Evaluation of serogroup A meningococcal vaccines in Africa: a demonstration project.
ABSTRACT Endemic and epidemic meningococcal disease constitutes a major public-health problem in African countries of the 'meningitis belt' where incidence rates of the disease are many-fold higher (up to 25 cases per 100,000 population) than those in industrialized countries, and epidemics of meningococcal disease occur with rates as high as 1,000 cases per 100,000 people. Using the precedent established during the licensing of conjugate vaccines against Haemophilus influenzae type b and serogroup C meningococci and components of currently-licensed meningococcal polysaccharide vaccines, new meningococcal conjugate vaccines will likely be licensed using immunological endpoints as surrogates for clinical protection. Post-licensure evaluation of vaccine effectiveness will, therefore, be of increased importance. One vaccine being developed is the serogroup A meningococcal (Men A) conjugate vaccine produced by the Meningitis Vaccine Project (MVP), a partnership between the World Health Organization and the Program for Applied Technology in Health. This vaccine will likely be the first meningococcal conjugate vaccine introduced on a large scale in Africa. This paper summarizes the general steps required for vaccine development, reviews the use of immunogenicity criteria as a licensing strategy for new meningococcal vaccines, and discusses plans for evaluating the impact of a meningococcal A conjugate vaccine in Africa. Impact of this vaccine will be measured during a vaccine-demonstration project that will primarily measure the effectiveness of vaccine. Other studies will include evaluations of safety, vaccine coverage, impact on carriage and herd immunity, and prevention-effectiveness studies.
- SourceAvailable from: Martin C J Maiden[Show abstract] [Hide abstract]
ABSTRACT: The development and implementation of conjugate polysaccharide vaccines against invasive bacterial diseases, specifically those caused by the encapsulated bacteria Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae, has been one of the most effective public health innovations of the last 25 years. These vaccines have resulted in significant reductions in childhood morbidity and mortality worldwide, with their effectiveness due in large part to their ability to induce long-lasting immunity in a range of age groups. At the population level this immunity reduces carriage and interrupts transmission resulting in herd immunity; however, these beneficial effects can be counterbalanced by the selection pressures that immunity against carriage can impose, potentially promoting the emergence and spread of virulent vaccine escape variants. Studies following the implementation of meningococcal serogroup C vaccines improved our understanding of these effects in relation to the biology of accidental pathogens such as the meningococcus. This understanding has enabled the refinement of the implementation of conjugate polysaccharide vaccines against meningitis-associated bacteria, and will be crucial in maintaining and improving vaccine control of these infections. To date there is little evidence for the spread of virulent vaccine escape variants of the meningococcus and H. influenzae, although this has been reported in pneumococci.Philosophical Transactions of The Royal Society B Biological Sciences 08/2013; 368(1623):20120147. · 6.23 Impact Factor
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ABSTRACT: An affordable, highly immunogenic Neisseria meningitidis serogroup A meningococcal conjugate vaccine (PsA-TT) was licensed for use in sub-Saharan Africa in 2009. In 2010, Burkina Faso became the first country to implement a national prevention campaign, vaccinating 11·4 million people aged 1-29 years. We analysed national surveillance data around PsA-TT introduction to investigate the early effect of the vaccine on meningitis incidence and epidemics. We examined national population-based meningitis surveillance data from Burkina Faso using two sources, one with cases and deaths aggregated at the district level from 1997 to 2011, and the other enhanced with results of cerebrospinal fluid examination and laboratory testing from 2007 to 2011. We compared mortality rates and incidence of suspected meningitis, probable meningococcal meningitis by age, and serogroup-specific meningococcal disease before and during the first year after PsA-TT implementation. We assessed the risk of meningitis disease and death between years. During the 14 year period before PsA-TT introduction, Burkina Faso had 148 603 cases of suspected meningitis with 17 965 deaths, and 174 district-level epidemics. After vaccine introduction, there was a 71% decline in risk of meningitis (hazard ratio 0·29, 95% CI 0·28-0·30, p<0·0001) and a 64% decline in risk of fatal meningitis (0·36, 0·33-0·40, p<0·0001). We identified a statistically significant decline in risk of probable meningococcal meningitis across the age group targeted for vaccination (62%, cumulative incidence ratio [CIR] 0·38, 95% CI 0·31-0·45, p<0·0001), and among children aged less than 1 year (54%, 0·46, 0·24-0·86, p=0·02) and people aged 30 years and older (55%, 0·45, 0·22-0·91, p=0·003) who were ineligible for vaccination. No cases of serogroup A meningococcal meningitis occurred among vaccinated individuals, and epidemics were eliminated. The incidence of laboratory-confirmed serogroup A N meningitidis dropped significantly to 0·01 per 100 000 individuals per year, representing a 99·8% reduction in the risk of meningococcal A meningitis (CIR 0·002, 95% CI 0·0004-0·02, p<0·0001). Early evidence suggests the conjugate vaccine has substantially reduced the rate of meningitis in people in the target age group, and in the general population because of high coverage and herd immunity. These data suggest that fully implementing the PsA-TT vaccine could end epidemic meningitis of serogroup A in sub-Saharan Africa. None.The Lancet Infectious Diseases 07/2012; 12(10):757-64. · 19.45 Impact Factor
