Vaccine 30S (2012) B78B86

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Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Future challenges in the elimination of bacterial meningitis

Matthew J. Bottomley a , Davide Serruto a , Marco Aurlio Palazzi Sfadi b , Keith P. Klugman c,d,
a

Novartis Vaccines & Diagnostics srl, Via Fiorentina 1, 53100 Siena, Italy
Department of Pediatrics, Santa Casa de So Paulo School of Medicine, So Paulo, Brazil
c
Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA
d
Respiratory and Meningeal Pathogens Research Unit, National Institute for Communicable Diseases, University of the Witwatersrand and Medical Research Council,
Johannesburg, South Africa
b

a r t i c l e

i n f o

Article history:
Received 3 November 2011
Received in revised form
19 December 2011
Accepted 20 December 2011

Keywords:
Meningococcus
Streptococcus
Vaccine
Surveillance

a b s t r a c t
Despite the widespread implementation of several effective vaccines over the past few decades, bacterial meningitis caused by Streptococcus pneumoniae, Haemophilus inuenzae, Neisseria meningitidis and
Group B Streptococcus (GBS) still results in unacceptably high levels of human mortality and morbidity.
A residual disease burden due to bacterial meningitis is also apparent due to a number of persistent
or emerging pathogens, including Mycobacterium tuberculosis, Escherichia coli, Staphylococcus aureus,
Salmonella spp. and Streptococcus suis. Here, we review the current status of bacterial meningitis caused
by these pathogens, highlighting how past and present vaccination programs have attempted to counter
these pathogens. We discuss how improved pathogen surveillance, implementation of current vaccines,
and development of novel vaccines may be expected to further reduce bacterial meningitis and related
diseases in the future.
2011 Elsevier Ltd. All rights reserved.

1. Introduction
Medical records of bacterial meningitis date back to the early
1800s (reviewed by Pace, in this issue), yet our current understanding of its global distribution and frequency is still far from
comprehensive. Since the 1980s, the most common causes of
bacterial meningitis in the United States (US), Europe and many
other developed countries have been Streptococcus pneumoniae,
Haemophilus inuenzae type b (Hib), Neisseria meningitidis, Group
B Streptococcus (GBS), and Listeria monocytogenes [13]. In Africa,
epidemics of meningococcal meningitis and septicemia represent
a great public health threat [4,5]. Following the initial introduction
of conjugate polysaccharide vaccines against S. pneumoniae, Hib,
and N. meningitidis during the 1980s and 1990s the epidemiology
of bacterial meningitis has changed dramatically. Further challenges to reducing the global burden of meningitis remain, among
them vaccines against the Group B Streptococcus and meningococcal serogroup B strains, which now account for most newborn
and infant meningitis deaths respectively in many parts of the
developed world [1,68]. Here, we review the current status of
disease caused by these pathogens, how past and current vaccination programs have affected these pathogens, and how improved
implementation of current vaccines and/or the development of

Corresponding author at: Hubert Department of Global Health, Rollins School

of Public Health, Emory University, Atlanta, GA 30322, USA.
E-mail address: keith.klugman@emory.edu (K.P. Klugman).
0264-410X/$ see front matter 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2011.12.099

novel vaccines may be expected to further reduce meningitis and

related diseases caused by these, or other emerging, pathogens in
the future.

2. The importance of monitoring bacterial meningitis

2.1. Detection of meningitis
Over recent decades, the overall awareness of bacterial meningitis outside of the African meningitis belt has grown signicantly, in
particular following a number of epidemics and severe outbreaks of
meningococcal meningitis, including the N. meningitidis serogroups
B (MenB) and C outbreaks in Brazil [9], Chile [10], New Zealand [11],
Norway [12], and the UK [13], which were collectively responsible
for hundreds of deaths and many serious sequelae of infection. Consequently many Western countries have improved and increased
their routine diagnostic assessment of meningococcal disease. Such
practices include more frequent use of lumbar puncture and blood
culture in order to allow PCR-based detection of the pathogens and
even MLST analysis of cerebral-spinal uid (CSF) isolates, yielding genetic signatures of bacterial isolates, coupled with the more
traditional analysis of isolates via bacterial culture techniques. It
is likely that the future incorporation of real-time (RT)-PCR into
routine public health surveillance of meningococcal disease will
greatly enhance the quality of screening.
The power of RT-PCR to diagnose the cause of meningitis, not
only in developed countries but also in a developing country, was

