Describe the changes in the etiology of bacterial meningitis in the US between 1986 and 2003, and what was the cause of this change?
Series
Bacterial Meningitis 3
E?ect of vaccines on bacterial meningitis worldwide
Peter B McIntyre, Katherine L O’Brien, Brian Greenwood, Diederik van de Beek
Three bacteria—Haemophilus in?uenzae, Streptococcus pneumoniae, and Neisseria meningitidis—account for most
acute bacterial meningitis. Measurement of the e?ect of protein-polysaccharide conjugate vaccines is most reliable
for H in?uenzae meningitis because one serotype and one age group account for more than 90% of cases and the
incidence has been best measured in high-income countries where these vaccines have been used longest.
Pneumococcal and meningococcal meningitis are caused by diverse serotypes and have a wide age distribution;
measurement of their incidence is complicated by epidemics and scarcity of surveillance, especially in low-income
countries. Near elimination of H in?uenzae meningitis has been documented after vaccine introduction. Despite
greater than 90% reductions in disease attributable to vaccine serotypes, all-age pneumococcal meningitis has
decreased by around 25%, with little data from low-income settings. Near elimination of serogroup C meningococcal
meningitis has been documented in several high-income countries, boding well for the e?ect of a new serogroup A
meningococcal conjugate vaccine in the African meningitis belt.
Introduction
Primary prevention of meningitis is paramount, since
death and long-term disabling sequelae are substantial in
all settings, especially those with least access to health
care.1 Low-income and middle-income countries account
for 98% of the estimated 5·6 million disability-adjusted
life years attributed to meningitis globally and bacterial
meningitis ranks among the top ten causes of death in
children younger than 14 years in high-income countries.2 Several vaccines are relevant to prevention of
bacterial meningitis worldwide, such as BCG vaccine for
the prevention of tuberculous meningitis, but in this
review, we focus on the three most common causes
of acute bacterial meningitis: Haemophilus in?uenzae,
Streptococcus pneumoniae, and Neisseria meningitidis. We
compare patterns of meningitis attributable to these
three pathogens, key issues for measurement of disease
burden and vaccine e?ect, and the future role of vaccines
in prevention of acute bacterial meningitis.
Causative bacteria before vaccine availability
H in?uenzae, S pneumoniae, and N meningitidis are the
predominant causes of bacterial meningitis, but their
relative contribution di?ers over time, by location, and by
age group. Before vaccines became available, H in?uenzae
was the most common cause of bacterial meningitis in
the USA, followed by S pneumoniae,3 whereas in Europe
N meningitidis was most common in the UK,4 and
H in?uenzae in Scandinavia.5 In high-income countries,
Streptococcus agalactiae and Listeria monocytogenes were
other substantial causes.4,6 In Africa, epidemics of
meningococcal disease occur in a well de?ned region—
the meningitis belt.7 In this region, even in interepidemic
periods, incidence of all-cause bacterial meningitis was
15 times greater than that in the USA in 1986.3,8 Both
within8 and outside9 meningitis-belt countries, infants
had the highest incidence of bacterial meningitis, predominantly caused by H in?uenzae.9 Other important
www.thelancet.com Vol 380 November 10, 2012
causes of meningitis in low-income countries are
Enterobacteriaceae (especially non-typhoidal salmonella
species) in children in sub-Saharan Africa,8,10 and
Streptococcus suis in adults in southeast Asia.11
H in?uenzae, S pneumoniae, and N meningitidis have
several similarities and di?erences (table 1). Similarities
with important implications for vaccine development
include being largely or entirely human pathogens,
possession of a polysaccharide capsule that is the main
determinant of virulence, and that capsular types associated with meningitis are only a small subset of those
that colonise the nasopharynx. Important di?erences
include the proportion of disease accounted for by one
serotype and propensity to cause outbreaks.