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ABSTRACT: Major epidemics of serogroup A meningococcal meningitis continue to affect the African meningitis belt. The development of an affordable conjugate vaccine against the disease became a priority for World Health Organization (WHO) in the late 1990s. Licensing of meningococcal vaccines has been based on serological correlates of protection alone, but such correlates might differ in different geographical regions. If high pre-vaccination antibody concentrations/titers impacts on the response to vaccination and possibly vaccine efficacy, is not clearly understood. We set out to define the pre-vaccination Meningococcal group A (Men A) antibody concentrations/titers in The Gambia and study their impact on the immunogenicity of Men A containing vaccines. Data from subjects originally enrolled in studies to test the safety and immunogenicity of the MenA vaccine recently developed for Africa meningococcal A polysaccharide conjugated to tetanus toxoid, MenAfriVac(®) (PsA-TT) were analyzed. Participants had been randomized to receive either the study vaccine PsA-TT or the reference quadrivalent plain polysaccharide vaccine containing meningococcal groups A, C, W, and Y, Mencevax(®) ACWY, GlaxoSmithKline (PsACWY) in a 2:1 ratio. Venous blood samples were collected before and 28 days after vaccination. Antibodies were assayed by enzyme-linked immunosorbent assay (ELISA) for geometric mean concentrations and serum bactericidal antibody (SBA) for functional antibody. The inter age group differences were compared using ANOVA and the pre and post-vaccination differences by t test. Over 80% of the ≥19 year olds had pre-vaccination antibody concentrations above putatively protective concentrations as compared to only 10% of 1-2 year olds. Ninety-five percent of those who received the study vaccine had ≥4-fold antibody responses if they had low pre-vaccination concentrations compared to 76% of those with high pre-vaccination concentrations. All subjects with low pre-vaccination titers attained ≥4-fold responses as compared to 76% with high titers where study vaccine was received. Our data confirm the presence of high pre-vaccination Men A antibody concentrations/titers within the African meningitis belt, with significantly higher concentrations in older individuals. Although all participants had significant increase in antibody levels following vaccination, the four-fold or greater response in antibody titers were significantly higher in individuals with lower pre-existing antibody titers, especially after receiving PsA-TT. This finding may have some implications for vaccination strategies adopted in the future.Vaccine 05/2014; 32(33). · 3.49 Impact Factor
J HEALTH POPUL NUTR 2004 Sep;22(3):275-285
ISSN 1606-0997 $ 5.00+0.20
© 2004 ICDDR,B: Centre for Health and Population Research
Evaluation of Serogroup A Meningococcal
Vaccines in Africa: A Demonstration Project
Montse Soriano-Gabarró1,2, Nancy Rosenstein1, and F. Marc LaForce3
1Meningitis and Special Pathogens Branch, Centers for Disease Control and Prevention,
C-09 1600 Clifton Road, Atlanta, GA 30333, USA, 2Departamento de Salud Pública,
Universidad de Barcelona, Casanova 143, 08036, Barcelona, Spain, and
3Meningitis Vaccine Project, Program for Appropriate Technology in Health,
13, Chemin du Levant, Bâtiment Avant-Centre, 01210 Ferney-Voltaire, France
Endemic and epidemic meningococcal disease constitutes a major public-health problem in African
countries of the 'meningitis belt' where incidence rates of the disease are many-fold higher (up to 25
cases per 100,000 population) than those in industrialized countries, and epidemics of meningococcal
disease occur with rates as high as 1,000 cases per 100,000 people. Using the precedent established
during the licensing of conjugate vaccines against Haemophilus influenzae type b and serogroup C
meningococci and components of currently-licensed meningococcal polysaccharide vaccines, new
meningococcal conjugate vaccines will likely be licensed using immunological endpoints as surrogates
for clinical protection. Post-licensure evaluation of vaccine effectiveness will, therefore, be of
increased importance. One vaccine being developed is the serogroup A meningococcal (Men A) con-
jugate vaccine produced by the Meningitis Vaccine Project (MVP), a partnership between the World
Health Organization and the Program for Applied Technology in Health. This vaccine will likely be
the first meningococcal conjugate vaccine introduced on a large scale in Africa. This paper summa-
rizes the general steps required for vaccine development, reviews the use of immunogenicity criteria
as a licensing strategy for new meningococcal vaccines, and discusses plans for evaluating the impact
of a meningococcal A conjugate vaccine in Africa. Impact of this vaccine will be measured during a
vaccine-demonstration project that will primarily measure the effectiveness of vaccine. Other studies
will include evaluations of safety, vaccine coverage, impact on carriage and herd immunity, and pre-
Key words: Neisseria meningitidis; Meningococcal vaccines; Conjugate vaccines; Vaccine development;
Immunization; Evaluation studies; Impact studies; Africa
One of the most significant accomplishments in medi-
cine and public health is the development and use of
vaccines for the prevention and control of infectious
diseases of major public-health concern. This preventive
Correspondence and reprint requests should be addressed to:
Dr. Montse Soriano-Gabarró
Meningitis and Special Pathogens Branch
Centers for Disease Control and Prevention
C-09 1600 Clifton Road
Atlanta, GA 30333
Fax 404 639 3059
approach is fundamental to improving health in develop-
ing countries, where curative services are scarce and dis-
proportionately costly (1). Since the 1980s, consider-
able progress has been made in introducing and improv-
ing immunizations, especially among young children.As
a result, almost three million lives are saved each year,
and 750,000 children are saved from disability (2).