M.J. Bottomley et al. / Vaccine 30S (2012) B78B86

recently demonstrated in a multi-center study focused in So Paulo,

Brazil. It was found that routine use of a multiplex RT-PCR assay
testing for S. pneumoniae, N. meningitidis and Hib increased the
diagnostic yield for bacterial meningitis by 52%, 85% and 20%,
respectively [14]. The success of this approach is partly due to a
reduction in the rate of false-negatives, which are typically caused
by the presence of antibiotics in the CSF, particularly in cases of
meningococcal disease. Moreover, the rapidity of this or similar
assays, such as a rapid immuno-chromatographic test for S. pneumoniae [15], may improve the speed of detection of meningitis
and hence treatment, especially in resource-poor countries. These
technical advances argue for a wider adoption of additional diagnostics in routine practice. To date, RT-PCR has been incorporated
into more traditional microbiological surveillance, but its introduction into routine microbiological laboratories for the detection of
bacterial meningitis has been slow.
2.2. Disease surveillance
In regions where improved diagnostic procedures have been
implemented, the improved surveillance has provided a clearer
description of the status of bacterial meningitis, as has been
reported for Brazil [14], Egypt [16], Mongolia [17], and the meningitis belt of sub-Saharan Africa stretching from Senegal to Ethiopia
[18].
In addition to providing a snapshot description of disease status, surveillance over longer periods also allows measurement of
the impact of vaccines. Bacterial meningitis and patient mortality have decreased in all age groups following Hib vaccination.
For example, the Hib vaccine introduced in North America in the
mid-1980s for >18 month old children and in 1990 for >2 month
old children led to a substantial decline in the incidence of Hib
disease, from a peak of 41 cases per 100,000 children aged <5
years in 1987 to approximately 0.11 cases per 100,000 in 2007
[19]. Similarly, impressive reductions in Hib meningitis following conjugate vaccine introduction have been observed in some
developing countries, e.g. The Gambia [20]. However, despite the
near elimination of Hib disease in many industrialized countries,
the vaccine has still not been introduced in several countries with
very large populations and the global coverage for the third dose
of Hib vaccine in infants in 2010 was only 42% according to estimates by the World Health Organization (WHO) [21]. It is notable
that, even after vaccine implementation, recent data suggest that
countries that have a high burden of HIV tend to have late vaccine failures (including cases of meningitis), at least in the setting
of the current EPI (Expanded Program on Immunization) recommendation of three doses of Hib conjugate without a booster
[22].
Vaccine efcacy has also been conrmed by surveillance studies of pneumococcal meningitis and invasive pneumococcal disease
(IPD) in children and adults, which decreased following introduction of the pediatric heptavalent pneumococcal conjugate vaccine
(PCV7) in the US in 2000. Across all age groups, rates of PCV7serotype meningitis decreased by 73% from 1999 to 2005 [23] and
the effectiveness of this vaccine was further underlined by a more
recent study, showing a sustained decrease of IPD in US children
under 5 years old between 1998 and 2007 [1,24].
The importance of disease detection and surveillance cannot be
overstated since improved surveillance enables scientic opinion leaders to provide more reliable, geographically tailored advice
to political decision makers regarding introduction of vaccines for
improved disease control and prevention. In contrast, where there
is little or no routine diagnosis, there are very few cases of meningitis reported, with the unfortunate consequence that the perception
of meningococcal disease burden is very low. The latter results
in an underestimated need for healthcare intervention, such that

B79

offering and uptake of vaccines may be slow, and disease is likely

to persist.

3. Current vaccines against bacterial meningitis

3.1. Hib and pneumococcal vaccines
Prior to the development of conjugate vaccines, Hib was the
most common cause of bacterial meningitis in children [25]. Since
becoming available in the 1980s, global use of Hib vaccines has
increased enormously, particularly since the year 2000. Almost all
high and middle-income countries introduced Hib vaccination by
2002, and almost all the lowest-income Global Alliance for Vaccines
and Immunization (GAVI)-eligible countries by 2010. Nonetheless,
although over 80% of WHO member states used infant Hib immunizations by 2009, only 45% of the worlds children had been fully
vaccinated. This apparent contradiction likely results from the fact
that a few countries with very large birth cohorts had not introduced the vaccine [26]. To prevent disease incidence remaining
high, special focus is needed in such regions, and in lower-middle
income countries that have not yet introduced the vaccine. However, the success of Hib conjugate vaccines in countries that have
immunized the majority of children has been signicant. After the
introduction in the US of routine immunization with Hib conjugate vaccines in the late 1980s, the incidence of Hib meningitis
disease decreased by >80% within just three years [27]. By 1999, the
reduction in invasive Hib disease was 99%, compared with the 1987
baseline incidence rates [28]. However, as global vaccination with
Hib vaccines spread it has emerged that some socio-economically
disadvantaged sub-groups within the general population had low
immunization rates [29]. Moreover, the experiences with minor
resurgences of Hib disease in both developed and developing
countries emphasize the importance of continued surveillance
[30].
Uptake of the heptavalent PCV (PCV7) in the US led to a dramatic, almost 100% decrease in disease in children <5 years old
caused by the corresponding PCV7 vaccine strains (which previously accounted for 80% of IPD in children, 60% in adults),
while the amount of disease caused by non-PCV7 strains increased
slightly [24]. More recently, in 2010, second generation PCV vaccines with broader serotype coverage were licensed [31], and if
these emulate the successful PCV7 results it is possible that IPD
will be dramatically reduced in the <5 age group. However, despite
the almost 100% reduction of some serotypes following implementation of PCV7, it is unlikely for the foreseeable future that these
serotypes could be removed from current or forthcoming multivalent PCVs. The genetic lability, possibility for capsular switching
and low probability of achieving universal immunization suggest
that global eradication of the pneumococcal types in the vaccine is
unlikely to be achievable. Indeed, while PCV7 may cover 8090%
of serotypes causing IPD in young children in North America and
Australia, the coverage may fall to 7075% in western Europe
and Africa, possibly being as low as 5065% in Latin America and
Asia [32]. The latter regions would therefore likely benet from
improved coverage, since recent analyses of incidence and cause
of bacterial meningitis in the US between 1998 and 2007 suggest
that following widespread vaccination we can reasonably expect
the almost complete elimination of bacterial meningitis in young
children and a dramatic reduction in adults [1].
Vaccination of children with PCV7 is associated with reduced
nasopharyngeal carriage of the seven pneumococcal serotypes
present in the vaccine, even in unvaccinated subjects; i.e. there is
evidence of herd protection. The herd effect gives further hope
to the possibility of the complete elimination of these pneumococcal serotypes in vaccinated geographic areas. However, due to

