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The Immunological Basis
for Immunization Series
Module 5:
Tuberculosis
Immunization, Vaccines and Biologicals
The Immunological Basis
for Immunization Series
Module 5:
Tuberculosis
Immunization, Vaccines and Biologicals
WHO Library Cataloguing-in-Publication Data
The immunological basis for immunization series: module 5: tuberculosis.
(Immunological basis for immunization series ; module 5)
1.Tuberculosis - prevention and control. 2.Tuberculosis -microbiology. 3.Tuberculosis - immunology. 4.BCG vaccine - therapeutic use.
5.BCG Vaccine - adverse effects. 6.Vaccination. I.World Health Organization. II.Series.
ISBN 978 92 4 150241 2
(NLM classification: WF 200)
© World Health Organization 2011
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Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary
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the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation
and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use.
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thanks the donors whose unspecified financial support
has made the production of this document possible.
This module was produced for Immunization, Vaccines and Biologicals, WHO, by:
Lewellys F. Barker
Aeras Global TB Vaccine Foundation, Rockville MD, USA
Gregory Hussey
University of Cape Town, Cape Town, South Africa
Printed in October 2011
Copies of this publication as well as additional materials
on immunization, vaccines and biological may be requested from:
World Health Organization
Department of Immunization, Vaccines and Biologicals
CH-1211 Geneva 27, Switzerland
• Fax: + 41 22 791 4227 • Email: [email protected] •
© World Health Organization 2011
All rights reserved. Publications of the World Health Organization can be obtained from WHO Press,
World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel: +41 22 791 3264;
fax: +41 22 791 4857; email: [email protected]). Requests for permission to reproduce or translate
WHO publications – whether for sale or for noncommercial distribution – should be addressed to
WHO Press, at the above address (fax: +41 22 791 4806; email: [email protected]).
The designations employed and the presentation of the material in this publication do not imply the
expression of any opinion whatsoever on the part of the World Health Organization concerning the
legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its
frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may
not yet be full agreement.
The mention of specific companies or of certain manufacturers’ products does not imply that they are
endorsed or recommended by the World Health Organization in preference to others of a similar nature
that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished
by initial capital letters.
All reasonable precautions have been taken by the World Health Organization to verify the information
contained in this publication. However, the published material is being distributed without warranty of
any kind, either expressed or implied. The responsibility for the interpretation and use of the material
lies with the reader. In no event shall the World Health Organization be liable for damages arising from
its use.
The named authors alone are responsible for the views expressed in this publication.
Printed by the WHO Document Production Services, Geneva, Switzerland
ii
Contents
Abbreviations and acronyms..............................................................................................v
Preface............................................................................................................................... vii
1. TB disease..................................................................................................................1
2. Bacteriology..............................................................................................................3
3. The host response to infection...............................................................................5
4. Characteristics of BCG vaccines...........................................................................7
5. Response to vaccination with BCG vaccines......................................................9
5.1 Route of administration of BCG vaccines.......................................................9
5.2 BCG vaccination scars.....................................................................................10
5.3 Delayed type hypersensitivity reactions and cell-mediated response ..........11
5.4 Adverse events..................................................................................................11
5.5 Protective efficacy and duration of immunity...............................................13
6. Future prospects ...................................................................................................18
References.........................................................................................................................20
iii
iv
Abbreviations and
acronyms
AIDS
acquired immunodeficiency syndrome
BCG
bacille Calmette-Guérin (vaccine)
CFU
colony-forming units
CI
confidence interval
DOTS
WHO-recommended directly observed treatment tuberculosis control
strategy
DTH
delayed type hypersensitivity
ELISPOT
enzyme-linked immunospot assay
EPI
Expanded Programme on Immunization
GACVS
Global Advisory Committee on Vaccine Safety (WHO)
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
IGRA
interferon gamma release assay
IFN-γ
interferon-gamma
IL-2
interleukin-2
LTBI
latent tuberculosis infection
M.
Mycobacterium
MDR-TB
multi drug-resistant tuberculosis
MRC
Medical Research Council (United Kingdom)
Mtb
Mycobacterium tuberculosis
NRAMP
natural resistance associated monocyte protein
PBMC
peripheral blood mononuclear cells
PPD
purified protein derivative
RD1
deletion region 1
SCID
severe combined immunodeficiency
v
TB
tuberculosis
TH1/2
T helper cells type 1/2
TNF-α
tumour necrosis factor-alpha
ToC
test-of-concept (trial)
TST
tuberculin skin test
WHO
World Health Organization
USA
United States of America
XDR-TB
extensively drug-resistant tuberculosis
vi
Preface
This module is part of the series The Immunological Basis for Immunization,
which was initially developed in 1993 as a set of eight modules focusing on the vaccines
included in the Expanded Programme on Immunization (EPI)1. In addition to a general
immunology module, each of the seven other modules covered one of the vaccines
recommended as part of the EPI programme — diphtheria, measles, pertussis, polio,
tetanus, tuberculosis and yellow fever. The modules have become some of the most
widely used documents in the field of immunization.
With the development of the Global Immunization Vision and Strategy (GIVS)
(2005–2015) (http://www.who.int/vaccines-documents/DocsPDF05/GIVS_Final_
EN.pdf) and the expansion of immunization programmes in general, as well as the
large accumulation of new knowledge since 1993, the decision was taken to update
and extend this series.
The main purpose of the modules — which are published as separate disease/vaccinespecific modules — is to give immunization managers and vaccination professionals
a brief and easily-understood overview of the scientific basis of vaccination, and also
of the immunological basis for the World Health Organization (WHO) recommendations
on vaccine use that, since 1998, have been published in the Vaccine Position Papers
(http://www.who.int/immunization/documents/positionpapers_intro/en/index.html).
WHO would like to thank all the people who were involved in the development of
the initial Immunological Basis for Immunization series, as well as those involved in
its updating, and the development of new modules.
1
This programme was established in 1974 with the main aim of providing immunization for children
in developing countries.
vii
viii
1. TB disease
Tuberculosis (TB) is a bacterial disease which has been prevalent since ancient
times. TB is currently one of the most important health problems in developing
countries where it imposes a tremendous burden of suffering and economic loss.