The main antigens used in immunization programmes
in developing countries include those against measles,
polio, pertussis, diphtheria, tetanus, and tuberculosis.
Introducing newer vaccines has proven more difficult.
One group of vaccines currently being developed and
Soriano-Gabarró M et al.
J Health Popul Nutr Sep 2004
introduced in these countries are conjugate vaccines
against the three main causes of bacterial meningitis
and pneumonia: Streptococcus pneumoniae, Haemophilus
influenzae type b (Hib), and Neisseria meningitidis (3).
These three bacteria, responsible for more than one
million deaths per year, are a major cause of morbidi-
ty among children and young adults (4). Of these three
bacteria, only N. meningitidis causes major epidemic
disease, particularly in the 'African meningitis belt', an
area that extends from Ethiopia in the East to Senegal
in the West (5,6). Most of these epidemics are caused
by serogroup A meningococci. Mortality from menin-
gococcal meningitis is 8-12%, and 12-15% of survivors
have long-term sequelae, such as hearing loss, neuro-
logical disability, or limb amputation (7,8).
In the African meningitis belt, rates of meningococcal
disease are many-fold higher (up to 25 cases per 100,000
people) than those in industrialized countries, and epi-
demics of meningococcal disease in meningitis-belt
countries occur with rates as high as 1,000 cases per
100,000 people. Disease occurs in annual cycles with
large-scale epidemics every 8-12 years (5,6). In addi-
tion, during the past few decades, major epidemics
have been reported in countries which are not usually
considered part of the African meningitis belt, e.g.
Kenya, Tanzania, and Rwanda (9). In 1996, the largest
outbreak ever reported occurred in the meningitis belt;
the total number of cases reported to the World Health
Organization (WHO) (probably a substantial underes-
timate) was 152,813, with 15,783 deaths (10).
Meningococci are classified into serogroups accor-
ding to immunologic reactivity of their capsular poly-
saccharides that are the basis for currently-licensed menin-
gococcal vaccines. Worldwide, serogroups A, B, and C
account for most cases of meningococcal disease with
serogroups B and C responsible for the majority of dis-
ease in Europe and the Americas and serogroups Aand
C predominating throughout Asia and Africa. In the
African meningitis belt, meningococcal disease is usually
caused by serogroup A(5). In addition, epidemics caused
by serogroup C, and more recently by serogroup W-135,
have been reported (11,12).
Because of its epidemic potential and high endemic
burden, meningococcal disease is a priority disease for
prevention and control in Africa. In this paper, we review
the general steps required to develop meningococcal
vaccines and discuss plans for evaluation of a new menin-
gococcal A conjugate vaccine in Africa.
The success of a vaccine in preventing disease depends
on potency, effectiveness, safety, and appropriate dis-
tribution and use. The vaccine-development process
takes several years and includes multiple disciplines,
such as pre-clinical and clinical testing, and regulatory
issues (13-15). Pre-clinical testing focuses on detailed
physico-chemical characterization of the vaccine and
safety and immunogenicity in animals to support its
use in humans. Once the safety and biological activity
of the investigational vaccine has been evaluated in ani-
mals, phased clinical studies are conducted in humans.
