
whole cell with 6 weeks apart, oral years depending on reactions Recommended for
recombinant subunit age use only in high-risk
(WC/rBS) vaccine populations, not for
Bivalent inactivated 2 doses, oral, 14 days Every 2 years country-wide
whole cell apart implementation
Diphtheria Toxoid (D or d) in DTP, 3 doses before 1 year of DTP at 1–6 years; Td in Mild local or systemic Schedules and number
DT, and Td age, IM adolescence reactions of booster doses vary
by country. DTP is
increasingly used as
platform for
combination with
hepatitis B, Hib, IPV,
and meningococcal A
or C conjugates
Haemophilus Conjugate; monovalent 3 doses or 2 primary Depends on schedule Mild local reactions
influenzae type b or combined with doses followed by used
DTP booster dose, IM
Hepatitis A Inactivated from cell At least 1 dose 1 year Mild systemic and local Not given to infants <1
culture or from of age, IM reaction year; adult high-risk
purified HAV; alone groups, and travelers
or in combination
with hepatitis B; or
live attenuated
Hepatitis B Recombinant DNA 3–4 doses, first within Local soreness and Birth dose
vaccine 24 h of birth; 2–3 redness; rarely
other doses from age anaphylactic reaction
6 weeks with 4 weeks
minimum interval, IM
Human Recombinant viruslike 2  doses at least Pain, swelling, 100% efficacious
papillomavirus particles (VPL) 6 months apart, for erythema, pruritus, against HPV 16 and
(HPV) against HPV 16, 18 females 9–13 years fever, nausea, 18 infection, and
(bivalent); or with 6, of age, IM dizziness precancerous lesions
11 (quadravalent)
Influenza Inactivated viral 1–2 doses depending Local pain, fever New vaccine annually
on age, SC, or IM
Japanese (1) Cell culture derived, 1 dose from age of 9– After 1 year Use in areas where JE is
encephalitis (JE) live attenuated 12 months, SC a public health
(2) Mouse brain– 2 doses from age of 1 After 1 year, then every Rare cases of acute problem. Cell
derived, purified, year, 4 week (min) 3 years disseminated culture–derived,
inactivated interval, SC encephalomyelitis inactivated vaccine
and hypersensitivity used in China; other
reactions reported in new vaccines under
children from development.
endemic regions and
in travelers in
nonendemic areas
Measles Live attenuated, 2 doses from age of Fever, rash; rarely Increasingly
monovalent, or in 9 months, 4 week encephalitis and administered in
combination with (min) interval, SC meningitis combination with
rubella or mumps rubella and mumps
and rubella vaccine (MMR)
 Immunization 191

Table 3 Main vaccines and their characteristicsdcont'd

Primary schedule and

Disease Vaccines route Booster doses Adverse reactions Comments

Meningococcal MenA conjugate 1 dose, for adults and

meningitis and children over one or
septicemia age IM
Meningococcal C 2 doses for infants or 1 None Occasional mild local
conjugate dose for older reaction or fever
children, IM
Quadrivalent conjugate 2 doses 9–23 months After 1 year Redness, pain, and
of age, 1 dose after swelling
the age of 2 years, IM
Mumps Live attenuated, viral 1 dose, after 9 months, Not required Parotitis and low-grade Usually administered
SC fever; rare: aseptic with measles and
meningitis may occur rubella vaccines
Pertussis Inactivated whole cell 3 doses before 1 year of DTP 1–6 years Mild local or systemic Schedules and number
(wP) or acellular (aP) age, IM reactions of booster doses vary
by country; duration
of protection with aP
may wane sooner.
Pneumococcal Conjugate vaccine 3 doses before 1 year of Alternative schedule 2 Mild local or systemic
meningitis, against 10 and 13 age, or 2 primary doses plus booster at reactions
pneumonia, serotypes 1, 4, 6B, doses followed by 9–15 months
sepsis 7F, 9V, 14, 18C, 19F, booster dose IM
23F (and 3, 6B, 19A)
Poliomyelitis Live attenuated OPV 3 doses (4 in endemic Supplemental doses in Rare occurrence of Global switch from
(trivalent) countries) in first endemic countries vaccine-associated tOPV to bOPV
year of life, oral; plus paralytic planned as part of
1 dose IPV poliomyelitis Polio Eradication
Endgame. Most
industrialized
countries use IPV.
Inactivated (IPV) 3 doses in first year of Yes, if first dose
life, IM given <8 weeks of
age.
Rabies Inactivated from cell 3 doses IM Only for those whose Mild systemic or local Production and use of
culture or occupation puts reactions; rare nerve-tissue rabies
embryonated egg them at continual risk neuroparalytic vaccines to be
vaccine reactions discontinued and
phased-out
Rotavirus Live human monovalent 2 doses (1 ml) at least None Mild gastrointestinal These vaccines,
G1P strain 4 weeks apart, from symptoms; fever, licensed in 2006,
6 weeks of age, oral fatigue were studied in trials
of nearly 70 000
infants, the largest
prelicensure trials in
vaccine history
Live, contains 5 3 doses (2 ml) 4 weeks None Rare: upper respiratory The Rotashield®
reassortant apart, from 6 weeks tract infection, vaccine was removed
rotaviruses of age, oral hoarseness from the market in
1999 due to risk of
intussusception
Rubella Live attenuated viral; 1 dose from 9 to None Fever, rash; rarely Adolescent girls and/or
combination with 12 months with anaphylaxis, arthritis childbearing-aged
measles (MR) measles containing women if not
vaccine, IM, or SC previously vaccinated
Tetanus Tetanus toxoid in DTP, 3 doses before 1 year of DTP 1–6 years; Td Mild local or systemic
DT, Td, or TT age, IM adolescence and reactions increase
early adulthood with number of
doses
(Continued)
192 Immunization
Table 3 Main vaccines and their characteristicsdcont'd
Primary schedule and
Disease Vaccines route
Typhoid Ty21a, live attenuated 3–4 doses (capsules)
viral (Salmonella 2 days apart from 5
Typhi) years of age, oral
Vi polysaccharide single 1 dose from 2 years of
dose age, SC, or IM
Varicella Live attenuated, viral 1 dose under 13 years
of age; 2 doses for
older groups,
4 weeks apart, SC
Yellow fever Live viral 1 dose from 9 months
of age, SC
0.5 ml dose unless otherwise stated; DTP, diphtheria–tetanus–pertussis; IM, intramuscular; SC, subcutaneous; ID, intradermal.
pneumonia are common. Infants under 1 year of age have the
highest case-fatality ratios, sometimes reaching 20% in
epidemics. An old Arabic saying advised ‘do not count the chil-
dren before measles has passed.’