Mycobacte­rium tuberculosis (Mtb) is responsible for almost nine million new TB cases,
and 1.7 million deaths per year, mostly in developing countries, although annually
there are over 400 000 new cases in industrialized countries. In fact, as infection with
human immunodeficiency virus (HIV), drug resistance and travel between developing
and developed countries have become increasingly common, tuberculosis has become a
serious global-health problem. Substantial progress has been made worldwide in slowing
the TB pandemic, especially through the WHO-recommended directly observed
treatment short course strategy (DOTS). However, serious obstacles to DOTS success
include low case-detection rates, the emergence of multi-drug resistant (MDR-TB)
and extensively drug-resistant (XDR-TB) TB strains, the severe and widespread risk
of HIV/TB coinfection, and the logistic shortcomings of modern tools to diagnose,
treat and prevent the disease. In sub-Saharan Africa the rise in TB disease incidence
has been strongly associated with HIV infection; in some countries more than half of
individuals with TB have concurrent HIV infection, and HIV-infected persons have
a ten-fold greater risk of developing overt clinical TB disease upon infection with
Mtb than non-HIV-infected persons. TB is also the leading cause of death among
HIV-infected persons, accounting for approximately 23% of AIDS deaths
worldwide. In 2008 WHO estimated that there were nearly half a million new cases of
multi-drug-resistant TB (MDR-TB) a year, which is about 5% of over nine million new
TB cases of all types (1). WHO also found that extensively drug-resistant tuberculosis
(XDR-TB), a virtually untreatable form of the respiratory disease, has been recorded
in 45 countries, and that there is also a link between HIV infection and MDR-TB.
Surveys in several countries found nearly twice the level of MDR-TB among TB patients
living with HIV compared with patients without HIV.
TB is a poverty-related disease; it has long been recognized that war, malnutrition,
population displacement and crowded living and working conditions favour the spread
of TB among human populations, whereas improvements in social conditions and
hygiene lead to its decline. By far the most important source of human infec­tion is an
already infected person who spreads the infectious bacilli via respiratory droplets when
they cough. TB is highly contagious; left untreated, each patient with active pulmonary
TB can infect between 10 and 15 people every year. Transmission is common in families,
schools, hospitals and prisons. Another factor that contributes to the spread of TB
is the global movement of people; as many as 50% of the world’s refugees may be
infected with TB. In many industrialized countries half or more of new TB cases occur
in foreign-born people or migrant populations from endemic areas.
1
Pri­mary infections can occur at any age, but children in areas of high incidence
and high population density are most often affected. Even after resolution,
the disease can be reactivated and spread again. Agents that depress the immune system,
such as corticosteroid treatment or HIV infection, facilitate reactivation.
Primary infection may be asymptomatic and often resolves spontaneously without
progression to active disease. In 90% of infected persons the bacterium is contained
by the host immune response as a latent TB infection (LTBI). In approximately
5% of infections, progression to disease occurs in the first 2–3 years after infection
and an additional 5% of infections progress later to active TB disease from LTBI,
including in old age. TB may progress by local spread in the lungs to cause pleurisy
or bron­chopneumonia. If the infection spreads through the bloodstream, it can affect
many organs, including the meninges, the bones or the internal organs. TB disease can
be accompanied by tuberculous lymphadenopa­thy or, in the absence of other features,
this manifestation can occur.
2
The Immunological Basis for Immunization Series - Module 5: Tuberculosis - Update 2011
2. Bacteriology
Mycobacte­rium tuberculosis (Mtb), the main agent of human TB disease, was discovered
in 1882 by Robert Koch. All members of the Mycobacte­rium genus are slender,
non-motile rod, Gram-positive bacteria with the property of acid-fast (Ziehl-Nielsen)
staining due to their complex mycolic acid-rich cell wall structure. The genus includes
four members of the M. tuberculosis complex: M. tuberculosis and M. africanum,
which are primary human pathogens, M. bovis, the agent of TB in cattle and other
animals which can also cause disease in humans, and M. ulcerans, which causes Buruli
ulcer disease. Other mycobacteria include M. leprae, the agent which causes leprosy,
and a large number of nontuberculous environmental mycobacteria such as those
belonging to the M. avium-intracellulare complex, of which M. avium is an opportunistic
pathogen in AIDS patients. M. bovis, from which bacille Calmette-Guérin (BCG)
vaccine was derived, causes disease in a wide range of domestic animals, including cattle,
bison, buffalo and pigs, and also in feral hosts such as badgers, New Zealand brush-tail
possums, kudus, antelopes, deer, lion and baboons. Infection of humans with M. bovis
can occur by inhalation of aerosols (especially affecting farmers, abattoir workers and
veterinarians), or through consumption of contaminated milk and milk products.
M. tuberculosis has a long generation time (18–24 hours) and growth on solid media
such as Lowenstein-Jensen medium is detectable only after 2–6 weeks. Using fluid
medium and automated detection systems, growth can be detected in 1–2 weeks.
Under field conditions, the diagnosis of pulmonary TB is usually based on microscopy
by demonstrating acid-fast bacilli in sputum; isolation of the organism is required
for a definitive species diagnosis and for drug sensitivity testing. Modern molecular
techniques based on nucleic acid amplification and genetic probes can provide rapid
species information on clinical material or laboratory isolates, and are now widely used
in modern laboratories to supplement traditional microbiological diagnostic methods.
Since the late 1980s, an increase in mycobacterial drug resistance has been reported
from many countries.
The success of mycobacteria as pathogens comes mostly from their ability to
survive in the environment and to persist in infected hosts for long periods of time.
No Mtb toxins are known, and the virulence of different strains of Mtb rests
largely within its ability to grow and persist within host cells. The waxy cell wall
protects the bacteria and promotes their intracellular persistence by inhibiting
phagosome-lysosome fusion, which in turn keeps them away from terminal endocytic
processes. Mycobacteria induce the formation of granulomas that wall-off sites of
infection and limit its spread, but also restrict macrophage killing of the bacteria resulting
in persistence of latent infection.
3
Starting in 1998, the complete genome of Mtb (H37Rv strain) and subsequently
other mycobacterial genomes, including BCG, have been sequenced (2–6).
Comparative genomics have uncovered interesting polymorphisms among
species of the M. tuberculosis complex, as well as among and within BCG strains.
Research revealed a number of genes that are expressed during intracellular infection,
that encode products required for survival and progressive infection or dormancy
within the host (7–10). Mycobacterial mechanisms to direct or block host-cell immune
responses have also been uncovered (11,12).