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increasing global travel, local elimination may not preclude the

necessity for vaccination, which may remain essential in order to
protect against travel-related infection. In order for this to be efcacious, it is important that the molecular epidemiology of disease
is well-understood on a global basis. Such data should be regularly
monitored, to track changes in serotype distribution due to the
possibility of serotype replacement following use of a vaccine that
does not cover all serotypes. This would appear particularly important for the pneumococcus, where 100% serotype replacement
in the nasopharynx has been observed [33]. A universal vaccine
covering all 93 known pneumococcal serotypes remains a potential
vaccine of great importance for the future of public health.
With a view to creating a universal vaccine, different approaches
including library immuno-screening with patients sera and
genome-based analyses were used to identify all possible surfaceexposed and immunogenic molecules encoded by S. pneumoniae
[34]. For example, these approaches resulted in the identication
of novel pilus-like structures on the surface of pneumococcus that
have been shown to be protective in animal models of infection
[35]. However, a major limitation in the use of pilus subunits as
vaccine candidates is that pili are not consistently widespread
in pneumococcal isolates [36]. Although additional broadly conserved vaccine candidates need to be identied in order to offer
universal protection against pneumococcal infections, the role of
pili in pathogenesis, in addition to strain coverage, suggests these
antigens may be considered as components of next-generation
protein-based vaccines [37]. To this end, there are ongoing global
studies to sequence the whole genome of thousands of both invasive and carriage strains of pneumococcus which will aid the
selection of vaccine antigens, at least with respect to their global
distribution in the species.
Approaching an era in which all possible PCV serotypes might be
covered by vaccines and consequently eliminated, there arises the
possibility for an impact on the frequency of other, contextually
similar diseases. For example, a reciprocal relationship between
administration of the PCV7 vaccine and staphylococcal nasopharyngeal colonization in children was recently reported [38]. Though
there is currently no clear link to increased disease, only carriage,
such effects should be carefully monitored.
3.2. Meningococcal vaccines
Six meningococcal serogroups, A, B, C, W-135, X, and Y cause the
majority of disease worldwide and are considered epidemiologically important by the WHO [4]. Conjugate vaccines are available
against serogroups A, C, W-135 and Y. In many countries, routine
immunization with the serogroup C conjugate vaccines dramatically reduced disease incidence and asymptomatic carriage, thus
leading to herd protection. Several combinations of serogroups
A, C, W-135 and Y polysaccharide vaccines have been successfully used over the years in different countries [39,40]. A very
signicant advance in this eld is the recent implementation of
a serogroup A conjugate vaccine in the African meningitis belt
[41]. Since the widespread introduction of the conjugate MenC
vaccine into infant immunization schedules, and the increased
use tetravalent vaccines, serogroup B remains the largest challenge in combating meningococcal disease in developed countries.
The potential of forthcoming MenB vaccines [42,43], containing
meningococcal surface-exposed proteins with broad strain coverage (reviewed by Serruto, in this issue), may also affect the coverage
of meningococcal non-B serogroups. To address this question, a
study of N. meningitidis isolates from South Africa showed complete conservation in all major serogroups of one of the protein
vaccine components the factor H binding protein [44]. Similarly, in the US, all isolates of serogroups B, C, W-135 and Y,
contain one or more genes corresponding to antigens included in

the MenB vaccines currently under development, suggesting that

these candidate vaccines may also protect against non-serogroup B
strains [45]. Nonetheless, intra-serogroup variation can be extensive for many meningococcal antigens, highlighting the necessity
for continued characterization of antigens in clinical isolates, both
routinely and upon emergence of outbreaks [46].
In order to understand better these cross-protective effects, it
will be important to survey serogroups and preferably also analyze MLSTs or genome sequences on a broad basis. Further, the
presence of genes shared with serogroup B would not be sufcient to predict coverage by recombinant protein MenB vaccines.
Rather, an accurate prediction of whether non-serogroup B protection could be obtained would likely require the demonstration of
gene expression data and surface exposure of the relevant antigen
and, ultimately, cross-serotype serum bactericidal assays should
be performed using sera from immunized subjects. The recent
development of an assay designed to provide qualitative and quantitative assessment of meningococcal antigens [47] promises to
facilitate the acquisition and organization of this data, such that
global degrees of strain and serogroup coverage of protein-based
vaccines can be more readily estimated (reviewed by Vogel, in this
issue).