Measles vaccine was first licensed in 1963 in the United
States as the Edmonston B live attenuated vaccine. Several
attenuated vaccines are now in use, many of them derived
from the original strain, such as the Schwartz and Moraten
strains with the Edmonston-Zagreb strain being the most
widely used today. Infant immunization against measles has
significantly reduced cases and deaths. Most industrialized
countries now use the combination measles–rubella (MR),
measles–mumps–rubella (MMR) or measles–mumps–
rubella–varicella (MMRV) vaccine. As a result, most monova-
lent measles vaccines are now produced in India and other
developing countries, with industrialized country manufac-
turers preferring the more lucrative combination vaccines.
Since population immunity needs to be > 93–95% to
prevent measles epidemics and because primary vaccination
failure occurs in 10–15% of infants vaccinated at 9 months
of age, every child needs to be reached with two doses of
measles vaccine.
In 2010, the World Health Assembly set milestones
toward global measles eradication, to be reached by 2015.
Achieved in the Americas in 2002, all regions now have goals
for the elimination of measles (sometimes combined with
rubella). During 2000–2012, estimated measles deaths
decreased by 78%, from 562 400 to 122 000 (WHO, 2014c).
While elimination has been maintained in the Americas, and
the Western Pacific Region is on track for elimination, it seems
likely that targets for European, Eastern Mediterranean, and
African regions will not be achieved on time.
Poliomyelitis
Until the introduction of live or inactivated polio vaccines
(IPVs) in the 1950s, epidemics caused the death and paralysis
of hundreds of thousands of children. The trivalent live atten-
uated oral poliovirus vaccine (OPV), widely used since the early
1960s, elicits intestinal mucosal immunity. Spurred on by
Booster doses Adverse reactions Comments
Every 3–7 years None significant
Every 3 years
At 4–6 years old
Hypersensitivity to egg; Yellow fever vaccination
rarely hepatic failure; is strictly regulated
very rare reports of by the International
death from organ Health Regulations
failure
earlier success with smallpox, in 1988 at the World Health
Assembly, all WHO member states agreed to eradicate polio-
myelitis by the year 2000. Since then, a massive global pro-
gram has been in operation, the largest public–private
partnership for health led by a coalition of four partners:
WHO, UNICEF, the U.S. Centers for Disease Control and
Prevention, and Rotary International. The number of cases of
polio has been reduced by over 99%. In 2014, only three coun-
tries (Afghanistan, Nigeria, and Pakistan) remain polioen-
demic, down from more than 125 countries in 1988.
However, until poliovirus transmission is interrupted in these
countries, all countries remain at risk of importation of polio,
especially in the ‘poliovirus importation belt’ of countries
from West Africa to the Horn of Africa.
In global eradication effort, OPV has been used extensively
to stop circulation and transmission of wild poliovirus types 1,
2, and 3. To break the last chains of wild poliovirus transmis-
sion, more highly immunogenic bivalent and monovalent
vaccines against types 1 and 3 were developed and licensed
in 2005 for supplementary immunization in remaining
endemic areas. While live attenuated OPV vaccines are effective
against the wild virus, in very rare cases they can lead to
vaccine-associated paralysis. This has led most industrialized
countries to use IPV at a significantly higher price.
Low-income countries continue to use OPV due to the benefit
of inducing mucosal immunity, ease of administration, and
lower cost. Necessarily to achieve global polio eradication,
vaccination with OPV will have to cease. This is proceeding
in a phased way starting with the global withdrawal of type-2
OPV (a switch from trivalent OPV to bivalent) and the intro-
duction of one-dose of IPV in OPV-only using countries to
migrate the risk of reintroduction of type-2 virus
(Figure 8) (WHO, 2014d).
Hepatitis B
Hepatitis B is a viral infection that attacks the liver and can
cause both acute and chronic disease. It is a major global health
problem, and the most serious type of viral hepatitis. It is esti-
mated that about 600 000 people die each year due to
 Immunization 193

A country will be
0considered as having
7501,500 3,000 Kilometers
made a formal decision
when formal
documentation of its Introduced to date (71 countries or 37%)
decision to introduce IPV
has been verified by the Introduction to occur in 2014 (3 countries or 2%)
relevant WHO Regional Declared intent to introduce in
Office Introduction to occur in 2015 (6 countries or 3%)
2014 (6 countries or 3%)
Not Available, Not Introduced /No
Declared intent to introduce in
Plans (58 countries or 30%)
Not applicable 2015 (50 countries or 26%)

Figure 8 Countries using IPV and formal decision or declared intent to introduce. Data Source: WHO/IVB Database, as at 28 March 2014 and AFR/
EUR/EMR EPI Managers Meetings in Feb/March 2014 and Summary of POB indicators status as of 06 March 2014. Map production: Immunization
Vaccines and Biologicals, (IVB), World Health Organization. Date of slide: 28 March 2014

consequences of hepatitis B, such as liver cirrhosis and liver
cancer (WHO, 2009b). The virus is highly contagious and is
transmitted through contact with the blood or other body
fluids of an infected person. Hepatitis B virus can survive
outside the body for at least 7 days, and is an important occu-
pational hazard for health workers.
Hepatitis B vaccine was first licensed in the United States in
1982; the first vaccine against a cancer-causing pathogen. It has
proven to be one of the safest, most immunogenic, and effective
vaccines. Despite a 1992 World Health Assembly resolution,
introduction worldwide was slow primarily because of the
limited vaccine supply and high price. The launch of the GAVI
Alliance in 1999 accelerated the uptake of hepatitis B vaccine in
the poorest countries and 184 countries were using the vaccine
by the end of 2012. A dramatic decline in the vaccine price has
now made this sustainable. Since perinatal or early postnatal
transmission is an important cause of chronic infections globally,
the first dose of vaccine should be given as soon as possible after
birth, preferably within 24 h. The birth dose should be followed
by 2 or 3 doses to complete the primary series.
Delivering a birth dose requires special programmatic
measures and coordination between immunization and maternal
health services. In many resource-poor countries, home births are
common. Efforts to develop new heat-stable and freeze-stable
hepatitis B vaccines are underway to support innovative outreach
by trained birth attendants who function beyond the cold chain.