In the case of H in?uenzae, before immunisation one
capsular serotype (H in?uenzae type b—Hib) caused
almost all cases and the age-range of cases was largely
limited to children younger than 5 years.3,4,8 Outbreak
potential is greatest for N meningitidis, which has
caused regular epidemics in sub-Saharan Africa.7 These
epidemics are attributable mainly to serogroup A meningococci, but outbreaks attributable to serogroup C and, in
the past 10 years, serogroups W135 and X have been
Lancet 2012; 380: 1703–11
See Comment page 1623
This is the third in a Series of
three papers about bacterial
meningitis
National Centre for
Immunisation Research and
Surveillance of
Vaccine-Preventable Diseases,
The Children’s Hospital at
Westmead and the University
of Sydney, Sydney, NSW,
Australia (Prof P B McIntyre MD);
International Vaccine Access
Center (IVAC) and Center for
American Indian Health (CAIH),
Johns Hopkins Bloomberg
School of Public Health,
Baltimore, MD, USA
(Prof K L O’Brien MD); Faculty of
Infectious and Tropical
Diseases, London School of
Hygiene and Tropical Medicine,
London, UK
(Prof B Greenwood MD);
Department of Neurology,
Center for Infection and
Immunity Amsterdam
(CINIMA), Academic Medical
Centre, University of
Amsterdam, Amsterdam,
Netherlands
(Prof D van de Beek MD)
Correspondence to:
Prof Peter McIntyre, National
Centre for Immunisation
Research and Surveillance of
Vaccine-Preventable Diseases,
Locked Bag 4001, Westmead,
Sydney, NSW 2145, Australia
[email protected].
gov.au
Search strategy and selection criteria
We searched the Cochrane Library (The Cochrane Library 2011, issue 1), Medline (1966 to
March, 2012), and Embase (1974 to March, 2012). We used the search terms “bacterial
meningitis” or “meningitis” or “meningococcal disease” or “Neisseria meningitidis” or
“pneumococcal disease” or “Streptococcus pneumoniae” or “Haemophilus in?uenzae” or
“Haemophilus infections” in combination with the terms “vaccination” or “vaccines” or
“prevention” or “epidemiology” or “surveillance”. We largely selected publications from
the past 5 years, but did not exclude commonly referenced and highly regarded older
publications. We also searched the reference lists of articles identi?ed by this search
strategy and selected those we judged relevant. Review articles and book chapters are
cited to provide readers with more details and more references than can be included in
this review. We modi?ed our reference list on the basis of comments from peer reviewers.
1703
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Haemophilus in?uenzae
Streptococcus pneumoniae
Neisseria meningitidis
Cell wall
Gram negative
Gram positive
Gram negative
Capsular types
6 capsular types (a–f)
Capsular type b in >90%
Other capsular types can cause meningitis,
especially type a; unencapsulated rarely
>90 capsular types
Prominent serotype variation; by region, time period,
and invasive potential
Wide distribution of serotypes with high incidence
12 serogroups
Most disease due to 6 serogroups
(A, B, C, W135, X, Y)
Unencapsulated meningococci
predominate in carriage
Laboratory
detection
Fastidious, requires speci?c culture media Fastidious, requires speci?c culture media
Specialised laboratory facilities required for Specialised laboratory facilities required for serotyping
capsular typing
Colonisation vs
disease
Carriage 3–5% in high-income countries,
2 to 3 times higher in settings with high
incidence of invasive disease
Carriage increases steeply in early infancy in
low-income settings, later increase elsewhere
Up to 90% of infants 1000 (epidemic)*
Lowest incidence region (Europe)
16 (12–22)
6 (5–9)
Highest mortality region (Africa)*
31 (20–35)
28 (7–36)
··
Lowest mortality region (Europe)†
4 (3–6)
3 (1–7)
··
Cases
1–2 (endemic)†
2–10 (epidemic)†
Deaths
Morbidity
9·5% (7·1–15·3)
Proportion of survivors with
major long-term sequelae1
24·7% (16·2–35·3)
7·2% (4·3–11·2)
Data are n per 100 000 population per year (95% CI) unless otherwise speci?ed. Mean proportion of survivors with
major long-term sequelae for all organisms combined in the highest incidence regions is 25% (95% CI 19–32), and in the
lowest incidence regions is 9% (7–12).1 *African meningitis belt. †Low incidence regions for invasive meningococcal
disease—Europe, USA, and Australia.
Table 2: Estimates of global disease burden for meningitis attributable to Haemophilus in?uenzae type b,
Streptococcus pneumoniae (children younger than 5 years), and Neisseria meningitidis (all ages), by
organism and region
A
Under 5 population (million)
150
130
India
110
90
China
70
Nigeria
50
Bangladesh
30
Pakistan
Brazil
10
Mozambique
Democaratic Republic
of the Congo
Ethiopia
Côte d’Ivoire
–10
B
150
Under 5 population (million)
low-income countries.1,12,21–23 For Hib, ascertainment is
fairly uniform for all invasive disease including meningitis in high-income countries, although less so for other
H in?uenzae serotypes because appropriate laboratory
methods are sometimes lacking. For S pneumoniae,
even in high-income countries, ascertainment of nonmeningitic invasive disease varies substantially,15,25 but
ascertainment of meningitis has been more consistent.17,25
Molecular methods for diagnosis have increased case
ascertainment and might also help to establish serotype
distribution.26 During epidemics, the burden of meningococcal disease in the African meningitis belt greatly
exceeds that for H in?uenzae or pneumococcal meningitis
in other low-income countries. Outside epidemic situations, the incidence of cases attributable to Hib or
pneumococcal meningitis in low-income countries
exceeds that in high-income settings by a factor of three,
with six times more deaths. The increased probability of
severe sequelae in survivors of pneumococcal meningitis
adds to its overall disease burden.