Clinical trials in humans include phase I, phase II,
and phase III studies (Table). The overall goal of these
clinical studies is to establish: (a) the clinical tolerance
and safety of the investigational vaccine, (b) the type,
level, and persistence of immune response after its admi-
nistration to a representative target population using a
defined administration schedule, and (c) the clinical
safety and efficacy of the investigational vaccine, where
efficacy is defined as the outcome of clinical protec-
tion and/or immunological surrogate endpoints in
phase III clinical trials (15). Phase III clinical studies
involve the recruitment of a large number of study par-
ticipants who will receive the investigational vaccine and
another group of study participants who will receive an
inert substance or unrelated vaccine (placebo); efficacy
of vaccine is calculated directly from the number of
cases occurring in each study group. Phase III random-
ized, controlled clinical trials are conducted under ideal
study conditions to estimate the best possible efficacy
and constitute the best approach for evaluating health
interventions. However, because large samples and rela-
tively prolonged and complete follow-up may be nece-
ssary for adequate statistical power, these studies often
are very expensive and require lengthy follow-up.
While the first vaccine developed for a given disease
is frequently evaluated in a phase III randomized, pla-
cebo-controlled trial, newer vaccine formulations in
the United States and Europe have been licensed based
on active-control immunogenicity trials, where the
licensed vaccine is administered to the control group,
and the experimental group receives the new formula-
tion. Measurements of immunogenicity of capsular
polysaccharide-based vaccines that are surrogates for
protection are calculated through enzyme antibody con-
centrations, e.g. enzyme-linked immunoabsorbent assay
(ELISA), antibody avidity, and functional antibody assays,
Evaluation of serogroup A meningococcal vaccines in Africa
e.g. serum bactericidal activity and opsophagocytic tests.
In an active-control immunogenicity trial, 'non-inferiority'
of the new vaccine may be evaluated by confirming that
the effects in the investigational vaccine group are no
worse than that in the control vaccine group by more than
prescribed amounts (15-19). Polysaccharide and conju-
gate meningococcal vaccines and conjugate Hib vaccines
have been licensed based on such studies (20-23).
POST-LICENSURE PHASE IV
Following licensure, evaluation of safety and effectiveness
of vaccine is referred to as post-marketing surveillance or
post-licensure phase IV studies. The purpose of phase IV
studies is to evaluate the performance and impact of a vac-
cine in the large target population under conditions of rou-
tine use. The main objective is to evaluate the effective-
ness of vaccine, defined as the impact of the vaccine in a
population, where the effects of vaccination will also dep-
end on coverage, distribution of the vaccine and its
efficacy in preventing disease and colonization (24).
The effectiveness of vaccine is measured through
case-control and cohort studies, which constitute useful
alternatives to placebo-controlled vaccine-efficacy trials.
These studies measure the relative risk or odds ratio of
disease among the vaccinated compared to the unvacci-
nated. Their design is based on four critical aspects: (a)
case definitions, (b) case findings, (c) ascertainment of
vaccination status, and (d) assuring comparability of vac-
cinated and unvaccinated groups (25).
Table. Main characteristics of phase I, II, and III studies in human clinical research (16)
To evaluate clinical tolerability and
reactogenicity of vaccine
Population under studyStudy duration
To provide preliminary information
on biological activity of elicited anti-
bodies to predict vaccine efficacy
using standardized serological assays
To further evaluate safety
To evaluate immunological activity,
and dose-ranging and 'optimal'
schedules of vaccination
To provide clinical evidence of con-
sistency of vaccine manufacturing
To demonstrate safety, efficacy, and
clinical protection of vaccine in a
To evaluate immunogenicity using
standardized serological assays
To assess duration of protection
To evaluate impact of vaccine at
population level, where effects of
vaccination also depend on cover-
age, distribution of vaccine, and effi-
cacy preventing disease and colo-
Small number of highly-selected
normal healthy adult volunteers
Larger numbers of individuals
who may more closely resemble
the ultimate target population
Large sample of individuals
from the intended target popula-
Overall population under sur-
Restricted sample of the popula-
tion required for vaccine-effec-
tiveness case-control study
Long duration for
Soriano-Gabarró M et al.
J Health Popul Nutr Sep 2004
Because these studies are non-experimental, they are
particularly subject to bias. To keep potential biases to a
minimum, case definitions used in post-licensure stud-
ies should be sensitive and specific for gaining the
most precise estimate. When sensitivity is low, it will
be important that case definitions have equal sensitivity
in vaccinees and non-vaccinees and that case definition
is specific through laboratory confirmation of cases.