4. How can disease prevention be increased?

4.1. Factors driving uptake of existing vaccines
Many effective vaccines are now available and yet are
under-utilized, particularly in developing countries where uptake
depends on an interdependent array of socio-economic factors
including vaccine price, disease burden data, existence of immunization infrastructures, complexity of immunization schedules,
possibilities to roll-out streamlined multivalent combinations,
donor nancing for vaccines and national politics and economics
[48,49]. The adoption of vaccines by national immunization programs is an essential step toward a global reduction in childhood
disease and mortality. Studies of Hib vaccine implementation have
provided considerable insight in this arena. For example, an analysis of Hib vaccine uptake and efcacy data collected from 147
countries between 1990 and 2007 suggested that membership
of GAVI is associated with accelerated decisions to adopt the
Hib vaccine and, interestingly, that the inuence of two or more
neighboring countries also has a strong impact on uptake policy
[49]. Likewise, a study of Hib vaccine introduction in the Americas (19912007) showed in countries of Latin America and the
Caribbean a substantially reduced morbidity and mortality due
to invasive Hib infections such as pneumonia or meningitis. Factors favoring vaccine adoption included a strong political drive
combined with data showing Hib disease burden and impact of vaccination in early adopting countries, and again exchange of positive
experiences among proximal countries [50]. Uptake of vaccination has also been facilitated logistically by making cost-effective,
multi-valent combination vaccines [51]. Though this offers a simplied vaccination routine, an unexpected increase in incidence
of Hib disease in the United Kingdom coincided, along with other
factors, with the distribution of a combination vaccine (diphtheriatetanus-acellular pertussis-Hib vaccine, or DTaP-Hib) [52,53]. This
nding emphasizes the importance of long-term surveillance of
vaccine-preventable diseases in the population, especially as vaccine combinations become more complicated and changes to
routine immunization schedules are introduced. Such studies provide useful guidance for mechanisms to encourage vaccine uptake,
and yet routine Hib vaccination is not always considered a cost
effective option, as reported following a study of <5 year olds in
Moscow [54]. Such a study, in conict with data gathered in many

M.J. Bottomley et al. / Vaccine 30S (2012) B78B86

other parts of the world, underlines the importance of epidemiology and disease surveillance studies, in order to discern whether
the differences observed reect a real local situation or result from
an ascertainment bias (i.e. low levels of disease surveillance and
diagnosis will inevitably lead to an apparent low disease burden).
The issue is also strongly debated in India, where surveillance is
relatively low and thus a low tendency for uptake is compounded
by the local concern that disease strains covered by vaccines may
not necessarily be those most needed by the population [55].
The factors discussed above should be carefully considered
in order to facilitate the roll-out of successively more complex
combination vaccines. While this may seem logistically challenging, the rewards in standards of health warrant the investment.
Moreover, if future immunization schedules can be coordinated
at successively higher levels, it would be of benet for long-term
surveillance, providing more comparable data globally, and better
enabling vaccination routines to meet the requirements of each
population.
4.2. MenA vaccine uptake and follow-up
In comparison with the struggles encountered during uptake
of some vaccines (see above), the development and uptake in the
African meningitis belt of a novel conjugate vaccine against N.
meningitidis serogroup A (MenA) provides a very positive model for
disease prevention by large scale vaccination. Following enhanced
awareness of MenA disease and strong advocacy by GAVI and the
World Health Organization (WHO), several African countries made
a clear request for a vaccine to prevent MenA. In 2001, a partnership
was forged between PATH and the WHO, with funding from the Bill
and Melinda Gates Foundation, thus creating the Meningitis Vaccine Project (MVP), charged with the aim of developing, testing and
licensing meningococcal conjugate vaccines for sub-Saharan Africa
[56]. The MVP has resulted in a group A meningococcal conjugate
vaccine (PsA-TT, MenAfriVac), with which widespread vaccination
in meningitis belt countries began in 2010 [41]. The MenA vaccine
targeting children, adolescents and adults from 1 to 29 years of age
in sub-Saharan countries is expected to dramatically reduce the
burden of serogroup A disease in these African countries. A high
degree of vaccine distribution has already been achieved in many
areas, including 100% coverage in the target group of Burkina Faso
(reviewed by Aguado, in this issue). While it is not anticipated that
the MenA vaccine will result in serogroup replacement in Africa, the
evidence for recent epidemics of Men W-135 and X in the meningitis belt highlight the additional need for a multivalent vaccine
covering serogroups A, W-135 and X [5759]. The potential scale of
the meningococcal disease problem in Africa demands that surveillance be maintained in order to be able to act quickly if medical
needs change. It should be noted that the response to such changes
may be on the time scale of 510 years, depending on regulatory
demands; therefore forward planning will be essential in order to
provide a relevant, effective vaccine in response to needs. Longterm vaccine-induced protection, and its variance with dosage
and geography, is dependent on herd protection effects. Although
duration of protection still remains to be determined, the positive
experience of rapid vaccine introduction against MenA provides an
inspirational model for uptake of future vaccines an inuence
potentially spreading to neighboring countries, as reported above
for Hib vaccine uptake.
4.3. Diagnostics of disease, carriage, and herd protection
As introduced above, improving the quality of surveillance data
on meningococcal disease across different age groups and countries would be highly benecial for implementation of vaccination
strategies. The molecular epidemiology of each pathogen should be