In the setting of a vaccine trial, disease estimates can be
enhanced by the so-called vaccine probe design. This
technique measures the vaccine-preventable fraction of
meningitis de?ned by syndromic surveillance, whereby
cases identi?ed in individuals randomised to receive
vaccine are subtracted from those randomised to receive
placebo. In a hamlet-randomised study of Hib vaccine on
the island of Lombok, Indonesia,27 because of increased
sensitivity of the vaccine probe approach, the estimated
incidence of Hib meningitis was revised from 16 per
100 000 (95% CI 1–31) on the basis of microbiologically
con?rmed cases alone to 158 per 100 000 (42–273). The
Lombok trial estimates are consistent with those from
populations in Africa with high quality surveillance and
laboratory methods and low use of antibiotics before
specimen collection,28 and with data from indigenous
populations that share many epidemiological characteristics and risk factors with low-income countries.29,30
Researchers have attempted to quantify pathogen-speci?c
meningitis burden at the country level on the basis of a
systematic review of incidence and case-fatality rate, with
data assessed according to quality metrics and, when adequate, included in a model that adjusted for access to
care, HIV prevalence, and Hib vaccine use.21,22,24 Figure 1
shows the estimated number of Hib and pneumococcal
meningitis deaths in the ten countries with the greatest
absolute number of such deaths in 2000, on the basis of
global burden of disease studies.21,22
130
India
110
90
China
70
50
Indonesia
30
Nigeria
Bangladesh
Democratic Republic
of the Congo
Tanzania
Pakistan
10
Ethiopia
Philippines
–10
0
5
10
15
20
25
30
35
Meningitis deaths (per 100 000) in children younger than 5 years
40
45
Figure 1: Estimated number of Hib and pneumococcal meningitis deaths in children aged 1–59 months,
in 200021,22
Bubble size indicates number of Haemophilus in?uenzae type b (Hib, A) or pneumococcal (B) meningitis deaths.
1705
Series
B cells.31,35 Consequently, after vaccination antibody concentrations wane rapidly in young children, there is no
anamnestic response to later doses of the polysaccharide,
and little or no e?ect on nasopharyngeal or oropharyngeal
carriage.35 E?ectiveness of polysaccharide vaccines against
meningitis has been shown most convincingly for serogroup A meningococcal disease, but protection waned
after 3 years, and was poor among children younger than
2 years.13,36 Similarly, antibody responses to most serotypes
after pneumococcal polysaccharide vaccines are poor in
children younger than 2 years. In adults, these vaccines
are e?cacious against invasive pneumococcal disease
attributable to vaccine serotypes, and by implication also
meningitis, but no speci?c data are available.37 Little e?ect
of Hib polysaccharide vaccine on disease, especially
meningitis, was recorded during routine use of this
vaccine in US children older than 24 months despite
documented e?cacy,38 probably because of the small
proportion of Hib meningitis cases in this age group.