Specificity of case definition is usually more critical
than sensitivity for accurately determining the effective-
ness of vaccine. Appropriate case-finding also dimin-
ishes the potential of bias on cohort and case-control
studies. Ideally, population-based case-finding or sur-
veillance should be used. For severe diseases, such as
meningitis, provider-based surveillance systems may
be adequate, provided all patients, vaccinated or unvac-
cinated, seek medical care. Ascertainment and confirma-
tion of vaccination status is another important aspect to
consider for diminishing bias. Vaccination status should
be verified using vaccination cards and vaccination
registries. If vaccination records are lost or inaccurate,
study participants can be misclassified in regard to
their vaccination status, which can result in incorrect
estimates of vaccine effectiveness. Finally, assuring
comparability of vaccinees and non-vaccinees will be
important to avoid potential confounding; such con-
founding can produce underestimates or overestimates
of vaccine effectiveness and can even lead to negative
estimates when the true effectiveness is positive. For
case-control studies, matching of controls to cases on
potential confounders, such as age, place of residence,
or socioeconomic status, can adjust for differences in
recognized potential confounders between cases and
controls. Potential confounding can be avoided in cohort
studies by collecting information ahead of time on vac-
cinees and non-vaccinees on variables known or sus-
pected to be related to the risk of diseases. Subsequent
analyses can be carried out separately for sub-groups
that are comparable in terms of the potentially-con-
founding variable. The use of statistical techniques,
such as stratification or logistic regression, can also be
used for adjusting for confounding (25-28).
Case-control studies are often used for measuring
the effectiveness of vaccine in the field because their
design allows maximal resources to be applied to small
numbers of cases and controls to accurately assess vac-
cine and history of disease, improving quality of data,
and limiting misclassification errors. In addition, case-
control studies allow identification of risk factors of
disease and later adjustment of potential confounding
factors (25). Post-licensure vaccine studies also include
assessments of safety, coverage, and impact of vaccine
on carriage and herd immunity. Herd immunity is also
assessed because conjugate vaccines are expected to
have an impact on carriage, which would produce a
reduction in exposure among unvaccinated persons and,
therefore, an impact of the vaccine in reducing disease
among non-vaccinated persons (herd immunity effect).
CURRENT AND FUTURE
With the exception of serogroup B, meningococcal poly-
saccharide vaccines have been developed against the
other most common serogroups (A, C, Y, and W-135)
causing disease. The first of these vaccines, against
serogroups Aand C, was produced in 1969 by Gotcshlich
et al. (29). Since then, two bivalent A/C meningococcal
polysaccharide vaccines have been licensed based on
clinical efficacy data (30-32). Studies of serogroups Y
and W-135 polysaccharides found them to be safe and
immunogenic, and a tetravalent A/C/Y/W-135 meningo-
coccal polysaccharide vaccine was licensed in the USA,
despite lack of efficacy data, based on the principle
that the new combination vaccine only added new sero-
groups to an already-licensed multivalent product (23,33).
More recently, a trivalent A/C/W-135 meningococcal
polysaccharide vaccine was licensed by Belgian regu-
latory authorities for use in Africa (34).
Meningococcal polysaccharide vaccines have inhe-
rent limitations (35). The C polysaccharide is poorly
immunogenic in young children with little or no effica-
cy in children aged less than 24 months (36-38). The
serogroup Apolysaccharide induces some antibody res-
ponse in infants and young children but efficacy of
vaccine declines rapidly (39). In addition, meningo-
coccal polysaccharide vaccines do not elicitate long-
lasting immunity (39,40) and do not have a major
impact on carriage (41,42). Lastly, repeated doses of
meningococcal polysaccharide vaccines have been
associated with hypo-responsiveness (43).
To overcome the limitations of polysaccharide vac-
cines, conjugate vaccines against meningococcal disease
are under development. Conjugation of polysaccha-
rides to proteins changes the nature of anti-polysaccharide
immune response from T-independent to T-dependent,
leading to a substantial primary response among infants
and a strong booster response at re-exposure (20,35).
Since 1992, a series of safety and immunogenicity
studies have evaluated bivalent A/C and quadrivalent
A/C/Y/W-135 meningococcal conjugate vaccines (44-
50). These studies have been remarkably consistent
showing safety and improved immune response in
infants. Induction of immunological memory is well-
established for serogroup C and is being studied for the
serogroup A polysaccharide.
In 1999, regulatory authorities in the UK licensed
three serogroup C meningococcal conjugate vaccines,
based on safety and immunogenicity data, without a
phase III efficacy study (51). The basis of this decision
was the existing licensure of plain serogroup C poly-
saccharide vaccines for children aged two years and
above for whom there was direct evidence of efficacy
and accepted serological correlates of protection. Cor-
relates of protection were validated for infants (21,51).