4
The Immunological Basis for Immunization Series - Module 5: Tuberculosis - Update 2011
3. The host response to
infection
Primary infection by tubercle bacilli induces both innate and adaptive immune and
nonimmune inflammatory reac­tions. Several different types of immune responses
include: interferon gamma (IFN-γ) producing Th1 CD4+ T-cells and major
histocompatibility complex Class I restricted CD8+ T cell-mediated immune responses;
increased macrophage activity; delayed hypersensitivity, granulomatous inflammation
and circulating antibodies. These responses may be protective, or contribute to pathology
depending on the specificity and function of the activated T-cells. Typically a strong
T cell-mediated immune response kills infected macrophages and also induces extensive
necrosis in host tissue. The production of anti-inflammatory cytokines in response to
Mtb antigens may downregulate the immune response and limit T helper cells type
2 (TH-2) driven tissue injury. Cell-mediated immunity, not production of humoral
antibodies, is considered the major kind of immunological defence in tuberculosis.
The granulomatous reaction is an immune re­sponse that limits the dissemination
of the organisms. The first exposure of the host to the tubercle bacillus may be
completely asymptomatic, with a small “Ghon focus” of inflammation seen in the lung.
A Ghon complex is a usually calcified healed granuloma in the lung and the draining
lymph nodes.
As an intracellular pathogen, Mtb has developed mechanisms to survive inside
host mononuclear phagocytic cells and thus evade the host immune response.
TB bacilli usually multiply first in pulmonary alveolar macrophages and draining
lymph nodes. Killing of infected macrophages progressively creates a primary tubercle.
Delayed cutaneous hypersensitivity develops and, together with other cellular host
immune reactions, leads to caseous necrosis of the primary complex. CD4+ T-cells
accumulate in large numbers in early granulomatous lesions, where CD8+ T-cells
later join them (13,14). The bacilli can spread to many parts of the body including
spleen, liver, meninges, bones, kidneys and lymph nodes, where they are sometimes a
source of overt extrapulmonary TB disease or, more commonly, remain dormant (15).
When the infection is brought under control, Mtb may remain in a dormant state in host
tissue for life. Reactivation of dormant bacilli is often associated with immunodeficiency,
for instance in patients with HIV/AIDS (16).
CD4+ T-cells producing interferon gamma (IFN-γ) and tumour necrosis factor-alpha
(TNF-α) play a major role in containment of TB infection, but they do not appear
to be the whole story. The TH1 type cytokines contribute to walling of Mtb inside
granulomas and the controlling of the evolution of disease. In addition, CD8+ T-cells
and T-cells expressing γδ T-cell receptors with specificity for small phosphorylated
ligands, and T- cells for glycolipids are stimulated (17). As long as the host remains
immunocompetent, granulomas can persist for years and can keep Mtb in a dormant
state. Individuals with deficient CD4+ T-cells or deficient IFN-γ signalling, suffer from
rapid evolution of TB disease (18), and individuals with latent TB infection treated with
anti-TNF-α antibodies are at increased risk of reactivation of TB disease (19,20).
5
A positive tuberculin skin test, erythema and induration 24 to 48 hours after injection
of purified protein derivative (PPD) antigens, has long been used as evidence of
active or latent TB infection, and as a sign of an immune response to BCG vaccine.
However, it has not been possible to establish a clear relationship between this delayedtype hypersensitivity reaction and protective immunity, and a positive test does not
necessarily indicate immunity to reinfection. Newer tests use IFN-γ release following
in vitro stimulation of peripheral blood mononuclear cells (PBMCs) to detect current
or past infection with Mtb; appropriate selection of antigens that are missing in BCG
for PBMC stimulation make these interferon gamma release assays (IGRAs) more
specific than the skin test with PPD (21,22). A number of antigens found in Mtb (e.g.
Ag85A and B, ESAT-6, CFP10, MPT64 and others) have been identified, that may play
a major role in protective cellular immunity and are being evaluated in new vaccines
for TB (see below).
6
The Immunological Basis for Immunization Series - Module 5: Tuberculosis - Update 2011
4. Characteristics of
BCG vaccines
By culturing an M. bovis strain isolated from a cow by Nocard in 1904 for a period of
13 years, and a total of 231 passages, on potato slices cooked in beef bile supplemented
with glycerol, physician Calmette and Guérin, a veterinarian, at the Institut Pasteur in
Lille, France, created a live, attenuated vaccine, bacillus Calmette-Guérin or BCG (23).
The first human vaccination by Weil-Halle in Paris in 1921 was given to an infant by
the oral route with several successive doses (24). Additional methods of administration
employed subsequently include intradermal, and percutaneous by multiple puncture
or scarification. Since 1974, BCG vaccination of infants has been included in the WHO
Expanded Programme on Immunization (EPI) resulting in more than three billion
cumulative vaccinations worldwide and approximately 100 million vaccinations per
year.
BCG has never been cloned and there are now multiple different BCG seed strains
(sub-strains) used in BCG manufacture. There have been many (WHO estimated 40 or
more in 1999) manufacturers of BCG around the world. The most widely-used strains
in international immunization programmes include: “Danish 1331” strain; “Moscow”
strain, and “Tokyo 172” strain. The use of other strains is largely limited to their country
of origin, e.g. “Moreau” strain (Brazil) or “Tice” strain (USA). In 1966, the WHO
Expert Committee on Biological Standardization established the first requirements
for BCG vaccine (WHO Expert Committee on Biological Standardization, 1966).
These requirements were subsequently revised (WHO Expert Committee on Biological
Standardization, 1987 and 1988). They outline procedures for production of BCG
vaccines to ensure potency, safety and efficacy, and describe certain tests which should
be done on the vaccine seeds and on the final vaccine itself. The WHO requirements
were designed to reduce the variability among BCG strains seen in clinical and animal
trials, by requiring each manufacturer to correlate laboratory test results with clinical
efficacy data.
Recent genomic analysis of BCG strains by Behr, Cole and others (25,26,27) has
documented multiple molecular changes between the introduction of Pasteur BCG
in 1921 and lyophilization of the BCG Pasteur 1173 strain in 1961. With continuous
passage in vitro prior to lyophilization of seed strains, all BCG strains presumably
continued to evolve, and possibly became over-attenuated (28). As recently shown
by genome sequencing, the original Pasteur BCG strain probably lost the deletion
region 1 (RD1) of M. bovis in the course of multiple passages used for the original
selection process. Loss of the RD1 region appears to have occurred in 1927–1931,
so that strains prior to that time contained mpt64 and those subsequent to 1931 did not.