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followed by designated reference laboratories, with agreed welldened typing systems being adopted by all participants, to allow
linking of data into a global network of disease data collection
and analysis. In order to potentiate the use of PCR-based analysis
and multi-locus sequence typing (MLST) for diagnosis of infections,
it will be necessary for lumbar puncture and blood sampling to
become routinely performed on patients suspected of meningococcal disease. The use of PCR-based analyses reduces the need for
certain expertise and facilities required for culturing pathogens that
may be challenging in developing countries. Ultimately, diagnostic
analyses should enable a consensus to emerge for what each country needs and wants the uptake of the vaccine against MenA in
the African meningitis belt was successful largely because of the
awareness of the disease and the solution to that disease problem.
Surveillance of disease and/or pathogen carriage can provide an
understanding not only of the duration of protection in vaccinated
subjects, but also of the degree of herd protection in non-vaccinated
subjects afforded by a vaccination program. Herd protection can be
critical to the success of vaccination since it can eventually lead to
the virtual disappearance of the targeted pathogen [60]. A notable
example is provided by the 30% decrease in IPD caused by vaccine serotypes in the non-immunized adult population due to herd
protection induced by pediatric PCV7 vaccination [24,61].
As criteria for the introduction of new vaccines into public health
practice become more stringent, knowledge of the extent of vaccination coverage required to afford total population coverage when
including the herd effect may facilitate policy deliberations and
guide strategy at a national level. To date, herd effects have generally been considered only after a vaccine has been introduced,
and not when evaluating clinical trials, which by necessity are performed on only a small percentage of the overall target population.
However, cluster-randomized trial methodology, may allow the
assessment of herd protection at an earlier stage, which may bring
forward the inuence of herd protection on decisions about vaccine
implementation [62].
4.4. New approaches and strategies for vaccination
Increased diagnosis, typing and surveillance should enable
analyses that indicate ways in which current vaccines could be
improved, for example by addition of single or multiple new
components in order to provide further breadth of coverage. As
discussed above, serotype replacement of S. pneumoniae with
non-vaccine serotypes has occurred following widespread use
of limited-serotype conjugate vaccines. Moreover, pathogens are
under selection pressure to evolve resistance to their host, and vice
versa. Consequent changes in both host and pathogen may lead
to new genotypes of both: a phenomenon known as Red Queen
dynamics, in which, like the Red Queen in Alice in Wonderland
who ran all the time to remain in one place, evolution in conjugate
vaccination will be met by evolution in the pathogen so that we
remain in the same place [63].
If serotype/serogroup replacement is unavoidable, alternative
strategies to the capsular polysaccharide-based vaccinations may
be pursued. In a survey of meningococcal isolates from 17 African
countries, it was revealed that MenX shows high expression levels of the factor H binding protein (fHBP), an important antigen
included in two recombinant protein vaccines under development
for prevention of MenB disease [64]. While protection induced
by meningococcal conjugate vaccines is serotype- or serogroupspecic, protein-based vaccines elicit protective antibodies against
strains with different serogroup capsules, extending the potential
coverage of these vaccines. The development of a new fully proteinbased vaccine is probably not an economically viable solution for
developing countries, yet it is also possible that an fHBP-containing
vaccine against MenB may already provide some protection against

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MenX. A recent study in which a broadly protective fHBP protein

was created by combining onto a single protein scaffold immunogenic epitopes from 3 non-cross protective strains shows how a
molecular understanding of virulence factors can aid vaccine design
[65]. Indeed, it is anticipated that our growing understanding of key
features in the life cycle of each pathogen such as the molecular
basis of the colonization process may also enable new vaccine
strategies [66].
Aiming still higher, a single, near-universal meningitis vaccine could be proposed by employing Hib, pneumococcal and
meningococcal antigens in a combination vaccine. This general concept could then be tailored according to demand,
such that in Africa it might include protective antigens to
combat MenA, MenW135 and Hib. If serotype frequencies
causing meningitis change with time (serotype replacement),
compositional adjustments to combination vaccines might be
introduced.