The serogroup C meningococcal conjugate vaccine was
introduced in November 1999 for all children aged less
than 18 years, and a post-licensure evaluation pro-
gramme estimated that the serogroup C meningococcal
conjugate vaccines used in the UK have had a dramatic
impact on serogroup C disease (21). The effectiveness
of vaccine was 96% (91-98%) (22,52,53). In addition,
the vaccine reduced serogroup C nasopharyngeal car-
riage by 66% (54) and decreased disease by 52% in
unvaccinated children and adolescents, demonstrating
herd immunity (52).
Licensure for other new meningococcal conjugate
vaccines will also likely be based on safety and immu-
nogenicity data without phase III clinical efficacy stu-
dies. Protective efficacy of meningococcal conjugate
vaccine will be inferred from immunological endpoints
based on the following observations: (a) serum bacte-
ricidal activity constitutes a good indicator of clinical
protection against serogroup A and serogroup C menin-
gococcal disease (51,55); (b) serogroup A/C and A/C/
Y/W-135 meningococcal polysaccharide vaccines
were licensed for persons aged two years and above
with serological correlates of protection (31-33,36); (c)
safety and immunogenicity studies showed that sero-
group A-containing conjugate vaccines are safe, im-
prove immune response in infants, prime immunologic
memory, and lead to a booster response to subsequent
doses (48,44-47); (d) Hib conjugate vaccines are licen-
sed for infants and children for whom there is post-
licensure evidence of vaccine efficacy and effective-
ness (48,56); and (e) serogroup C meningococcal
conjugate vaccine is licensed for infants and young
adults for whom there are accepted serological corre-
lates of protection and clinical efficacy of the vaccine
has been demonstrated after licensure (22,53). In addi-
tion, randomized placebo-controlled phase III trials may
be ethically and logistically difficult to conduct in African
countries, especially in epidemic situations, where menin-
gococcal polysaccharide vaccines have proven to have
an impact in reducing incidence of disease, and where
the priority will be on responding to the epidemic and
PROJECT FOR MENINGOCOCCALA
CONJUGATE VACCINES IN AFRICA
Because pre-licensure studies of new meningococcal
conjugate vaccines will not include evaluation of clinical
vaccine protection, post-licensure evaluation of the
vaccine is essential. Ademonstration project will evaluate
vaccine effectiveness in a real-world situation, providing
information that can be used for stimulating the intro-
duction and routine use of vaccines in African countries.
A serogroup A meningococcal (Men A) conjugate
vaccine is currently being developed by the Meningitis
Vaccine Project (MVP) with financial support from the
Bill and Melinda Gates Foundation. Clinical lots of a
Men A conjugate vaccine are anticipated in 2004, and
phase I and II clinical studies will begin in 2005 and
last through 2008 with licensure of the vaccine in
2009. The goal of MVPis to make available 25 million
vaccine doses annually with a transfer vaccine price of
about US$ 0.40 per dose (57). The Men Avaccine will
be primarily introduced through country-wide mass vac-
cination campaigns among persons aged 1-29 year(s);
in addition, a Men A conjugate vaccine will be intro-
duced as part of Expanded Programme on Immuniza-
tion for children aged less than one year.
By 2009, the Men Aconjugate vaccine will be intro-
duced in selected African countries at high risk for epi-
demics of meningococcal disease. Retrospective epi-
demiological and laboratory data will be used for deter-
mining likelihood of epidemics of serogroup Ameningo-
coccal disease in the country or countries being consi-
dered for the introduction of the vaccine.
Among these 'early introducers', one country will be
chosen to conduct a post-licensure demonstration pro-
ject during the first year of vaccine introduction.
Evaluation of serogroup A meningococcal vaccines in Africa
Soriano-Gabarró M et al.
J Health Popul Nutr Sep 2004
Selection criteria will include the existence of strong
public-health infrastructure with epidemiological and
laboratory surveillance systems able to implement and
monitor Men A mass vaccination campaigns and to
rapidly detect and bacteriologically confirm cases of
meningococcal disease. The demonstration country
should have the capacity to organize and carry out a
major mass vaccination campaigns with the Men Acon-
jugate vaccine. Necessary infrastructure will include use
of vaccination cards and registries, trained vaccination
teams, and plans for storage, transport, and administra-
tion of the vaccine. Because of the need to develop
substantial infrastructure and the necessity of obtaining
pre-vaccination baseline surveillance data, considera-
tion should be given to the development of several
demonstration sites so that the optimal site can then be
chosen for the demonstration project.
Strong laboratory-based surveillance will be critical
for the detection and confirmation of meningococcal
disease cases and for the evaluation of vaccine effec-
tiveness against serogroup A meningococcal disease.