Haemophilus influenzae Type B Infection
Haemophilus influenzae type b (Hib) is the bacteria responsible
for severe pneumonia, meningitis, and other invasive diseases
almost exclusively in children aged less than 5 years. It is
transmitted through the respiratory tract from infected to suscep-
tible individuals. In the year 2000, before the widespread intro-
duction of Hib vaccine in resource-poor countries, Hib was
responsible for about 8 million cases of serious disease and
371 000 deaths in children under 5 years of age (WHO,
2013). Today more than 80% of the world’s children live in
countries that include Hib vaccine in the national immunization
schedule and have benefitted from dramatic declines (>90%) in
Hib disease. Hib vaccines consisting of Hib capsular polysaccha-
ride conjugated to a protein carrier are licensed for use in infancy,
and available in a variety of formulations and often in combina-
tion with DTP, DTP-Hep B, or DTP-Hep B-IPV. The schedule and
number of primary doses, and use of a booster depends on
consideration of the local epidemiology and vaccine
presentation (monovalent versus combination), but because
serious Hib disease occurs most commonly in children
between 4 and 18 months, immunization should start as early
as possible from 6 weeks of age.
Rotavirus
Rotaviruses are the most common cause of severe diarrheal
disease in young children throughout the world. According to
WHO 2008 estimates, about 450 000 children aged <5 years
die each year from vaccine-preventable rotavirus infections;
the vast majority of these children live in low-income countries
(WHO, 2013c).
The first rotavirus vaccine licensed in 1988 was withdrawn
from the market when it was found to be associated with intus-
susception, a serious condition that causes bowel obstruction.
Since then, two orally administered, live, attenuated rotavirus
vaccines were found to be safe and efficacious in large-scale
194 Immunization
clinical trials in the Americas and Europe, and were licensed in
2006. In low-income countries, vaccine efficacy may be lower
than in industrialized settings, similar to other live oral
vaccines, but even with this lower efficacy a greater reduction
in absolute numbers of severe gastroenteritis and death was
seen, due to the higher background severe rotavirus disease
incidence. The public health impact of rotavirus vaccination
has been demonstrated in several countries. For example, in
the USA, a measurable decrease was seen in the number of rota-
virus gastroenteritis hospitalizations accompanied by a sug-
gested herd effect protecting older nonvaccinated children,
while in Mexico, a decline of 41% in diarrheal deaths in
infants <11 months was attributed directly to the use of the
vaccine (Richardson et al., 2010).
As the rotavirus vaccine does not protect against all causes of
diarrhea, their use should be part of a comprehensive strategy
to control diarrheal diseases with the scaling up of both preven-
tion (promotion of early and exclusive breastfeeding, hand-
washing with soap, improved water and sanitation) and
treatment packages (including low-osmolarity ORS and zinc).
The introduction of rotavirus (and pneumococcal) vaccine is
part of the Integrated Global Action Plan for Pneumonia and
Diarrhoea (GAPPD) (WHO, 2013d), which advocates for
a cohesive approach bringing together the critical services and
interventions needed to ‘protect, prevent, and treat’ all children.
Human Papillomavirus
HPV causes cervical cancer, which is the fourth most common
cancer in women. In 2012, there were an estimated 528 000
new cases and 266 000 deaths due to cervical cancer (GLOBO-
CAN, 2012). A large majority (around 85%) of the global burden
occurs in the less developed countries, where it accounts for 13%
of all female cancers. Virtually all cases are attributable to genital
HPV infection. More than 100 HPV genotypes are known, but
types 16 and 18 alone cause about 70% of all cases of invasive
cervical cancer worldwide. Cervical cancer screening and treat-
ment programs have achieved remarkable success in industrial-
ized countries. However, these are difficult to establish in
developing countries where access to health services is limited.
First licensed in 2006, two HPV vaccines based on viruslike parti-
cles, with unprecedented efficacy of 100% against precancerous
lesions due to HPV 16 and 18 infections, are now widely avail-
able. Originally, license requiring three doses over 6 months,
recent evidence has demonstrated that reduced 2-dose schedules
with a longer interval (at least 6 months) between doses have
a comparable immune response. As the vaccines are most effica-
cious in females who are naive to HPV types, it is important to
achieve high coverage among adolescent girls before initiation
of sexual activity. Many countries are implementing
school-based vaccination strategies to reach this target group
but the combined high vaccine price and operational costs are
challenging. Linkage with other adolescent health interventions
and rubella and tetanus vaccination provide opportunities for
synergy.
Meningococcal Meningitis
Neisseria meningitidis (meningococcus) is a leading cause of
bacterial meningitis and septicemia. Endemic disease occurs
worldwide, with outbreaks most frequently occurring in the
‘Meningitis Belt’ a region of 25 sub-Saharan countries, stretch-
ing from Senegal to Ethiopia, with a total population of about
500 million people. There are no reliable estimates of global
meningococcal disease burden due to inadequate surveillance
in several parts of the world (WHO, 2011). Invasive meningo-
coccal disease has a very high fatality rate (>50% if untreated)
and many survivors develop permanent sequelae. Of the 12
N. meningitidis serogroups identified, A, B, C, X, W135, and Y
are responsible for the majority of disease, but serogroup distri-
bution varies by location and time. Meningococcal infections
are transmitted through contact with respiratory droplets or
secretions.
Currently there are several polysaccharide and conjugate
vaccines available for protection from the most common
serogroups of meningococcal disease. Polysaccharide vaccines
are available in bivalent (A, C), trivalent (A, C, W135), and
quadrivalent (A, C, W135, Y) formulations. Conjugate
vaccines, which are more immunogenic and can provide herd
protection, are available in monovalent (A or C), quadrivalent
(A, C, W135, Y), or combination (serogroup C and Haemophilus
influenzae type b) formulations. There are no vaccines available
against serogroup X disease.
In December 2010, a new meningococcal A conjugate
vaccine MenAfriVacÒ developed through the WHO-PATH
Meningitis Vaccine Project was introduced in Africa, reaching
over 150 million by the end of 2013. MenAfriVacÒ marks
many milestones for the region: the first time in history that
a vaccine has been specifically designed for Africa; the first
vaccine ever introduced in Africa before reaching any other
continents; and developed at less than one-tenth the cost of
a typical new vaccine, it is a groundbreaking solution for
a killer disease.
Pneumococcal Disease
Streptococcus pneumoniae is a bacterium that is the cause of
a number of common diseases, ranging from serious diseases
such as meningitis, septicemia, and pneumonia to milder infec-
tions such as sinusitis and otitis media. Pneumococcal diseases
are a leading cause of morbidity and mortality worldwide,
though rates of disease and death are higher in developing
countries than in industrialized country settings, with the
majority of deaths occurring in sub-Saharan Africa and Asia
(WHO, 2012a). Disease is most common at the extremes of
age, that is, in young children and among the elderly. The
organism is transmitted mainly through respiratory droplets
and colonizes the back of the nose. Infection of other parts of
the body, resulting in disease, occurs through direct spread or
through invasion of the bloodstream.