5. Future challenges
5.1. Group B Streptococcus
Following the PCV7-induced reduction of IPD in the USA, the
major burden of meningitis in children aged <17 years is now
equally caused by Group B Streptococcus (GBS) and the pneumococcus. It is particularly notable that 86% of cases among those less
than 2 months of age are attributed to GBS [1]; i.e. the contribution
of GBS to the residual burden of meningitis has increased signicantly. Moreover, in regions where vaccines against pneumococcus
and Hib are not routinely available, e.g. sub-Saharan Africa, GBS
is still an important cause of meningitis in the rst 3 months of
life [67,68]. In the USA, and beyond, the widespread screening of
pregnant women for GBS, coupled to timely deployment of antibiotics, has reduced GBS sepsis showing early onset (weeks 15). In
contrast, there has been no signicant reduction in GBS meningitis occurring in children or adults, which may even be emerging in
the USA with an approximate 4% increase in total number of cases
between 1997 and 2007 [1].
The high incidence of HIV in much of Africa, and generally higher
rates of transmission due to relative crowding, could impinge on the
efcacy of any vaccines deployed. For example, despite moderate
efcacy of PCV among HIV-infected infants [69], more recent data
suggest that older HIV-infected children have higher rates of colonization with PCV vaccine types than HIV-uninfected children [70].
It is currently unclear whether herd protection in developing countries will be sufcient to protect these children from vaccine-type
pneumococcal acquisition and disease such as meningitis. This is
relevant to GBS disease, because there is a large problem of GBSlinked sepsis in sub-Saharan Africa. Due to many children being
born at home, neonates are often already ill on day 1 (80% of
early onset cases) and the practical aspects of diagnosis and treatment within hours are so challenging that many children remain
untreated and die within the rst 48 h post-partum. Rather than
treatment, a better alternative would be a preventative strategy,
using maternal immunization prior to child birth. GBS conjugate
vaccine formulations have shown promising results in Phase I and
II clinical trials in the USA, with safety and sustained functional
antibody responses in mothers and infants 2 months after delivery, suggesting that maternal immunization with GBS capsular
polysaccharide tetanus toxin (CPS-TT) conjugates could prevent
GBS disease [71,72]. Larger scale trials of a conjugate vaccine containing GBS CRM197-CPS (serotypes Ia, Ib and III) antigens are
currently under way. There are now at least 9 different capsular
types known, suggesting that it may be worthwhile planning the
design of a universal vaccine, aspiring for total serotype coverage,

for example by combining polysaccharides conjugated to conserved surface proteins [73].

Indeed, GBS has been shown to possess several surface-exposed
proteins potentially suitable as vaccine antigens that could overcome serotype specicity [74]. Aided by a reverse vaccinology
strategy and emerging technologies, a vaccine combination based
on the GBS pilus proteins has been developed and tested in preclinical studies [75,76]. The results of these studies provided strong
support for the development of a pilus-based vaccine protecting
against GBS infection. A combination of glycoconjugates representing the most common serotypes plus a combination of highly
protective proteins such as conserved pilus proteins might therefore be considered a promising route toward a universal GBS
vaccine [74].
In light of the above, GBS is similar to many diseases, where a
single component vaccine is insufcient, due to variability in strains
of the bacterial pathogen. This problem can sometimes be partially
overcome by including in the vaccine combination several antigens
against different pathogenic types. When a universal multivalent
vaccine is not attainable, the concept of a more dynamic vaccine
might be entertained. For example, new polysaccharide components from the most relevant serotypes or serogroups could be
included to address changes in emerging medical need, resembling
to some degree the current model for inuenza vaccines, in which
amino acid sequences of some or all of the vaccine antigens may be
changed each year. While this would present an appealing solution,
it is impractical given current regulatory approval requirements.
In short, for conjugate vaccines there needs to be a quicker process for licensing of vaccines containing different capsular types.
However, recombinant protein vaccines have an even more difcult
regulatory path to licensure. Yet, if detailed genomic and biochemical analyses demonstrate that greater protection against disease
could be afforded by a few changes to the amino acid sequence of
a previously approved vaccine component, then it could similarly
be benecial to be able to make such changes without needing to
embark on extensive clinical trials.
The real burden of Group B Streptococcal infection in the developing world is still a point of debate, with highly variable rates of
disease incidence having been reported [6]. Despite levels of maternal colonization being similar to those found in wealthy countries,
GBS was reported as being responsible for less than 1% of neonatal
sepsis in Asian studies, with incidence rates of symptomatic early
neonatal GBS bacteremia being as low as 0.17/1000 live births in a
10-year retrospective study in India [77].
Few published studies from Latin America have addressed
the etiology of neonatal bacterial meningitis and, in general,
Gram-negative organisms (such as Escherichia coli, Klebsiella spp.,
Pseudomonas sp., Enterobacter sp. and Acitenobacter sp.) appear to
be more important pathogens than in the developed countries, with
a very limited role of L. monocytogenes [78,79]. Inadequate culture
and molecular techniques employed regionally are likely responsible for the variable incidence rates of maternal colonization and
also neonatal disease attributed to GBS in the region.
Even after development and licensure, a lack of blood sampling
and sub-optimal microbiological methods used for diagnosis in
developing countries can result in a lack of perception of the need
for emerging vaccines. If there is no availability of a long-lasting GBS
vaccine that could be given to women upon reaching child-bearing
age, with a booster during pregnancy, other strategies may have to
be considered in order to provide effective protection; for example,
to vaccinate early in the third trimester of pregnancy [80]. Several
possibilities may exist, for example by using GBS polysaccharides
coupled to tetanus toxin (TT), or by proposing a combined vaccine
such as TDaP, or a multi-valent vaccine simultaneously protecting against Hib, PCV and meningococcus. The logistic and efcacy
advantages of such combinations may encourage developing