Conjugate vaccines
Conjugate vaccines are T-cell-dependent, allowing development of memory B cells, and consequent anamnestic
responses and, importantly, they a?ect carriage.31,35
The ?rst commercially viable conjugate vaccine was
produced against Hib.14 Manufacturers used di?erent
proteins (diphtheria toxoid [D], the outer membrane
protein of N meningitidis serogroup B [OMP], tetanus
toxoid [TT], or mutant diphtheria toxin [CRM] conjugated
to Hib polysaccharide [PRP]).14,31 One vaccine, PRP-OMP,
was associated with antibody response after one dose, an
important advantage for settings where Hib disease
occurred very early in life. Other Hib conjugates (PRP-T,
PRP-CRM, and PRP-D) required two or three doses to
achieve such antibody response.14,39 The ?rst pneumococcal conjugate vaccine (PCV), which used CRM as the
protein carrier, was ?rst licensed and recommended for
routine use in the USA in 2000. It included seven of the
most common serotypes causing invasive disease (4, 6B,
9V, 14, 18C, 19F, 23F). Other vaccines with nine, ten, 11,
or 13 conjugates (including serotypes 1, 3, 5, 6A, 7F, 19A)
have been studied, with the ten-valent and 13-valent
products reaching licensure. For these products,
immunogenicity varies by serotype, number of doses,
concomitant vaccine administration, and population
studied.40 Trials with both immunogenicity and clinical
outcome measures have allowed development of antibody correlates of protection deemed su?cient for
licensure without e?cacy trials.41
The ?rst meningococcal conjugate vaccine to become
available used the serogroup C polysaccharide conjugated
to CRM; subsequently TT conjugates and serogroup A,
W135, and Y conjugates have been developed.42 Epidemiological studies have shown a well de?ned threshold for
serogroup C serum bactericidal activity, which correlates
with protection against serogroup C invasive disease; all
meningococcal C conjugates met this threshold.42 A
1706
monovalent serogroup A meningococcal conjugate
vaccine has been developed speci?cally for use in the
meningitis belt, with immunogenicity studies showing
that it is signi?cantly better than polysaccharide A vaccine
after one or two doses in children and young adults.43
E?cacy trials
The interplay between vaccine immunogenicity and
disease epidemiology was underlined by the ?rst two
Hib conjugate vaccine clinical trials, which used PRP-D
in very di?erent settings. In Finland, PRP-D had an
e?cacy of 94% (lower 95% CI 83%),44 whereas in Alaska,
USA, where Hib incidence was much higher and peaked
in the ?rst 6 months rather than the second year of life,
vaccine e?cacy was 35% (–233%).45 By contrast, when
researchers assessed PRP-OMP in Navajo infants,
among whom Hib disease occurred predominantly in
the ?rst few months of life,29 as in Alaska Native and
Australian Aboriginal infants, e?cacy was 95% (72%)
after two doses and protective after one dose (lower
95% CI for one dose 45%).46
Trials of a seven-valent PCV with a four-dose schedule
were done in California, USA,47 and also in Navajo infants48
who have higher incidence and greater serotype diversity
of invasive pneumococcal disease than do infants in the
general US population. These trials showed high e?cacy
against vaccine serotype invasive pneumococcal disease of
94%47 and 83%,48 respectively. Trials of a nine-valent vaccine
given in a three-dose primary schedule at 6, 10, and
14 weeks of age according to Expanded Programme on
Immunization recommendations in South Africa and The
Gambia showed similar e?cacy against vaccine serotypes,
except in HIV-infected children.49,50 The e?cacy against all
serotype meningitis or sepsis in these trials was less than
recorded in US studies, because of higher baseline
incidence of non-vaccine serotype disease.49,50 Despite this
?nding, in the high mortality setting of The Gambia,
vaccination resulted in a 16% (95% CI 3–28) reduction in
all-cause mortality.50
None of the meningococcal conjugate vaccines have
been tested in randomised controlled trials with disease
endpoints, because these were not thought justi?ed in
the context of immunological correlates of protection
that reliably predict vaccine e?ectiveness.42 E?cacy
against meningococcal meningitis is, therefore, inferred
from post-licensure studies of e?ectiveness.
Post-licensure studies
More data are available for the e?ect of Hib vaccines when
delivered through routine immunisation programmes
than for either pneumococcal or meningococcal vaccines.
First, in high-income countries, routine use of Hib vaccine
preceded that of pneumococcal or meningococcal vaccines
and the background rate of Hib meningitis was high.4,5
Second, the proportion of invasive H in?uenzae disease
caused by the vaccine serotype (ie, serotype b) was 90–95%
and concentrated in one age group.