Out of over 90 serotypes of S. pneumoniae, only a small
minority cause most disease. First used in the United States
in 2000 as a 7-valent vaccine, there are now two available
PCV that target either 10 or 13 of the most prevalent serotypes.
In many countries, routine use of PCV has dramatically reduced
the incidence of invasive pneumococcal disease (IPD), and in
some places IPD caused by vaccine serotypes has virtually dis-
appeared, even in age groups not primarily targeted by the
immunization program (herd immunity effect). The observed
increases in nonvaccine serotype IPD with PCV7 are likely to

be mitigated by the use of vaccines with broader serotype
coverage, but high-quality sentinel surveillance is recommen-
ded to monitor changes in serotype prevalence in those with
serious disease.
Tuberculosis
Tuberculosis (TB) is caused by a bacterium, Mycobacterium
tuberculosis (Mtb). It is a curable and preventable disease that
most often affects the lungs. TB is transmitted from person to
person, by people with pulmonary (lung) TB who release
Mtb into the air through coughing, sneezing, or spitting. A
person needs to inhale only a few of these germs to become
infected. About one-third of the world’s population is esti-
mated to be infected by Mtb, but is not (yet) ill with disease
and cannot transmit the disease. People infected with TB
bacteria have a lifetime risk of falling ill with TB of 10%, as
opposed to persons with compromised immune systems,
such as people living with HIV, malnutrition or diabetes, or
people who use tobacco, who have a much higher risk of falling
ill. When a person develops active TB (disease), the symptoms
(cough, fever, night sweats, weight loss, etc.) may be mild for
many months. This can lead to delays in seeking care, and
results in transmission of the bacteria to others. People ill
with TB can infect up to 10–15 other people through close
contact over the course of a year. Without proper treatment,
up to two-thirds of people ill with TB will die.
Live Bacille Calmette-Guérin (BCG) vaccine, derived from
the TB vaccine developed in 1921 remains the only vaccine
against TB. Unfortunately, it is only partially effective: it
provides some protection against severe forms of pediatric non-
pulmonary TB, such as TB meningitis, but is unreliable against
adult pulmonary TB, which accounts for most of the TB disease
burden worldwide.
WHO continues to recommend the vaccination of neonates
with BCG, due to its protective effect in infants and young chil-
dren. However, children infected with HIV through vertical
transmission from their HIV-infected mother are at risk of
developing severe vaccine-related disease (‘BCGosis’).
Therefore, children known to be HIV infected should not be
vaccinated with BCG.
There is an urgent need for a new, safe, and effective vaccine
that prevents all forms of TB, including drug-resistant strains, in
all age groups and in people with HIV. TB vaccine development
is a very active field of research and by the end of 2010, 12
vaccine candidates had begun clinical evaluation in humans.
Assuming that one of the most advanced vaccine candidates
shows sufficient efficacy, the first new TB vaccine in a 100 years
could become available around 2018.
Malaria
Malaria is a preventable and treatable mosquito-borne illness.
There were an estimated 207 million cases of malaria in 2012
(uncertainty range: 135–287 million) and an estimated
627 000 deaths (uncertainty range: 473 000–789 000)
(WHO, 2013e). Most malaria deaths occur in sub-Saharan
Africa, and three-quarters of these occur in children under
five. There is currently no commercially available malaria
vaccine, despite many decades of intense research and
Immunization 195
development effort. The complexity of the malaria parasite
makes development of a malaria vaccine a very difficult task.
Over 20 subunit vaccine constructs are currently being evalu-
ated in clinical trials or are in advanced preclinical develop-
ment. The most advanced vaccine candidate against
Plasmodium falciparum is RTS,S/AS01. A large clinical trial with
more than 15 000 children is ongoing in seven countries in
sub-Saharan Africa: Burkina Faso, Gabon, Ghana, Kenya,
Malawi, Mozambique, and the United Republic of Tanzania.
Depending on the timing of the full phase 3 results, any recom-
mendation on use is not expected until 2015 at the earliest.
There are many effective interventions now available that
have dramatically reduced the burden of malaria. These
include: prevention through mosquito vector control and use
of long-lasting insecticidal bed nets and, in some settings,
indoor residual spraying with insecticides; seasonal malaria
chemoprevention in some settings; intermittent preventive
treatment for infants and during pregnancy; prompt diagnostic
testing; and treatment of confirmed cases with effective antima-
larial medicines. Given the efficacy results obtained so far in the
neighborhood of 30–50%, the potential role of RTS,S/AS01
will only be in addition to fully scaled-up access to and use
of nonvaccine malaria preventive measures, prompt diagnostic
testing, and effective antimalarial medicines. The need for
high-quality, safe, and effective drugs to treat malaria will
continue regardless of any deployment of a first-generation
malaria vaccine such as RTS,S/AS01.
Human Immunodeficiency Virus
HIV vaccine development is complex. First attempts to develop
a vaccine against HIV in the late 1980s were based on eliciting
an antibody response, which is how most vaccines are thought
to work. However, because HIV mutates rapidly, and its outer
spike protein conceals itself from the immune system, creating
the appropriate viral antigens to use in a vaccine proved
remarkably difficult, and the approach was abandoned. More
recently, many scientists believe that an AIDS vaccine candidate
will provide robust protection against HIV infection only if it
engages both arms of the adaptive immune system, i.e.,
cell-mediated and antibody-based immune responses. HIV
vaccine development is complicated by the variability of the
virus, and, in particular, its envelope protein at both the indi-
vidual and population level. Thus, the evolving number of
virus subtypes and recombinations renders vaccine develop-
ment targeting the viral envelope constituents very difficult.
Consequently, vaccines may have to be carefully adapted to
the virus forms in circulation in the precise location where their
use is intended.
Although there is currently no vaccine against HIV/AIDS,
there are a number of very encouraging leads. In 2009, the
combination of two vaccines, a modified poxvirus expressing
HIV antigen, and a so-called protein subunit vaccine, was
shown to provide over 30% protection against HIV infection
in a human clinical trial, the ‘RV144 protocol,’ in Thailand.
The current vaccine development effort is therefore
two-pronged: to improve on the results of the RV144 protocol,
in trials planned in Thailand and South Africa, and to develop
a whole range of ‘second generation’ products to address chal-
lenges such as the extreme variability of the HIV virus, which is
196 Immunization
recognized as an important bottleneck to HIV vaccine develop-
ment. If the required efficacy can be shown in any of the trials,
an HIV/AIDS vaccine could become available from 2020.