M.J. Bottomley et al. / Vaccine 30S (2012) B78B86

countries to use new vaccines (see above). The value of multivalent

vaccines may be particularly appreciated in regions where HIV is
prevalent, given the wide variety of diseases to which HIV infected
people are susceptible.
To date, vaccines have been used to improve the survival
chances for children in the age group from 3 months to 6 years,
but little progress has been made for neonates. In this context, it is
promising that there is a large-scale trial involving GBS vaccination
of pregnant mothers planned in South Africa, Malawi and South
America where the aim is to protect both mothers and newborn
children. The issues surrounding GBS represent a prime example
for maternal vaccination, which if successful could also act as a
model for other diseases, including MenB.
5.2. Tuberculous meningitis
Over the past decades, tuberculosis (TB) has been fought by
hundreds of millions of doses of the Mycobacterium bovis bacillus
Calmette-Guerin (BCG) vaccine that have been given to children
worldwide and are thought to have provided some protection
against childhood tuberculous meningitis (TBM) and miliary tuberculosis. Nonetheless, TB remains a leading cause of global infectious
disease mortality and is a worsening problem due to co-infection
with HIV and emerging drug-resistant strains [81,82]. The BCG vaccine is less efcacious in preventing adult pulmonary TB, but is a
highly cost-effective measure against severe childhood disease and
its continued usage is recommended in high-incidence countries
[83]. However, there is much effort ongoing in aiming to produce
improved vaccines to protect against TB [84], since estimates report
over 9 million new cases and 1.7 million deaths occurring worldwide in 2009 [85].
In a report by the Centers for Disease Control and Prevention
(CDC), an analysis of data from 2005 indicated that central nervous
system (CNS) involvement was present in 6.3% of approximately
3000 extrapulmonary tuberculosis cases in the United States [86].
Concurrently in Taiwan, a large study reported that increasing rates
of tuberculosis deaths were attributable to CNS disease [87]. Moreover, in determined Latin American countries, there is a notable
degree of TBM in children <5 years, even among communities
where the reported BCG population coverage is 100%: incidence
rates of 0.3 cases/100,000 children <5 years were reported in Brazil,
with case fatality rates as high as 40%) [88].
In short, BCG vaccination has proved to be a cost-effective and
efcacious intervention against tuberculous meningitis, supporting the continued use of the vaccine in areas where the disease is
endemic. However, after a century of tuberculosis vaccine development, there remains a clear need for an improved vaccine to
reduce the global burden of severe tuberculosis, a goal that may
be achievable within the next ten years [89].
5.3. NTHi, Hia and Hif
Non-typable H. inuenzae (NTHi), together with S. pneumoniae,
is one of the leading causes of acute otitis media (AOM) [90], complications of which occasionally include meningitis [91]. A vaccine
containing polysaccharides from 10 pneumococcal serotypes, 8 of
which conjugated to NTHi protein D, one conjugated to tetanus
toxoid and one conjugated to diphtheria toxoid has shown efcacy against pneumococcus and may also provide some protection
against AOM caused by NTHi [32]. However, there are currently no
data on the effectiveness of this vaccine in the prevention of NTHi
meningitis. Further combinations could be considered in order to
increase breadth of coverage of H. inuenzae vaccines e.g. polysaccharide or protein components of H. inuenzae types A and/or F
could be added to Hib vaccines that currently provide no cross
protection. This might be benecial particularly for infants and