Multiple other deletions probably contribute to phenotypic differences between BCG
strains, but their specific relevance to the protective efficacy and reactogenicity/safety
of different BCG strains is not entirely clear. Although there are clear reactogenicity
7
differences between strains (Adverse Events, see below), Brewer & Colditz (29) did
not find evidence based on limited data that strain differences are a significant factor
contributing to variable BCG vaccine efficacy against tuberculosis.
A WHO consultation on the characteristics of BCG strains in 2003 (30) discussed the
extensive evidence for molecular variation in BCG sub-strains, which was also reflected
in laboratory studies of their phenotypic and immunological properties.
Although there is good evidence to support the notion that the induced immune
response and protection afforded against tuberculosis differs between BCG vaccine
strains, currently there are insufficient data to favour or recommend one particular
strain (31).
Clinical and epidemiological studies also indicated differences in vaccine performance
in clinical trials, but the presence of many confounding variables made it difficult
to determine the influence of sub-strain. Nevertheless, the consultation reached a
consensus that for future use of BCG vaccines, both as conventional preparations for
routine vaccination, or as part of a prime-boost strategy and as genetically modified
strains, better characterization was needed, and that the current WHO requirements
for BCG vaccines were outdated and should be reviewed. Application of molecular
characterization methods to the modern production and quality control of BCG is
being undertaken, as well as efforts to determine the significance of known genetic
variations and genomic decay in relation to the quality and performance of current
BCG vaccines.
8
The Immunological Basis for Immunization Series - Module 5: Tuberculosis - Update 2011
5. Response to vaccination
with BCG vaccines
Clinical trials in the past have shown that BCG vaccine may induce some protec­tion
against tuberculosis. Vaccination with BCG spreads from the inoculation site via
the lymphatic system to local lymph nodes, and produces an immune response with
similar characteristics to that produced by natural infection with Mtb. As in the case of
natural tuberculosis infection, the resistance is cell-mediated and is largely attributable
to activation and destruction of macrophages by sensitized T-cells. BCG-induced
immunity develops about six weeks after vaccination.
Experimental studies indicate that the mechanism of protection by BCG vaccination
consists in reduc­tion of the haematogenous spread of bacilli from the site of primary
infection (32,33) mediated by memory, and T-lymphocytes induced by the first exposure
to BCG and effector T-lymphocytes induced by Mtb infection in BCG vaccinated
persons. There is no evidence that BCG reduces the risk of becoming infected with
tuberculo­sis bacilli, but the fact that it prevents disseminated childhood tuberculosis
is taken as an indication that it impairs the haematogenous spread of the bacillus.
This inhibition of the haemato­genous spread of bacilli thus reduces the risk of
disseminated primary disease and possibly also of disseminated disease due to
reactivation.
5.1
Route of administration of BCG vaccines
WHO recommends BCG vaccination by the intradermal route, generally by injection
in the deltoid insertion region of the upper arm with a 25 or 26 gauge needle.
The infant dose is generally 0.05 ml. Some countries, especially Japan, employ
percutaneous administration with special multipuncture devices. Percutaneous
administration methods are generally simpler to perform than intradermal, but are less
consistent with regard to the amount of vaccine delivered. Fewer adverse events were
reported following percutaneous administration of BCG compared with intradermal
administration (34,35). However, more positive delayed type hypersensitivity (DTH)
skin reactions and greater in vitro cellular responses to BCG were demonstrated when
the vaccine was given to healthy adults by intradermal rather than by percutaneous
administration (36). Similarly, greater lymphoproliferative and TH1-type cytokine
responses were found in newborns in response to intradermal BCG compared with
percutaneous BCG (37). A literature review comparing intradermal and percutaneous
routes reached the same conclusion, adding that the lower dosage inoculated
by the percutaneous route may account for the lower immune responses (38).
However, in a large randomized prospective trial that compared administration of
BCG vaccine by either the intradermal or percutaneous route in over 11 000 newborns,
there was no difference in TB events or adverse events, i.e. the two different routes
gave equivalent results (39).
9
BCG can also be delivered via the oral routes. Moreover, there is limited past experience
with injection by jet-injector and by aerosol (40–43). The original route recommended
by Calmette and used by Weil-Halle in 1921 was oral administration given three times
at 2-day intervals shortly after birth in doses ranging from 2 to 10 mg — approximately
109 –1010 colony-forming units (CFU) (44). Many infants immunized by the oral route
did not react to tuberculin skin testing or, not until after many months had passed.
Increased reactivity to skin testing could be accomplished by increasing the oral BCG
dose to 50–100 mg (45). Factors favouring intradermal (or percutaneous) vaccination
(46) include:
•
oral vaccination requires much larger doses of BCG for skin test conversion
(10–300 mg compared with 0.1 mg for intradermal) and hence was more
expensive;
•
it is more difficult to control the effective dose with oral administration,
as some bacilli are inactivated in the stomach and some pass through the intestinal
tract;
•
intradermal administration is much more efficient at inducing tuberculin
conversion;
•
there were reports of cervical lymphadenopathy attributed to oral
administration.
5.2
BCG vaccination scars
Following intradermal injection of BCG vaccine into humans, a papule with
induration appears within two to three weeks. The papule ulcerates at six to eight
weeks, followed by a scar at the end of three months. The presence of such a scar in the
appropriate place (commonly the right arm just below the insertion of the deltoid) has
been used as evidence for prior BCG vaccination. With multiple puncture percutaneous
inoculation of BCG, there are many small papules which disappear more quickly,
and often without scarring.
Although the size of the scar follows a simple dose-response, various other factors
have been shown to influence the size and shape of the scar, including: the technique of
vaccine administration (intradermal administration is more likely to leave a uniform scar,
while improper, i.e. subcutaneous, administration may not; the characteristics of
the recipient (keloid formation may be associated with race), and the strain of BCG
used.
A number of studies have reported on the agreement between a documented history
of BCG vaccine and the presence of a BCG scar at one or two years after vaccination.
In studies in Brazil and Peru, BCG scar was shown to be a highly sensitive indicator of
vaccination in children vaccinated during the first month and before three months of
age, and examined respectively up to three years of age and in early adolescence (47,48).
However, Malawian infants who were vaccinated when they were less than one month
old or 1–4 months old, 24% and 16% respectively, did not have recognizable scars
four years later (49). From the latter results it was concluded that, when the vaccine
had been administered in infancy as is recommended by WHO and widely practiced,
use of presence or absence of BCG scar years later was not a highly sensitive and reliable
indicator of prior vaccination status. There is also no evidence of a correlation between
increased BCG scar size and protection against either tuberculosis or leprosy (50).