Seasonal Influenza
There are three types of seasonal influenza viruses – A, B, and C.
Influenza viruses circulate in all parts of the world and cause
acute respiratory illness. Type C influenza cases occur much
less frequently than A and B. That is why only influenza A
and B viruses are included in seasonal influenza vaccines. Influ-
enza occurs globally with an annual attack rate estimated at
5–10% in adults and 20–30% in children. Illnesses can result
in hospitalization and death mainly among high-risk groups
(the very young, elderly, or chronically ill). Worldwide, these
annual epidemics are estimated to result in about 3–5 million
cases of severe illness, and about 250 000 to 500 000 deaths
(WHO, 2012b). Immunization is the best intervention to
prevent influenza virus infection, and WHO recommends
that pregnant women be given the highest priority based on
the substantial risk of severe disease among this group, and
the evidence that seasonal influenza vaccine is safe throughout
pregnancy and effective in preventing influenza in both
mothers and their young infants for whom the burden of
disease is also high.
Influenza A viruses are the principal cause of epidemics and
worldwide pandemics. As influenza A viruses undergo frequent
surface antigen changes, infection by one strain may not
provide immunity against other variants. Consequently,
WHO established a Global Influenza Surveillance and
Response System (GISRS) to monitor antigenic shift and
provide annual recommendations for influenza vaccine
composition. New vaccines against influenza are designed
each year to match the circulating strains. Pandemics are char-
acterized by the rapid dissemination of a new, virulent influ-
enza A viruses to which there is little or no existing immunity
within the population. There have been four influenza
pandemics since 1900, with the most recent pandemic occur-
ring in 2009 caused by a new influenza A (H1N1) virus. Animal
influenza viruses, including avian influenza A (H5N1 and
H7N9) have occasionally caused illness in humans. While effi-
cient human-to-human transmission of these viruses has not
been identified, the high case-fatality rates of human infection
by these viruses underscore the importance of these pathogens
to public health. There are several vaccine candidates under
development against animal influenza viruses.
Quality, Safety, and Regulatory Aspects
Vaccines are given to healthy people and are therefore held to
the highest standards of quality and safety throughout the cycle
of research, production, and utilization. Regular revision of
manufacturing processes, legislation on production and
licensing, and postlicensure surveillance aims to ensure that
the highest standards are permanently adhered to. Since its
establishment in 1948, WHO has brought together scientists
from all over the world to define agreed international standards
for the manufacturing and testing of vaccines, and these are
published as a WHO Technical Report Series (see Relevant
Websites).
Research and Development
Vaccines are first carefully evaluated for effectiveness, and
potential harmful effects in vitro and in animals. If good results
are obtained, phased clinical trials of increasingly larger size are
performed to establish clinical tolerance and safety, quantify
immune response, and demonstrate protective efficacy.
Phase 1 trials look at safety and immune response in 20 or
fewer participants, usually healthy adults. These trials are
meant to identify any common adverse reactions. Phase 2 trials
involving fifty to several hundred participants help determine
the optimum vaccine composition to achieve adequate protec-
tion while ensuring safety. Phase 3 trials determine clinical effi-
cacy for disease prevention, provide further safety information,
and serve as the final gatekeepers before widespread use. They
involve thousands to tens of thousands of participants. In
general, such trials include a control group receiving a placebo
in order to compare the occurrence of adverse events among
vaccinated and unvaccinated individuals.
Production
Each step of the production process is documented and vali-
dated. Consistency of production must be demonstrated by
showing comparable clinical response to vaccine batches. Confi-
dence that vaccines are consistently safe and efficacious requires
continual oversight by an independent and competent National
Regulatory Authority (NRA). In addition to sophisticated tests,
vaccine regulation entails characterization of starting materials
by supplier audits, cell banking, seed lot systems, compliance
with the principles of good manufacturing practice, and inde-
pendent release of vaccines on a lot-by-lot basis by NRAs.
For some vaccines, WHO advises on their acceptability for
developing country immunization programs. This technical
advice known as ‘prequalification’ is required for vaccine
procurement through United Nations agencies such as UNICEF
(WHO, 2013f).
Monitoring of Licensed Vaccines
Severe reactions following immunization are extremely rare.
Adverse events following immunization range from the
common, innocuous redness or soreness at point of injection
to extremely rare, serious reactions. Adverse events may be
due to an immunological or allergic reaction, susceptibility to
a particular antigen, human error when administering the
vaccine, or, most frequently, coincidental events (not related
to the vaccine) occurring at the same time or after vaccination.
Once vaccines are licensed, ‘postmarketing surveillance’
identifies less-common reactions which may occur after
a long period of time or in specific subgroups of the popula-
tion. Adverse events occurring once in every 100 000 or 1
million vaccinations may be identified this way. Such moni-
toring is typically done through spontaneous reporting systems
whereby events thought to be related to the vaccine are re-
ported to health authorities. Sometimes postlicensure moni-
toring is conducted in more formal Phase 4 trials. Adverse
events reported following immunization are not necessarily
caused by the vaccine. Determination of a cause-and-effect rela-
tionship necessitates further investigation.

It is the joint responsibility of governments, industry,
health-care providers, and patients to report any suspected
adverse event related to immunization. Challenges lie ahead
as more complex vaccines require increasingly sophisticated
monitoring systems. Several countries have joined forces to
pool their AEFI data in a common global database. The data-
base is managed by the WHO Programme for International
Drug Monitoring.
The Global Advisory Committee on Vaccine Safety
(GACVS) established in 1999 is charged to provide the WHO
with independent advice on vaccine safety issues. The role of
the GACVS is both to analyze and to interpret reports of the
adverse effects of vaccines that impact on global vaccination
programs and strategies, and to foster the development of
improved surveillance systems to detect any adverse effects of
vaccines, particularly in low- and middle-income countries. It
also monitors the development of new vaccines during clinical
testing and advises on the safe use of vaccines in immunization
programs.
Public Concerns
Over the past 40 years, immunization programs have protected
hundreds of millions of children from deadly and debilitating
diseases. As some diseases have disappeared, however, public
perceptions have changed. Global communication, increasing
consumer awareness, and public debate about health matters
have all contributed to greater scrutiny of vaccines and immu-
nization. As the public, in some parts of the world, is no longer
familiar with infectious diseases such as diphtheria and
measles, attention is concentrated on the risk of
vaccine-associated adverse events. This leads to complacency
and a lack of confidence in immunization, which in turn results
in declining coverage and resurgence of the disease. In 2006,
fueled by a now-fully discredited claim of a link between the
MMR vaccine and autism, the UK experienced its largest
measles outbreak in 20 years and the first measles-related death
in 14 years. More recently, a combination of political consider-
ation and rumors about the safety of the OPV have led to the
refusal of vaccinations by groups of population in Nigeria
and Pakistan and in some cases to the killing of vaccinators.
