Elsevier

The Lancet

Volume 380, Issue 9854, 10–16 November 2012, Pages 1703-1711
The Lancet

Series
Effect of vaccines on bacterial meningitis worldwide

https://doi.org/10.1016/S0140-6736(12)61187-8Get rights and content

Summary

Three bacteria—Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis—account for most acute bacterial meningitis. Measurement of the effect of protein-polysaccharide conjugate vaccines is most reliable for H influenzae 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 influenzae 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 effect 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 influenzae, Streptococcus pneumoniae, and Neisseria meningitidis. We compare patterns of meningitis attributable to these three pathogens, key issues for measurement of disease burden and vaccine effect, and the future role of vaccines in prevention of acute bacterial meningitis.

Section snippets

Causative bacteria before vaccine availability

H influenzae, S pneumoniae, and N meningitidis are the predominant causes of bacterial meningitis, but their relative contribution differs over time, by location, and by age group. Before vaccines became available, H influenzae 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 influenzae in Scandinavia.5 In high-income countries, Streptococcus agalactiae and Listeria monocytogenes were

Measurement of disease burden before and after vaccination programmes

Disease burden from bacterial meningitis includes the sum of cases, deaths, and disability in survivors and is a function of age-specific incidence, access to effective treatment, pathogen virulence, and host immune responses. Such responses are related both to age and immune status, which can be compromised by disorders such as HIV infection,18 and, for pneumococcal meningitis, by sickle-cell disease.19 Optimum measurement of disease burden requires identification of all cases in a defined

Mechanisms of protective immunity

The absence of type-specific opsonising antibody is the most important determinant of susceptibility to bloodstream invasion and meningitis;31, 32, 33 non-capsular factors are also important determinants of virulence, although their role in pathogenesis is less clearly understood.31, 32, 33 Genetic factors are likewise important determinants of susceptibility to pneumococcal and meningococcal infection.34 The first vaccines used the polysaccharide capsule alone as an immunising agent. This

Efficacy trials

The interplay between vaccine immunogenicity and disease epidemiology was underlined by the first two Hib conjugate vaccine clinical trials, which used PRP-D in very different settings. In Finland, PRP-D had an efficacy of 94% (lower 95% CI 83%),44 whereas in Alaska, USA, where Hib incidence was much higher and peaked in the first 6 months rather than the second year of life, vaccine efficacy was 35% (–233%).45 By contrast, when researchers assessed PRP-OMP in Navajo infants, among whom Hib

Post-licensure studies

More data are available for the effect 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 influenzae disease caused by the vaccine serotype (ie, serotype b) was 90–95% and concentrated in one age group.

Herd protection and serotype replacement

For Hib, in low-incidence populations, a small but appreciable proportion of cases has occurred in individuals older than 5 years; indirect protection in this population has been documented in both the UK and Alaska, USA.53, 67 Although increases in non-b serotypes causing invasive disease have been documented (usually non-encapsulated strains and type f) after Hib immunisation in low-incidence populations,68 the pronounced decrease in type b and its predominance as a cause of H influenzae

Best use of existing vaccines

In high-incidence settings, commencing conjugate pneumococcal vaccination at birth has been considered in view of the very early onset of pneumococcal disease, and shown to be immunogenic and not associated with later immune tolerance.76 The issue of how to best use three doses of PCV has been the subject of review.77 Both three-dose primary schedules and two-dose primary schedules with a booster were acceptable, with decisions depending on the programmatic and epidemiological characteristics

Future challenges

In view of the challenges of several changing serotypes, intense interest surrounds development of protein vaccines with broad and ideally universal coverage for both meningococcal and pneumococcal disease. For meningococcal B disease, broad coverage is essential,32 and a multicomponent meningococcal B protein vaccine candidate is immunogenic in infants82 and adolescents,83 as assessed by a novel proxy measure of bactericidal activity. Pneumococcal protein vaccines have long been of interest

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 influenzae” or “Haemophilus infections” in combination with the terms “vaccination” or “vaccines” or “prevention” or “epidemiology” or “surveillance”. We largely selected

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