10
The Immunological Basis for Immunization Series - Module 5: Tuberculosis - Update 2011
5.3
Delayed type hypersensitivity reactions and cell-mediated response
Delayed hypersensitivity tuberculin reaction, tuberculin skin test (TST) to screen
people for prior exposure to tuberculosis, is measured by injection intradermally of
purified protein derivative (PPD), 0.1 ml containing 5 TU, on the volar surface of
the forearm (Mantoux test). The results are read 48 to 72 hours later as the area of
induration, with at least 5 mm in diameter as the threshold for indication of a positive
reaction. An alternative skin puncture method (Heaf test) uses a multiple needle
device to inject PPD spread on the forearm; results are read 5–7 days later and defined
Grades 2 to 4 are interpreted as positive reactions (Table 1).
Table 1: Heaf testing and Mantoux equivalents
Heaf grade
Reaction
Mantoux equivalent
(mm induration)
Negative
No induration
0
1
4–6 papules
<5
2
Confluent papules form indurated ring
5–14
3
Central filling to form disc
>15
4
Disc > 10mm with or without blistering
>15
Tuberculin positivity appears following BCG vaccination and decreases with time at
a rate depending on the age of vaccination. When BCG is administered to newborns,
a high proportion have reactions after a few years <5 mm in size, so that under these
circumstances a large reaction to PPD (>10–15 mm) remains a useful test for exposure
to/infection with Mtb. The tuberculin reaction can be boosted by repeated PPD tests
as well as by BCG vaccination and by infection with environmental mycobacteria,
all of which, depending on the epidemiologic circumstances, can complicate the
interpretation of the TST.
A recent meta-analysis indicated that in subjects without active tuberculosis,
immunization with BCG significantly increases the likelihood of a positive tuberculin
skin test and that the effect of BCG vaccination on PPD skin-test results was less after
15 years. Positive skin tests with indurations of >15 mm are more likely to be the result
of tuberculous infection than of BCG vaccination (51).
5.4
Adverse events
Although BCG vaccines are considered safe, i.e. to have a favourable benefit-torisk relationship, they are among the most reactogenic vaccines in common use.
BCG induces a local ulcer which was more acceptable in the past when populations
were accustomed to the local lesions produced by smallpox vaccine. The local lesion
begins as a papule two or more weeks after vaccination. It generally proceeds to
ulceration and heals after several months. A scar (typically round and slightly depressed)
remains in most vaccinees and, is a useful albeit imperfect indicator of past vaccination.
The probability that BCG vaccine leaves a lasting scar is lower after vaccination in early
infancy than at older ages. BCG is not easy to administer as an intradermal injection in
infants; the commonest mistake is to administer the injection too deep (subcutaneous),
which may result in local injection-site abscesses.
11
Local reactogenicity differs between vaccines, varying with both sub-strains and
dose of viable bacilli. Pasteur 1173P2, Danish 1331 and Sweden (Gothenburg)
sub-strains have been found to be more reactogenic than the Tokyo 172, Glaxo 1077 or
Brazilian (Moreau) strains (52). Several reports of “outbreaks” of BCG reactions,
manifested as large ulcers and local lymphadenopa­thy or suppurative lymphadenitis,
followed changes, e.g. from less reactogenic Glaxo to more reactogenic Pasteur
strain vaccines (53,54). Other complications of BCG vaccination include osteitis/
osteomyelitis and disseminated BCGosis, which is mainly seen in children with severe
congenital or acquired immunodeficiencies, such as severe combined immunodeficiency
(SCID), chronic granulomatous disease, Di George syndrome and homozygous
complete or partial interferon gamma receptor deficiency, as well as HIV/AIDS.
Osteitis/osteomyelitis has been reported in the past, particularly in Scandinavia and
Eastern Europe/Russia, and has been associated with the Russian and Gothenburg
strains of BCG (55–58).
5.4.1 Management of reactions and complications
•
Local injection-site lesions: It is generally considered that even large local lesions
are best left untreated. Secondary infections at the injection site are unlikely. In
extreme cases, systemic treatment with erythromycin (daily for up to one month)
may be helpful.
•
Keloids: Keloids are difficult to treat. Simple surgical removal is likely to make
them worse. A combination of surgery, irradiation and drug treatment may be
effective, but should only be undertaken by a specialized practitioner.
•
Local lymph gland involvement: Axillary or cervical lymphadenitis will heal
spontaneously and it is best not to treat the lesion if it remains unattached
to the skin. An adherent or fistulated lymph gland may be drained and an
anti-tuberculous drug may be instilled locally. Systemic treatment with antituberculosis drugs is ineffective.
•
Rare severe complications: Rare complications, including lupus vulgaris,
erythema nodosum, iritis, osteomyelitis and generalized BCGosis should be
treated systemically with anti tuberculosis regimens, including isoniazid and
rifampicin.
5.4.2 BCG and HIV/AIDS
The relationship of HIV/AIDS to safety and efficacy of vaccination with BCG vaccines
has been a concern for a number of years. WHO had previously recommended that,
in countries with a high burden of tuberculosis, a single dose of BCG vaccine should
be given to all healthy infants as soon as possible after birth unless the child presented
with symptomatic HIV infection. However, recent reports showed that children who
were HIV-infected when vaccinated with BCG at birth, and who later developed
AIDS, were at increased risk of developing disseminated BCG disease (59,60,61).
Among these children, the benefits of potentially preventing severe TB are outweighed
by the risks associated with the use of BCG vaccine. Therefore, in November 2006,
the WHO Global Advisory Committee on Vaccine Safety (GACVS) revised its previous
recommendations concerning BCG vaccination of children infected with HIV (62),
such that children who are known to be HIV-infected, even if asymptomatic, should
no longer be immunized with BCG vaccine. , WHO accordingly provided the guidance
to facilitate national and local decisions on the use of BCG vaccine in infants at risk
for HIV infection (63).
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The Immunological Basis for Immunization Series - Module 5: Tuberculosis - Update 2011
5.5
Protective efficacy and duration of immunity
The protective efficacy of a vaccine is measured in terms of the percentage
reduction in disease among vaccinated individuals that is attributable to vaccination.