Such events have also been the cause of the reintroduction of
the wild poliovirus into countries which had been free for
this disease for several years.
Research in Vaccine Delivery
New Immunization Technology
The increased use of auto-disable syringes (which lock after
a single injection) has improved safety by preventing reuse of
contaminated syringes, thus reducing the risk of transmission
of blood-borne pathogens such as hepatitis B, hepatitis C,
and HIV.
Single-dose presentations, widely used in industrialized
countries, also reduce the risk of contamination. Prefilled
monodose injection devices not requiring a separate needle
improve safety at the point of use. UniJectÒ is such a device
that has been successfully tested with hepatitis B and tetanus
toxoid vaccines administered by traditional birth attendants
Immunization 197
(Tsu, 2004). Need for additional cold storage space and cost
remains an obstacle, which may be balanced by lower vaccine
wastage with this technology.
Needle-free jet injectors are a promising technology for
improving efficiency and administration. Early model jet injec-
tors had safety issues with cross-contamination of multiuse
nozzles, and this has led to the development of single-use,
disposable components and the first licensed and WHO pre-
qualified device in 2013. Manufacturing economies of scale
have yet to be reached to achieve widespread use. Studies are
underway for bioneedle (implants)- and electroporation
(EP)-mediated vaccine delivery.
New Vaccine Formulations
Alternative vaccine formulations could further improve immu-
nization safety and reduce contaminated waste. Administration
routes such as oral, nasal, and transcutaneous are currently
being explored. The multiyear measles aerosol project devel-
oped a respiratory delivery method, which although not suit-
able for primary vaccination of infants, was recognized as
having potential benefits for use by nonhealthcare workers in
low-resource settings in the context of outbreaks, emergencies,
and outreach. Another interesting concept is plant-derived or
edible vaccines encoding protective antigens from pathogens
into transgenic plants. The plants are processed to deliver
a uniform dose of vaccines. Human clinical trials have been
conducted with bananas and raw potatoes, which showed
encouraging antibody responses. Potential advantages of this
technology include thermostability, low-investment needs,
multivalency, and oral administration.
Vaccine Management
Innovation would benefit all areas of vaccine management. For
instance, heavy reliance on the cold chain remains a major
economic and logistical barrier, and the introduction of
a number of new antigens is increasing the burden on already
stressed systems. Taking advantage of the real heat stability of
vaccines and increasing use of VVMs to use vaccines in
a ‘Controlled Temperature Chain’ outside the traditional
2–8 C range could therefore greatly facilitate immunization
campaigns and special strategies as well as reduce their costs
as was shown in Benin with the Meningitis A vaccine (Lydon
et al., 2014). Research into the development of thermostable
vaccines has not so far yielded significant results. Although
a number of avenues continue to be explored, uncertainty
about market prospects, the focus of procurement agencies
and donors on low purchasing prices, and the high cost of regu-
lation and licensing have impeded development in this area.
The Economics of Vaccines and Immunization
Economic Evaluation
Economic evaluation of vaccines and immunization explores
how scarce resources can be used to maximize technical and
allocative efficiency. Such studies require data on the burden
of disease, the effectiveness of vaccines and immunization
strategies being compared, the costs of delivering a vaccine,
198 Immunization
and the opportunity costs of not using it. Economic evaluations
in low- and middle-income countries face particular challenges
such as data availability, and quality and standardization of
methods (Walker, 2010). There are special considerations for
economic analysis for immunization (Beutels, 2008). Methods
of assessing vaccine effectiveness differ according to disease,
vaccine, and context. Increasingly, infectious disease modeling
is used, taking into account not only vaccine efficacy from clin-
ical trials, but also the force of infection and natural boosting in
a population, the protection offered by a vaccine over time
(e.g., waning immunity), and indirect protection of the non-
vaccinated (e.g., through vaccine shedding) or reduced disease
transmission (herd immunity). Valuing future impact presents
unique difficulties, and outcome measures should include at
least cases and deaths prevented and disability-adjusted life
years (DALYs) gained.
Costing should include all vaccine and program costs, and
present and future treatment costs. Whereas the cost of expanding
coverage may rise at higher coverage levels, effectiveness may also
increase as more vulnerable populations are reached, resulting in
stable or greater cost-effectiveness. Where a societal perspective is
adopted, costs to families and indirect costs of lost productivity
must also be considered. Discounting of future costs is recom-
mended for vaccines with future or long-lasting impact.
The WHO classifies an intervention as ‘highly cost-effective’
if one DALY is gained for less than the gross domestic product
(GDP) per capita of a given country, and ‘cost-effective’ for
interventions saving a DALY for between 1 and 3 times the
GDP per capita (Hutubessy et al., 2003).
Financing Vaccines
Economic evaluations are necessary for decision making but
are not sufficient. Policy goals must still be clear and value
judgments made about social and public health priorities. As
more and more costly vaccines become available, the question
of whether and how to fund them in the public sector takes on
new urgency: no matter how cost-effective a vaccine may be, it
must be affordable; that is, it should be possible to finance the
vaccine within an immunization budget over the medium- to
long-term without significantly affecting resources for other
public health priorities. In this context, price evolution must
be taken into account as product prices may decline with
time following licensing and expansion of the market.
There are numerous indicators for tracking immunization
financing. These include immunization costs per capita; per
immunized child; or as a proportion of the government health
budget, total health expenditure, or GDP. Cost savings engen-
dered by vaccine introduction may not be available to finance
the vaccine, as resources flow to other therapeutic services or
savings that occur in the future. In practice, private individuals,
employers, and health insurance companies often recognize
the health and economic value of vaccines before they are
offered in the public sector.
While encouraging such trends, fiscal space for immunization
can be expanded in the public sector by reallocating or preferably
increasing the national health budget and, in lower-income
countries, by seeking external funding. These avenues require
the highest level of policy dialog between ministries of health
and finance and their development partners.