B83

children because, although the rates of Hia disease in the US are

quite constant regardless of the use of Hib vaccination, Hia is an
important cause of meningitis in certain populations, including
some Native American communities [92].
5.4. Emerging causes of meningitis
In addition to the major pathogens outlined above, a small number of reports are emerging describing signicant disease burdens
from other causes of bacterial meningitis. In particular, numerous
cases of neonatal meningitis in developing countries have been
caused by E. coli (approximately 70% of which are K1 strains) and
other enterobacteria [6]. Another source of bacterial meningitis is
Staphylococcus aureus, which often aficts neonates, children and
adults with shunts [93]. Incidence rates of post-operative bacterial
meningitis associated with shunts have been reported to be only
about 10% [94], although this may rise to as much as 2539% in
some groups studied in Latin America [95,96].
In south-eastern Africa (Malawi), in addition to the typical
causes of bacterial meningitis, disease also arises from Salmonella
spp. [97], suggesting that this pathogen should be surveyed carefully, especially during vaccination campaigns targeting other
pathogens, which may allow Salmonella to exploit vacated niches.
Vaccines against Salmonella are not yet available, though a conjugated vaccine including the virulence capsular polysaccharide (Vi)
coupled to CRM197 is currently under investigation and development for the prevention of typhoid fever [98].
Streptococcus suis is emerging as an important cause of bacterial meningitis in adults in Viet Nam [99,100]. S. suis can cause
severe systemic infection in adults exposed to infected pigs, pig tissue, or after consumption of undercooked pig products. However,
recent implementation of screening by blood culture, CSF culture
and PCR testing proved effective in diagnosing S. suis and should
enable improved estimates of the disease burden in the community
[100]. Therefore, although the number of cases reported worldwide
is relatively low (700 in 2009), the frequency of disease due to
this pathogen should be carefully monitored, especially in developing countries with intense pig farming, such as those in Southeast
Asia. Disease detection and surveillance may enable prevention by
appropriate modications to pig handling practices.
6. Conclusions
We have reviewed the major impact that vaccines have had
on the reduction of meningitis in developed and developing countries and have highlighted challenging areas where efforts must be
focused in order to further reduce bacterial meningitis in the future.
Collectively, the conjugate polysaccharide vaccines introduced
against Hib (in the mid-1980s), S. pneumoniae (year 2000 onwards)
and N. meningitidis (several variations, mid-1990s onwards) have
dramatically reduced bacterial meningitis in several developed
countries. In these countries, there is remaining burden from a
small number of pneumococcal serotypes not covered by existing
PCVs, and in infants there are still signicant disease levels causes
by N. meningitidis serogroup B. To combat S. pneumoniae, revised
conjugate vaccines covering more serotypes have been developed.
Likewise, it should soon be possible to vaccinate against MenB,
using new recombinant protein-based vaccines [42,43,101], the
clinical effectiveness of which should be measurable in the next
few years.
As discussed above, the efcacy of Hib vaccination is now welldocumented for a number of developed countries, and as there is
insufcient surveillance in several developing countries, including India and China, the residual disease burden in these large
populations is not clearly established. Similarly, use of the rst

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M.J. Bottomley et al. / Vaccine 30S (2012) B78B86

generation of PCVs has been highly successful, and a second wave of

vaccines with greater serotype coverage could potentially greatly
reduce the disease. However, a major limitation of PCV is the
cost of these complex, multi-component products, which present
economic challenges particularly for middle income countries for
which GAVI-donated vaccine is not available, and the long term
funding of PCV beyond donation remains unclear for the poorest
countries. In addition, careful surveillance of serotype distribution
and incidence must be maintained in order to monitor the risk of
pneumococcal serotype replacement. Finally, though diminished
in many parts of the world, the threat from all meningococcal
serogroups remains in Africa and several developing countries.
However, the vaccines exist to potentially control the rates of disease caused by the major serogroups, and their widespread uptake
is crucial for future public health impact on meningitis exemplied by the recent success of MenA conjugate vaccination as
implemented in the meningitis belt.
The reduction in these major sources of meningitis in developed
countries has led to neonatal meningitis due to Group B Streptococcus becoming the most pressing unmet medical need causing
meningitis in young infants. The impact of GBS is also worrisome
in many parts of the developing world, where pre-birth screening and antibiotic treatment is not available indeed, widespread
antimicrobial prophylaxis of pregnant women is not a viable longterm solution to the problem of group B sepsis in neonates. Vaccines
against GBS have been developed and large clinical trials are currently under way to evaluate their efcacy in preventing neonatal
meningitis following maternal immunization [80].
The continued reduction of meningitis must remain a priority for
the modern world. Organizations including the WHO, PATH, GAVI
and the Gates Foundation can play a leadership role in improving disease detection and surveillance, in order to provide more
reliable, geographically tailored advice to political decision makers
regarding vaccine usage. Without reference laboratories around the
world with consistent methods to detect meningitis-causing bacteria an underestimation of the need for healthcare intervention
through vaccination for meningitis persists. An important advance
will be the widespread introduction of PCR-based detection of bacterial pathogens in CSF and blood.
Bacterial meningeal pathogens of particular importance in the
developing world, for which efcacious vaccines still do not exist,
include E. coli and other gram negative bacilli, and S. suis and
Mycobacterium tuberculosis. Novel vaccines against these important
pathogens are still in the early stages of their clinical investigation. This review has highlighted the great impact that bacterial
vaccines have had in the reduction of the burden of meningitis,
but what emerges is that even when effective vaccines are available, there is often still considerable work to be done in order to
ensure uptake and a long-term sustainable funding plan. Recent
studies have provided useful insights into how to promote greater
use of new vaccines. We believe it is therefore reasonable to hope
that the available and emerging vaccines, combined with growing
knowledge of their implementation, will lead to the near elimination of the dominant bacterial pathogens causing meningitis in
most countries within the next decade.
Conict of interest
MB and DS are employees of Novartis Vaccines; MS and KK have
consulted to a broad variety of vaccine manufacturers.
Acknowledgments
This review summarizes a workshop sponsored by Novartis Vaccines and held in Siena, Italy, in July 2011, which was chaired by

KK. We are grateful to all those that contributed during the workshop, including R. Clemens, P. Costantino, E. De Gregorio, D. Diop,
I. Ferlenghi, A. Gentile, D. Granoff, D. Pace, R. Rappuoli, M. Sanicas,
A. Tagliabue, J. Ward, L. Weckx, and X. Zhao. We thank I. Margarit
Y Ros for constructive criticism of the manuscript.

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