The best method for determining the protective efficacy of a vaccine is a prospective,
randomized, double-blind, placebo-controlled trial in previously unvaccinated
individuals. These studies are difficult and expensive; the last such trial was the
Chingleput trial in the 1960s (64). Many recent studies have used case-control
and contact follow-up methods (65,66,67). Both randomized controlled trials and
case-control studies have been evaluated on several occasions by meta-analyses and/or
systematic reviews (68–72). Although the WHO currently emphasizes BCG’s utility in
prevention of severe childhood TB disease, e.g. miliary tuberculosis and tuberculous
meningitis, the main public-health burden and source of spread of tuberculosis is
adult pulmonary disease. It is therefore reasonable to consider BCG vaccine efficacy
against severe childhood tuberculosis separately from that against adult tuberculosis,
leprosy and other mycobacterial diseases.
BCG and TB infection. There is some evidence to suggest that BCG does prevent
TB infection. In a recent outbreak of TB in a junior school in the United Kingdom,
the rate of TB infection, as detected by a reactive gamma interferon test, enzyme-linked
immunospot assay (ELISPOT), was 47% in unvaccinated children compared to 29%
in vaccinated children (73). Another study, in Istanbul, investigated risk factors for
tuberculosis infection in 979 child household contacts of 414 adult index patients with
sputum smear-positive pulmonary tuberculosis, and reported that BCG-vaccinated
children had an odds ratio of 0.60 (95% CI 0.43–0.83, p=0.003) for tuberculosis
infection (74).
Childhood tuberculosis, tuberculosis meningitis and miliary TB: There is evidence
that BCG provides consistent and appreciable protection against tuberculous
meningitis and miliary disease. A meta-analysis of five randomized controlled trials and
eight case-control studies indicated no significant heterogeneity and an average
protection of approximately 80% (86% with 95% CI: 65% to 95% for controlled trials
and 75% with 95% CI: 61% to 84% for case-control studies) (75). This was confirmed
by a meta-analysis of protection associated with vaccination in infancy as currently
recommended (76). Due to the rarity of these severe childhood TB events, most of
the data are from observational studies. For example, no cases of TB meningitis or
miliary TB were seen in the South India Chingleput trial (77,78), and only five cases of
miliary disease (all in the placebo group) were identified in the British Medical Research
Council (MRC) trial (78). Evidence of protection against pulmonary disease in children,
which is rarely smear-positive and hence difficult to diagnose is less consistent,
and appears to suggest lower protection in tropical than in temperate regions .
Adult pulmonary tuberculosis: This form of TB is responsible for the major
public-health burden of tuberculosis and is also associated with the greatest controversy
related to efficacy of BCG. A wide range of efficacy estimates, from 0 to approximately
80%, have come from prospective trials and observational case-control and contact
studies. This variability is highly significant (p<0.0001), indicating that the variation
reflects true biological differences and not just sampling errors. The reason, or reasons,
for the great differences remain unclear despite several hypothetical explanations
(see below). However, in a cohort of individuals vaccinated at ages 1–20 in the 1930s,
long-term follow-up revealed approximately 52% efficacy of a single BCG vacccination
13
against adult TB lasting for 50 to 60 years (79), and a report from Brazil described
substantial protection (39% efficacy, CI: 9%–58%) lasting 15–20 years following BCG
given to newborns against all forms of TB (80).
A major current TB control concern is increasing multi drug-resistant tuberculosis
(MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). Interestingly,
an observational study in Brazil found a decreased risk of TB disease in contacts of
MDR-TB cases was associated with previous BCG vaccination, including in persons
with prolonged exposure to MDR-TB cases (81). More information is needed regarding
BCG protection against drug-resistant strains of TB.
Tuberculosis and HIV/AIDS: Protection against clinical TB appears to be diminished.
Infection with HIV severely impairs the BCG-specific T-cell response during the first
year of life. Thus BCG provides little, if any, vaccine-induced benefit in HIV-infected
infants (82).
Leprosy and other mycobacterioses: Numerous controlled trials, cohort and
case-control studies and observational studies have shown some protection against
leprosy associated with BCG. A recent meta-analysis of six controlled trials,
two cohort studies and 14 case-control studies has reported summary protective effects
of 43 (27%–55%), 62 (53%–69%) and 58 (47%–67%), respectively (83). The highest
efficacy estimates have been reported from Kenya, Malawi and Uganda) (84,85,86).
Three different studies have evaluated protection by the same BCG vaccines against
tuberculosis and leprosy in the same population, and in each case the protection was
appreciably greater against leprosy (87,88,89). Importantly, there is evidence that
BCG vaccines impart as much protection against lepromatous as they do against the
tuberculoid forms of the disease, although this was not observed in the Chingleput trial
population (89). This has important public-health implications, given that lepromatous
disease is the most severe and is thought to be responsible for most transmission of
M. leprae in the community. Protection against leprosy provided by BCG given to
infants, may last for 30 years or longer (90).
There is also evidence that BCG provides some protection against Buruli ulcer
(M. ulcerans infection) (91,92), and against glandular disease attributable to various other
environmental mycobacteria, in particular M. avium-intracellulare. This evidence is
based upon observations in Sweden (93) and the Czech Republic (94), where increases in
childhood glandular mycobacterioses were identified in cohorts born after infant BCG
was discontinued. In Sweden among children under five years of age the protection
appeared to be in the order of 85%.
Non-specific immune stimulation: Mycobacteria and their cell-wall constituents
have long been known to exert non-specific immune stimulation. Complete Freund’s
adjuvant, a potent, albeit highly reactogenic, immune stimulator used in experimental
animal systems, contains killed mycobacteria (95,96). Live BCG is being used to
successfully treat non muscle-invasive bladder carcinoma, with an efficacy superior to
chemotherapy in terms of completeness of response and disease-free survival period
(97). Moreover, there are indirect indications that BCG provides a general survival
benefit to individuals who respond to vaccination with the development of a positive
tuberculin skin test (TST) or a BCG scar (98).
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The Immunological Basis for Immunization Series - Module 5: Tuberculosis - Update 2011
Booster doses: Despite the widespread use of boosters in many countries, there has
been very little formal evaluation of their utility. Analyses of data from Hungary (99)
and Poland (100,101) were consistent with revaccination providing some protection,
but were based on small numbers and inappropriate controls and were therefore
not convincing. A case-control study in Chile failed to find evidence of increased
protection associated with an increased number of BCG scars (102). In Finland,
no increase in tuberculosis was observed since that country discontinued revaccination
of schoolchildren in 1990, although overall case numbers are too small for convincing
analysis (103). A controlled trial to evaluate the efficacy of a BCG booster in protection
against tuberculosis was carried out in Malawi, and found no evidence for protection
(104). On the basis of such data, WHO did not encourage revaccination in 1995 (105).