Laboratory-based surveillance will also be important
to monitor meningococcal serogroups causing disease,
detect other causes of bacterial meningitis (S. pneumo-
niae and H. influenzae) not preventable by a Men A
conjugate vaccine, and monitor possible emergence of
other meningococcal serogroups as a cause of epidemic
disease. Laboratory surveillance will also allow imple-
mentation of accessory studies to evaluate carriage and
seroprevalence. In addition, because of concern that
hyper-invasive serogroup A and C meningococci may
be replaced by vaccine escape variants or other virulent
strains (54,58), laboratory-based surveillance will be
needed to monitor changes in molecular epidemiology.
Ideally, the entire country selected for the demon-
stration project should have sufficient laboratory capacity
to confirm all meningitis cases, but because this may
not be realistic, selected districts within the country
may be identified for the demonstration project. The
following criteria may be used for selecting these dis-
tricts: (a) capacity to accurately evaluate the quality of
vaccination campaigns through analysis of vaccination
cards or surveys, (b) sufficient health infrastructure to
allow detection of suspected meningitis cases and col-
lection of cerebrospinal fluid (CSF) samples in all sus-
pected cases, (c) local laboratory infrastructure to allow
Gram-staining and rapid serological testing on CSF
samples using latex seroagglutination tests, (d) infra-
structure to facilitate rapid transport of CSF samples
inoculated on transport media to a reference laboratory
(national or provincial bacteriology laboratory), and
(e) capability of reference laboratory (at regional or
national level) to perform culture and serogrouping of
meningococcal isolates. In addition, these districts
should have the necessary infrastructure to support special
studies, such as carriage and seroprevalence studies.
An area with a population of at least two million will
be required to provide adequate power to assess the
effectiveness of the vaccine.
Effectiveness and impact of vaccine
Using a case-control study, the effectiveness of the
vaccine will be measured by comparing the odds of
being vaccinated among cases and matched controls in
selected districts in the demonstration country using the
formula VE (%)=(1-OD)x100, where VE is vaccine effi-
cacy and OD is odds ratio (25). Cases will be defined
as 'suspected', 'probable', and 'definite' and will be
identified in districts where mass vaccination cam-
paigns with a Men A conjugate vaccine will be taking
place. Assessment and confirmation of vaccination sta-
tus will necessitate use of vaccination cards during vac-
cination campaigns. Vaccination cards will be distri-
buted during mass vaccination campaigns, and records
on distribution of cards will be maintained. Cards will
be completed and given to vaccinated persons at the
vaccination site. The vaccination cards will include
information on name and date of birth of person being
vaccinated, district, type of vaccine received, and vac-
cine lot number. Vaccination status will be defined as
'verified' and 'reported'. Controls will be matched by
age and residency with cases.
All clinically-suspected cases of meningitis will be
evaluated and be laboratory-confirmed at the district
and national laboratories. Eligible persons with con-
firmed meningococcal disease and matched controls
will be enrolled and interviewed. Demographic, clinical
and epidemiological data will be collected. To account
for possible confounding, information on risk factors
for meningococcal meningitis will also be collected.
The case-control study will be implemented following
similar to the methodology of a recently-conducted
vaccine-effectiveness study in Burkina Faso (59).
In addition to the case-control study, the impact of
the vaccine will be measured through cohort analysis
of all clinically-suspected meningitis cases in a larger area,
Evaluation of serogroup A meningococcal vaccines in Africa
preferably country-wide. Cohort analysis will measure
vaccine effectiveness as the reduction in incidence of
disease attributable to vaccination, using the formula
VE (%)=(1-ARV/ARU)x100, where VE is vaccine effi-
cacy, ARU is attack rate in the unvaccinated persons,
and ARV is attack rate in the vaccinated persons (25).
This analysis will allow a second estimate of vaccine
effectiveness and also additional data on impact of the
vaccine on rates of bacterial meningitis and on occur-
rence and magnitude of epidemics, and an estimate of
herd immunity. For such an analysis to succeed, retros-
pective surveillance will be essential to provide pre-vac-
cination-baseline data of epidemiology, such as previ-
ous epidemics of meningococcal disease, endemic rates
of disease, and laboratory-confirmation of suspected
meningitis cases. Prospective surveillance for clinical-
ly-suspected meningitis will then be used for detecting
changes in suspected meningitis cases, deaths, and inci-
dence rates of disease. This information will comple-
ment data on vaccine coverage, obtained through cov-
erage surveys. Surveillance will focus on clinically-sus-
pected meningitis, using standard case definitions of
clinical meningitis validated by WHO in previous vac-
cine studies (59,60). A clinical definition will be pri-
marily used since intensive laboratory surveillance will
be very difficult to implement country-wide. However,
for areas with good laboratory surveillance, trends in
laboratory-confirmed serogroup A meningococcal dis-
ease will also be monitored. The surveillance system
will collect information necessary to determine demo-
graphics, clinical presentation and outcome, and vacci-
nation status (e.g. vaccine received, vaccination card,
and registry confirmation). When available, laborato-
ry-confirmation information will also be collected.