An important financing mechanism, the GAVI Alliance has
helped mobilize resources for the 73 poorest countries. The
GAVI Alliance subsidizes introduction of a range of new and
underutilized vaccines and offers financial support to
strengthen immunization services and health systems. GAVI
partially funds its programs through innovative financing
mechanisms. The International Financing Facility for Immuni-
sation (IFFIm) developed in 2005 allows donor countries to
make legally binding aid commitments over 20 years. IFFIm
borrows against these pledges on capital markets to raise
US$4.5 billion for GAVI-supported programs in poor
countries. Another US$1.5 billion legally binding pledge has
been made for an Advance Market Commitment (AMC) to
accelerate the availability of a more effective pneumococcal
vaccine. Through the AMC, an initial price is guaranteed to
suppliers to recoup investment costs for developing a vaccine
that meets WHO specifications. In exchange, companies
commit to provide continued supply for 10 years at a lower
price affordable to low-income countries.
The Global Marketplace and Economic Development
Marginalized a few years ago, vaccines and immunization are
again central in global politics, economics, and finance.
Whereas, until recently, mergers in the pharmaceutical industry
radically reduced the number of companies investing in
vaccines, the winds of change have reversed this trend. With
the creation of a new market in developing countries, large
companies have a new interest not only in vaccine research
and development, but also in making their products more
attractive and affordable for resource-constrained settings.
There is also new vigor in the vaccine industry with companies
in, for example, India, China, South Korea, and Brazil entering
the scene, as returns on investment seem more certain.
Investing in health is increasingly recognized to be essential
for social and economic development. Vaccinations can affect
economic activity both at the individual and population level.
They result in lifetime productivity gains by preventing diseases
that cause cognitive impairment, physical handicap, or reduced
schooling. In addition, fewer child deaths will lead to lower
fertility rates over time. This, in turn, will decrease the ratio
of economically dependent people in society, which will
strengthen the labor force and the economy (Deogaonkar
et al., 2012).
For many countries, immunization is a key indicator for the
national poverty reduction strategic plan. The goal of protect-
ing people, especially infants and children, from VPDs is
increasingly shared as a core value throughout the world. The
global health architecture has been permanently changed by
the coming together of governments, institutions, and individ-
uals in partnerships to make this goal accessible to all.
Challenges Ahead
The future of vaccine development is bright. The astounding prog-
ress against infectious diseases has made many of them nearly
invisible, at least in wealthier societies. Progress in advanced
molecular biology and genetics is filling the pipeline with a versa-
tile array of new vaccines against more than 40 infectious and

noncommunicable diseases. These extraordinary developments
bring challenges for the public health community.
On the one hand, there is an ‘unconscious faith’ in the
power of new vaccines, recently demonstrated with the
licensing of HPV vaccines, which has created a powerful plat-
form for women’s health and right-to-health lobby groups. At
the same time, parents are increasingly concerned about
possible complications of more traditional vaccines. Managing
public expectations in this context must be a constant concern.
The advent of new products together with the growing
demand for safety will undoubtedly raise the profile of quality
assurance further and lead to a more stringent regulatory envi-
ronment. This trend will also affect developing country manu-
facturers eager to compete in global markets. Production costs
will continue to rise, making affordability for poorer countries
an even more challenging goal.
The wealth of medicinal and biological products available
challenges cost-conscious policy makers and professionals to
make difficult choices. For resource-poor countries to benefit
from new products and strengthen the systems to support
them, health budgets must grow faster than they have to
date. Immunization programs and logistics systems will have
to evolve to accommodate products of varying stability, formu-
lation, and presentation, and fit better in health systems
designed to deliver comprehensive health care.
Equity in access to vaccines and immunization, between
and within countries, will remain a constant challenge as new
products roll-off production lines. Conversely, vaccines of
public health importance may continue to suffer from insuffi-
cient investment in research and development if product
uptake is uncertain. The critical challenge, therefore, is to create
an environment for a healthy market, where research efforts
receive the necessary investment, financing mechanisms guar-
antee purchase on a large scale at affordable prices, and
national immunization programs are sufficiently robust to
adopt and safely deliver life-saving new products. Considerable
advocacy and financial resources will be required to meet this
challenge as the Global Vaccine Action Plan indicates.
These monumental challenges must be tackled for immuni-
zation to remain the pathfinder for primary health care and
deliver the benefits of science to prevent unnecessary illness
and death around the world.
Acknowledgment
Rosamund Lewis was the lead author of the first published 2007 version
of this article upon which this revision and update has been based.
See also: Hepatitis, Viral; Influenza, Historical; Influenza;
Measles; Poliomyelitis, Historical; Poliomyelitis; Smallpox;
Tetanus; Vaccines, Historical.
References
Beutels, P., Scuffham, P.A., MacIntyre, C.R., November 2008. Funding of drugs: do
vaccines warrant a different approach? Lancet Infect. Dis. 8 (11), 727–733.
Black, R.E., Cousens, S., Johnson, H.L., Lawn, J., et al., June 5, 2010. Global,
regional, and national causes of child mortality in 2008: a systematic analysis.
Lancet 375 (9730), 1969–1987.
Immunization 199
Deogaonkar, R., Hutubessy, R., van der Putten, I., Evers, S., Jit, M., 2012. Systematic
review of studies evaluating the broader economic impact of vaccination in low and
middle income countries. BMC Public Health 16 (12), 878.
Fenner, F., Henderson, D.A., Arita, I., Jezek, Z., Ladnyi, I.D., 1988. Smallpox and Its
Eradication. World Health Organization, Geneva, Switzerland.
Global Vaccine Action Plan: 2011–2020, 2013. World Health Organization, Geneva,
Switzerland.
GLOBOCAN, 2012. Estimated Cancer Incidence, Mortality and Prevalence Worldwide in
2012. International Agency for Research on Cancer, Lyon, France. www.globocan.
iarc (accessed 02.05.14.).
Grant, J., 1991. The Children’s vaccine initiative . and other promises to keep.
J. Trop. Pediatr. 37, 272–274.
Griffiths, U.K., Mounier-Jack, S., Oliveira-Cruz, V., et al., 2011. How can measles
eradication strengthen health care systems? J. Infect. Dis. 204 (Suppl. 1),
S78–S81.
Hutubessy, R., Chisholm, D., Tan-Torres Edejer, T., WHO Choice, 2003. Generalized
cost-effectiveness analysis for national-level priority-setting in the health sector.
Cost Eff. Resour. Alloc. 1, 8.
Lydon, P., Zipursky, S., Tevi-Benissan, et al., 2014. Economic benefits of keeping
vaccines at ambient temperature during mass vaccination: the case of meningitis A
vaccine in Chad. Bull. World Health Organ. 92, 86–92.
Mogedal, S., Stenson, B., 2000. Disease Eradication: Friend or Foe to the Health
System? Synthesis Report from Field Studies on the Polio Eradication Initiative in
Tanzania, Nepal and the Lao People’s Democratic Republic. World Health Orga-
nization, Geneva, Switzerland.