A more recent controlled trial in Brazil (106) failed to show evidence of increased
protection by revaccination in schoolchildren aged 7 to 14 years despite evidence of
an increase in immune response following revaccination (107). However, it has been
shown that oral administration of BCG, Moreau sub-strain, does boost the cell-mediated
immune response measured in PBMCs by ELISPOT in adults who received intradermal
BCG in childhood or adolescence (108).
Although there is no convincing evidence that BCG boosters are effective in preventing
tuberculosis, several studies have supported their utility against leprosy. A randomized
trial in Malawi and case-control studies in Venezuela (109) and Myanmar (110) have
shown an increase in protection associated with increasing numbers of BCG doses
(or BCG vaccine scars). The Malawi study is of interest because it was a formal trial
and because no protection against tuberculosis was observed by either an initial
or a repeated dose of BCG, despite the dose-dependent protection against leprosy.
However, in a more recent Brazilian study, no increase in protection against leprosy was
observed associated with a booster BCG vaccination (111). Taken together the evidence
is not entirely consistent but suggests that BCG boosters may give increased protection
sometimes, where an initial dose is effective, but not otherwise. The question of utility
of boosters is thus referred to the more basic issue of the inconsistent behaviour of an
initial BCG vaccination.
Duration of immunity
The duration of protection after neonatal BCG vaccination is not well known but
it is commonly believed to decline gradually to non-significant levels over 10 to
20 years (71). BCG vaccine is not thought to prevent reactivation of latent TB,
a main source of adult pulmonary disease and Mtb dissemination in the community.
Hence, neonatal BCG vaccination is not considered to be effective in preventing
acquisition or transmission of adult pulmonary TB. However, a long-term follow-up
of a randomized, prospective, controlled BCG trial in the 1930s revealed approximately
52% efficacy of a single BCG vaccination against adult TB lasting for 50 to 60 years in
a cohort of individuals vaccinated at ages 1–20 (79), and Barreto et al (2005) described
substantial protection (39% efficacy, CI: 9%–58%) lasting 15–20 years following
BCG given to newborns against all forms of TB (79). Studies of the immune response
produced by MVA85A, a new TB vaccine candidate for boosting neonatal BCG later
in life, have also produced evidence of very durable immunogical memory following
childhood or adolescent BCG vaccination (112).
15
Delaying BCG vaccination for a few weeks appears to be associated with a better
immune response. A study from South Africa showed that infants who received delayed
BCG vaccination demonstrated higher frequencies of BCG-specific CD4 T-cells,
particularly polyfunctional T-cells co-expressing IFN-gamma, TNF-alpha and IL-2,
and most strikingly at one year of age (113). However, the immune benefit of delaying
BCG vaccination must be weighed against the interim risk of an infection with Mtb,
in particular in TB high endemicity areas in general, or in children born to households
with active TB cases.
Reasons for variable BCG efficacy
The variation in protection by BCG in clinical trials against pulmonary tuberculosis
and against leprosy has attracted much attention, but few clear answers (114,115).
Several of the suggested hypotheses are below.
Differences between BCG vaccines, both in genetics of multiple sub-strains and
physical properties of vaccine preparations, including effects of manufacturing method,
multiple passages in production, freeze-drying and ratio of killed to live mycobacteria.
Although there is clear evidence of BCG strain variation association with reactogenicity
and adverse effects, there is no firm evidence based on limited data that strain differences
are a significant factor contributing to variable BCG vaccine efficacy against tuberculosis
(29).
Environmental mycobacteria are ubiquitous. There is evidence (a) from human and
animal studies, that exposure to environmental mycobacteria can provide some degree
of protection against subsequent challenge with tubercle bacilli (116), i.e. masking
of BCG-mediated protection; (b) from animal studies, that protection by BCG is
reduced in animals that have already received some protection by prior exposure to
environmental mycobacteria (117), and (c) that superinfection with environmental
mycobacteria can impair established BCG immunity (118), i.e. blocking of
BCG-mediated protection. Furthermore, BCG efficacy tends to be lower in populations
living in warmer and wetter regions (closer to the Equator), in particular in rural areas
where exposure to environmental mycobacteria is greater. This circumstantial evidence
suggests that exposure to environmental mycobacteria may be responsible for some of
the variation in BCG efficacy.
Human genetics. There is evidence that several genes that control cellular immune
mechanisms, including human leukocyte antigen DR (HLA-DR) and HLA-DQ,
vitamin D receptor and IFN-γ receptor polymorphisms, and natural resistance
associated monocyte protein (NRAMP) influence susceptibility to tuberculosis and
other mycobacterial infections (119–122). Hence it has been conjectured that population
genetic differences might explain some of the variable efficacy behaviour of BCG.
However, meta-analysis has shown that many of these studies are methodologically
flawed (123). Moreover, systematic review has demonstrated that these genetic
associations may be limited to certain populations (124)., Appropriate studies are
therefore needed, for example, comparing the frequency of genetic determinants
between protected and unprotected vaccinees.
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The Immunological Basis for Immunization Series - Module 5: Tuberculosis - Update 2011
Differences in Mtb were first suggested as an explanation for the failure of two different
BCGs in the Chingleput trial (125), but this hypothesis could not be supported by
animal challenge studies. Interest in the hypothesis has been sustained by increased
evidence of genetic heterogeneity of Mtb strains (126,127), but data from appropriate
studies are not available to address this possible factor in variable BCG efficacy.
Natural history of tuberculosis. It has also been suggested that protection by BCG
might reflect the local natural history of tuberculosis and, as such, be greater against
primary infection or (endogenous) reactivation disease than against disease attributable
to exogenous reinfection. The relevance of this hypothesis involves not only immune
mechanisms but also the level and temporal trend infection risk; a declining risk of
infection, as has occurred in many communities, will be associated with an increase
in the average age at infection and a decrease in the probability of reinfection (127).
Each of these trends may have important implications for protection by BCG.
Despite the existence of a large body of literature discussing these various hypotheses,
there is still no consensus regarding the variable efficacy of BCG in different studies
and populations.