www.thelancet.com Vol 380 November 10, 2012
Series
High-income countries
www.thelancet.com Vol 380 November 10, 2012
Annual incidence (all ages) per 100 000 population
6
Listeria monocytogenes
Streptococcus agalactiae
50
Neisseria meningitidis
Streptococcus pneumoniae
Haemophilus influenzae
Median case age
45
5
40
35
4
30
25
3
20
2
Median age (years)
Conjugate Hib vaccines were introduced into routine use
?rst in the USA, from 1987 at 18 months of age and from
1991 at 2 months of age, with most high-income countries
following during the 1990s; these vaccines have proved
highly e?ective in all settings.51 The ?rst conjugate
pneumococcal vaccine, containing conjugates of the
seven most common serotypes in the USA, was
introduced into routine practice in 2000. Figure 2 shows
changes in incidence estimates for bacterial meningitis
from surveillance of more than 10 million people in the
USA after the introduction of conjugate vaccines against
invasive Hib disease (after 1986) and invasive pneumococcal disease due to seven serotypes (after 1998).3,6,52
The reduction in all-age incidence of H in?uenzae
meningitis shown in ?gure 2—more than 97% in the
20 years from 1986 to 2007—shows the profound
population-wide e?ect of Hib vaccines in the USA.3,6,52
Furthermore, the proportion of H in?uenzae meningitis
cases due to serotype b decreased sequentially from
95%, to 33%, to 9%.3,6,52 Among high-income countries,
two exceptions to the near elimination of H in?uenzae
meningitis arose. In the UK, a rebound in Hib disease
occurred in the 1990s. This recurrence was attributed to
waning of herd e?ects generated by an initial catch-up
campaign among children younger than 5 years, low
PRP antibody concentrations after use of a Hib-acellularpertussis combined vaccine, and an accelerated primary
dose schedule with no booster dose.53 This rebound of
Hib disease resolved with the introduction of a booster
dose in the second year of life and a temporary catch-up
campaign in children aged 2–4 years.54 In Alaska, USA,55
with a historically high incidence of Hib disease, an
increase in H in?uenzae meningitis occurred after
replacement of PRP-OMP with PRP-CRM vaccine.55
This occurrence was presumed to result from an
insu?cient antibody response after the ?rst or second
dose of PRP-CRM, combined with persistent circulation
of Hib within the community despite a routine Hib
vaccine programme.14,55
De?nitive data for the e?ect of a seven-valent
pneumococcal conjugate vaccine on meningitis have
emerged from large populations in the USA52 and
England and Wales.56 All-age incidence of pneumococcal
meningitis of any serotype in the USA remained
stable before introduction of pneumococcal conjugate
vaccines from 1998, but by 2006–07 a 26% (95% CI
23–29) reduction had occurred (?gure 2).52 The decrease
in pneumococcal meningitis is closer to that recorded
for Hib meningitis when only vaccine serotypes or the
age group with the highest incidence of pneumococcal
meningitis is considered. Speci?cally, all-age incidence
of vaccine-serotype meningitis decreased by 92%
(91–93) and incidence of pneumococcal meningitis in
children younger than 2 years attributable to any serotype by 62% (58–66), despite an increase in the all-age
incidence of meningitis due to non-vaccine serotypes of
15
10
1
5
0
0
19863
19956
199862
200752
Year
Figure 2: Prevalence of bacterial meningitis in the USA attributable to Haemophilus in?uenzae, Streptococcus
pneumoniae, Neisseria meningitidis, Streptococcus agalactiae, and Listeria monocytogenes, 1986–20073,6,52
61% (54–69) and in children younger than 5 years of
92% (68–119).52 Similarly, in England and Wales, an
overall reduction of 44% (11–54) in pneumococcal
meningitis was recorded in children younger than
5 years after introduction of a seven-valent pneumococcal conjugate vaccine, despite an increase in nonvaccine serotypes of 77% (27–247).55 In the USA and
England and Wales, these reductions occurred in the
context of the seven serotypes in the vaccine, accounting
for almost 80% of pneumococcal meningitis before
vaccine introduction.52,56
Variability in the incidence of meningococcal disease
in the absence of vaccination, both overall and by
serogroup, complicates assessment of vaccine e?ect. For
example, in the USA, meningococcal meningitis steadily
decreased in the absence of speci?c interventions
including immunisation (?gure 2).3,6,52 However, several
countries with recent increases in the incidence of
serogroup C meningococcal disease have shown substantial reductions in serogroup C disease after largescale vaccination campaigns with meningococcal C
conjugate vaccines.23,57,58 Figure 3 shows the near disappearance of N meningitidis serogroup C disease in
England and Wales and the Netherlands after such
campaigns, with reductions of more than 98% in targeted
age groups and of more than 90% in age groups not
included.56,58 In New Zealand, a strain-speci?c group B
vaccine, based on the outer membrane vesicle protein,
was given in a broad population campaign, with special
focus on Maori Paci?c Island populations with the
greatest disease burden.59 Results of observational studies
showed a signi?cant vaccine e?ect that persisted after
adjustment for precampaign downward trends.60
1707
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Low-income countries
Data from several high-incidence settings in Africa show
rapid, pronounced decreases in both culture-proven Hib
meningitis and all presumptive bacterial meningitis in
the short term.61 However, in South Africa, 10 years after
routine vaccination, an increasing trend in Hib meningitis has been reported, mainly in children with HIV
infection.62 In The Gambia, after near elimination of
invasive Hib disease in 2002,63 an increase in the
Age groups not targeted by immunisation campaign in each country
Case age groups

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