Richardson, V., Hernandez-Pichardo, J., Quintanar-Solares, M., et al., 2010. Effect of
rotavirus vaccination on death from childhood diarrhoea in Mexico. N. Engl. J. Med.
362, 299–305.
Tsu, V.D., 2004. New and underused technologies to reduce maternal mortality.
Lancet 363, 75–76.
Walker, D.G., Hutubessy, R., Beutels, P., March 8, 2010. WHO guide for standardi-
zation of economic evaluations of immunization programmes. Vaccine 28 (11),
2356–2359.
World Health Organization, 2002. Distribution of the Estimated Deaths from Diseases
that Are Preventable by Vaccination. World Health Organization, Geneva,
Switzerland.
World Health Organization, 2005. 58th World Health Assembly: Revision of the
International Health Regulations. World Health Organization, Geneva, Switzerland.
World Health Organization, 2006. Weekly Epidemiological Record. Tetanus Vaccine
Position Paper, vol. 81. World Health Organization, Geneva, Switzerland, pp. 196–
208. No. 20.
World Health Organization, 2007. Quality of the Cold Chain: WHO-UNICEF Policy
Statement on the Implementation of Vaccine Vial Monitors in Immunization.
World Health Organization, Geneva, Switzerland.
World Health Organization, 2009a. Periodic Intensification of Routine Immunization:
Lessons Learned and Implications for Action. World Health Organization, Geneva,
Switzerland.
World Health Organization, 2009b. Weekly Epidemiological Record. Hepatitis B
Vaccines: WHO Position Paper, vol. 84. World Health Organization, Geneva,
Switzerland, pp. 405–420. No. 40.
World Health Organization, 2010. Weekly Epidemiological Record. Pertussis Vaccines:
WHO Position Paper, vol. 85. World Health Organization, Geneva, Switzerland,
pp. 385–400. No. 40.
World Health Organization, 2011. Weekly Epidemiological Record. Meningococcal
Vaccines: WHO Position Paper, vol. 86. World Health Organization, Geneva,
Switzerland, pp. 521–539. No. 47.
World Health Organization, 2012a. Weekly Epidemiological Record. Pneumococcal
Vaccines: WHO Position Paper, vol. 87. World Health Organization, Geneva,
Switzerland, pp. 129–144. No. 14.
World Health Organization, 2012b. Weekly Epidemiological Record. Vaccines against
Influenza WHO Position Paper, vol. 87. World Health Organization, Geneva, Swit-
zerland, pp. 461–476. No. 47.
World Health Organization, 2013a. Weekly Epidemiological Record. Global Routine
Immunization Coverage, 2012, vol. 88. World Health Organization, Geneva,
Switzerland, pp. 477–488. No. 44/45.
World Health Organization, 2013b. Weekly Epidemiological Record. Haemophilus
influenzae Type B (Hib) Vaccination Position Paper, vol. 88. World Health Orga-
nization, Geneva, Switzerland, pp. 413–426. No. 39.
World Health Organization, 2013c. Weekly Epidemiological Record. Rotavirus Vaccines:
WHO Position Paper, vol. 88. World Health Organization, Geneva, Switzerland,
pp. 49–64. No. 5.
World Health Organization, 2013d. Integrated Global Action Plan for Pneumonia and
Diarrhoea. World Health Organization, Geneva, Switzerland.
200 Immunization
World Health Organization, 2013e. World Malaria Report 2013. World Health Orga-
nization, Geneva, Switzerland.
World Health Organization, 2013f. WHO Expert Committee on Biological Standardi-
zation, 61st Report. Annex 6 Procedure for assessing the acceptability, in principle,
of vaccines for purchase by United Nations agencies. Technical Report Series.
World Health Organization, Geneva, Switzerland.
World Health Organization, February 2014a. Immunization Coverage: Factsheet No.
378. World Health Organization, Geneva, Switzerland. http://www.who.int/
mediacentre/factsheets/fs378/en/ (accessed 02.05.14.).
World Health Organization, 2014b. Principles and Considerations for Adding a Vaccine
to a National Immunization Programme: From Decision to Implementation and
Monitoring. World Health Organization, Geneva, Switzerland.
World Health Organization, 2014c. Weekly Epidemiological Record. Global Control and
Regional Elimination of Measles, 2000–2012, vol. 89. World Health Organization,
Geneva, Switzerland, pp. 45–52. No. 6.
World Health Organization, 2014d. Weekly Epidemiological Record. Polio Vaccines:
WHO Position Paper, vol. 89. World Health Organization, Geneva, Switzerland,
pp. 73–92. No. 9.
World Health Organization, 2014e. WHO–UNICEF Joint Statement on Effective Vaccine.
Management for Strengthening Immunization Supply Chains. (Draft April 2014).
World Health Organization, Geneva, Switzerland.
Further Reading
Alfonso, P.L., de Quadros, C.,A., Lal, A.A. (Eds.), 2013. Decade of Vaccines. Vaccine,
vol. 31 (S2), B1–B250.
Jamieson, D.T., Brennan, J.G., Measham, A.R., et al., 2006. Disease Control Priorities
in Developing Countries. Oxford University Press and World Bank, Oxford, UK.
Lydon, P., Gandhi, G., Vandelaer, J., Okwo-Bele, J.M., 2014. Health system cost
of delivering routine vaccination in low- and lower-middle income countries:
what is needed over the next decade. Bull. World Health Organ. 92,
382–384.
Plotkin, S., Orenstein, W.A., Offit, P.A., 2013. Vaccines, sixth ed. Elsevier Saunders,
Philadelphia, PA.
Relevant Websites
http://www.gavialliance.org – GAVI Alliance.
http://www.gavialliance.org/funding/pneumococcal-amc – GAVI Alliance, Advance
Market Commitments (AMC).
http://www.iffim.org – International Finance Facility for Immunisation (IFFIm).
http://www.unicef.org – United Nations International Children’s Emergency Fund
(UNICEF).
http://www.un.org/millenniumgoals/ – United Nations (UN), the Millennium Develop-
ment Goals (MDG).
http://www.who.int/immunization – World Health Organization (WHO), Immunization,
Vaccines and Biologicals.
http://www.who.int/immunization/policy/immunization_tables/en/ – WHO Recommen-
dations for Routine Immunization – Summary Tables.
http://www.who.int/biologicals/technical_report_series/en/ – WHO, Technical Report
Series (TRS).
http://www.who.int/immunization/documents/positionpapers/en/ – WHO, Vaccine Position
Papers.