17
6. Future prospects
In recent years there has been a dramatic increase in the number of candidate TB vaccines
evaluated in research laboratories. Better understanding of the immunological deficits
of BCG and impressive progress in knowledge of mycobacterial genomics have paved
the way for promising new products. What is needed in terms of new TB vaccines is
probably not one, but more likely two, or even three products with different profiles:
a priming vaccine to replace BCG to be given early in life and before exposure to MTB;
another one to boost antimycobacterial immune responses either early or later in life
when latent TB is potentially installed, and possibly a therapeutic vaccine against active
TB. It is unlikely that a vaccine can be identified which covers several or all of these
functional profiles. Priming vaccines are intended for use in newborns or young infants,
i.e. at a time-point when the individual’s immune system has not yet been exposed to
natural infection with Mtb or other mycobacteria. Booster TB vaccines are vaccines
that ideally can be given together with other childhood vaccines during the first year
of life, but also at almost any time-point, to schoolchildren, adolescents or adults.
TB vaccines to be used against firmly established latent TB may require a different
set of antigens than the ones that are expected to be active against primary infection,
and the type of immune response induced may differ. Also, the fact that later in life
TB can arise both from endogenous reactivation and from exogenous reinfection
may need to be reflected in the antigenic composition of a potent booster TB vaccine.
At least one of the new booster TB vaccine candidates has been shown to boost
pre-existing anti-mycobacterial T-cell immune responses, but it is currently unknown
if these booster responses will actually translate into improved protection against
TB-induced pathologies. Therapeutic vaccines, i.e. those that are to be given to individuals
with active TB disease, are usually intended as adjunct to antibiotic treatment, with the
aim of shortening the duration of anti-TB chemotherapy (128).
An argument can be made that since BCG is widely used, has a good safety record
and provides some protection against non-pulmonary forms of TB in infants,
we should develop a better BCG. Several approaches are currently underway to
genetically improve BCG (129,130,131). Currently however, it is unknown which
antigenic shortcomings render conventional BCG suboptimal as a vaccine. The fact
that BCG’s ‘parent’ organism, M. bovis, has primarily evolved in an adaptation to
bovine rather than human hosts has sparked numerous efforts to attenuate the actual
human pathogen Mtb. Examples include vaccine candidates carrying mutation in
genomic loci responsible for metabolic, regulatory or virulence pathways (132,133).
Non-living TB vaccine candidates include protein subunit and virus-vectored vaccines.
Protein subunit vaccines have been shown to be powerful vaccines against other
diseases, e.g. hepatitis B or human papillomavirus and, due to their stability, ease of
standardization and safety in the immunocompromized host, are certainly the first
choice of the vaccine industry. In this context, proteins secreted by Mtb have received
special attention as subunit vaccines because such antigens are among the first molecules
18
The Immunological Basis for Immunization Series - Module 5: Tuberculosis - Update 2011
of the pathogen to be encountered by the human immune system after infection.
Several adjuvanted protein subunit vaccines were in clinical trials during 2010 (134,135).
Virus-vectored approaches are currently receiving attention employing vectors that
have already been used for development of HIV/AIDS and malaria vaccines. One of
these, a vaccine based on a genetically modified version of the vaccinia virus, is the
most advanced of all the new TB vaccine candidates, with a test-of concept (ToC)
clinical trial ongoing in 2010 to establish preliminary efficacy (136). Another vaccine
candidate, based on an adenovirus platform (137), had also entered a Phase IIb ToC
trial in 2010 and, if proven efficacious, was expected to be ready for licensure sometime
between 2018 and 2020. The current plans for use of virus-vectored vaccines or protein
subunit vaccines imply their clinical evaluation and eventual use as either ‘early’ boosters
of a neonatal vaccination with live mycobacteria at one to six months of age, or as
‘late’ boosters in a post-exposure situation in schoolchildren, adolescents or adults.
However, there are also proponents for an inversed sequence, i.e. a non-living vaccine at
birth followed by a booster vaccination with BCG or a new live vaccine at 3–4 months
of age (138). Such an approach aims to avoid the severe adverse events observed in some
HIV-infected infants who had been vaccinated with BCG at birth — a time-point at
which HIV infection cannot be diagnosed.
19
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29
The World Health Organization has provided
technical support to its Member States in the
field of vaccine-preventable diseases since
1975. The office carrying out this function
at WHO headquarters is the Department of
Immunization,Vaccines and Biologicals (IVB).
IVB’s mission is the achievement of a world
in which all people at risk are protected
against vaccine-preventable diseases.
The Department covers a range of activities
including research and development,
standard-setting, vaccine regulation and
quality, vaccine supply and immunization
financing, and immunization system
strengthening.
These activities are carried out by three
technical units: the Initiative for Vaccine
Research; the Quality, Safety and Standards
team; and the Expanded Programme on
Immunization.
The Initiative for Vaccine Research guides,
facilitates and provides a vision for worldwide
vaccine and immunization technology
research and development efforts. It focuses
on current and emerging diseases of global
public health importance, including pandemic
influenza. Its main activities cover: i ) research
and development of key candidate vaccines;
ii ) implementation research to promote
evidence-based decision-making on the early
introduction of new vaccines; and iii ) promotion
of the development, evaluation and future
availability of HIV, tuberculosis and malaria
vaccines.
The Quality, Safety and Standards team
focuses on supporting the use of vaccines,
other biological products and immunizationrelated equipment that meet current international norms and standards of quality
and safety. Activities cover: i ) setting norms
and standards and establishing reference
preparation materials; ii ) ensuring the use of
quality vaccines and immunization equipment
through prequalification activities and
strengthening national regulatory authorities;
and iii ) monitoring, assessing and responding
to immunization safety issues of global
concern.
The Expanded Programme on Immunization
focuses on maximizing access to high
quality immunization services, accelerating
disease control and linking to other health
interventions that can be delivered during
immunization contacts. Activities cover:
i ) immunization systems strengthening,
including expansion of immunization services
beyond the infant age group; ii ) accelerated
control of measles and maternal and
neonatal tetanus; iii ) introduction of new and
underutilized vaccines; iv ) vaccine supply
and immunization financing; and v ) disease
surveillance and immunization coverage
monitoring for tracking global progress.
The Director’s Office directs the work of
these units through oversight of immunization
programme policy, planning, coordination and
management. It also mobilizes resources and
carries out communication, advocacy and
media-related work.
Department of Immunization, Vaccines and Biologicals
Family and Community Health
World Health Organization
20, Avenue Appia
CH-1211 Geneva 27
Switzerland
E-mail: [email protected]
Web site: http://www.who.int/immunization/en/
ISBN 978 92 4 150241 2