Evaluation of attack rates for the vaccinated and
unvaccinated persons will allow estimation of vaccine
effectiveness for clinically-suspected meningitis and
herd immunity; incidence rates of pre- and post-vacci-
nation will allow estimation of the impact of vaccine
on epidemics (25).
A series of special studies will be implemented to pro-
vide additional information on vaccine, including car-
riage and seroprevalence studies, vaccine-safety evalua-
tions, vaccine-coverage surveys, and studies of preven-
tion effectiveness. Other studies may include evaluation
of risk factors for non-vaccination and assessment of
acceptability of vaccination.
One of the most important attributes expected from
serogroup A conjugate vaccines is their ability to pre-
vent acquisition of carriage, resulting in herd immuni-
ty, through reduction in exposure among unvaccinated
persons and reduction of disease incidence among
non-vaccinated persons. Evaluation of the impact of a
Men Aconjugate vaccine on carriage and immune res-
ponse will be essential for taking decisions about intro-
duction of vaccines and development of vaccination
programmes. Carriage studies will allow monitoring of
possible emergence of other meningococcal serogroups
circulating in the population and the potential for
serogroup replacement by vaccine escape variants or
other virulent strains as has been observed with new
pneumocococcal conjugate vaccines (56). For these
reasons, a series of oropharyngeal carriage and sero-
prevalence surveys will be conducted in the districts
selected for intensive laboratory-based surveillance,
before and after immunization with Men A conjugate
vaccine. Seroprevalence studies will also allow meas-
uring possible existing natural immunity by serogroup
A meningococci acquired prior to vaccination cam-
paigns, especially in the event of recent epidemics of
meningococcal disease in the area.
Quality of vaccine product, safety of injections and
vaccine-delivery systems, management of sharps and
waste disposal, and monitoring of adverse events fol-
lowing vaccination with a Men A conjugate vaccine
will be evaluated through passive surveillance, if pos-
sible, conducted country-wide. A system for voluntary
reporting of adverse events will be set in place to detect
severe or fatal events and unusual clinical responses.
Because the true rate of adverse events is likely to be
considerably underestimated using this approach, addi-
tional targeted studies of specific adverse events may
be conducted as case-control or retrospective exposure
cohorts linked to historical controls. Cross-sectional
surveys of vaccine coverage using the widely-accepted
WHO sampling methodology will be conducted to allow
identification of overall population estimates of immu-
nization coverage using cluster surveys or the Lot Qua-
lity Assessment Sampling (LQAS) (57). Prevention-
effectiveness studies involve the systematic assess-
ment of the effect of public-health policies, programmes,
and practices on health costs and outcomes. Evaluation
of the introduction of the Men A conjugate vaccine,
implementation of vaccination campaigns, impact of
vaccine on morbidity and mortality, and costs and bene-
fits associated with vaccination will allow identification,
Soriano-Gabarró M et al.
J Health Popul Nutr Sep 2004
assessment, and optimization of possible strategies.
This will be done through a series of prevention-effec-
tiveness studies assessing the different possible approaches
for the introduction of vaccines, e.g. programme de-
sign and implementation process, evaluating potential
effects of vaccination on national immunization pro-
grammes, e.g. impact on delivery of other vaccines, coor-
dination with other vaccination campaigns, and use of
cold-chain systems, and economic analyses.
The use of serological criteria for the evaluation and
licensure of new meningococcal conjugate vaccines has
opened a new perspective in the field of vaccine evalua-
tion. This new approach will facilitate the introduction
of serogroup A meningococcal conjugate vaccines in
Africa. Under this licensure approach, field demons-
tration of the effectiveness of new meningococcal con-
jugate vaccines will be a critical phase in the evalua-
tion of vaccines. Demonstration projects will consti-
tute an important bridge between pre-licensure trials
and post-licensure use and wide acceptance of new
meningococcal vaccines by national and regional autho-
rities. Special studies, including those on carriage and
seroprevalence, safety, vaccine coverage, and preven-
tion effectiveness, will also have a great impact in
determining the most appropriate use of the vaccines
as part of national immunization programmes. Data
from demonstration projects on the Hib conjugate and
serogroup C meningococcal conjugate vaccines show
their impact on prevalence, carriage, and herd immunity,
and also importance of these types of studies. We antici-
pate that the studies outlined here will similarly demons-
trate the dramatic impact of a Men Aconjugate vaccine
in Africa, an essential step to widespread implementa-
tion and elimination of meningococcal epidemics.
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