Review
A vaccine against serogroup B Neisseria meningitidis: dealing with uncertainty

https://doi.org/10.1016/S1473-3099(13)70341-4Get rights and content

Summary

Neisseria meningitidis is an important cause of invasive bacterial infection in children worldwide. Although serogroup C meningococcal disease has all but disappeared in the past decade as a direct result of immunisation programmes in Europe, Canada, and Australia, meningitis and septicaemia caused by serogroup B meningococci remain uncontrolled. A vaccine (4CMenB) has now been licensed for use in the European Union, comprising three immunogenic antigens (identified with use of reverse vaccinology) combined with bacterial outer-membrane vesicles. The vaccine has the potential to reduce mortality and morbidity associated with serogroup B meningococci infections, but uncertainty remains about the breadth of protection the vaccine might induce against the diverse serogroup B meningococci strains that cause disease. We discuss drawbacks in the techniques used to estimate coverage and potential efficacy of the vaccine, and their effects on estimates of cost-effectiveness, both with and without herd immunity. For parents, and clinicians treating individual patients, the predicted benefits of vaccination outweigh existing uncertainties if any cases can be prevented, but future use of the vaccine must be followed by rigorous post-implementation surveillance to reassess its value to health systems with directly recorded epidemiological data.

Introduction

Neisseria meningitidis, a Gram-negative proteobacterium, is a leading cause of bacterial meningitis and septicaemia in children worldwide. The disease is of serious concern for both parents and health professionals, because of difficulties in early recognition, the rapid onset and escalation of infection, high mortality rates, and debilitating sequelae among survivors.1 Nasopharyngeal carriage rates are about 10%, but vary considerably with age, being very low in early childhood and peaking in late adolescence.2 However, the incidence of invasive meningococcal disease is generally low, and has continued to fall during the past decade in many high-income countries. Only 766 laboratory confirmed cases in the UK were reported to the Health Protection Agency in the epidemiological year 2011–12 (July, 2011, to June, 2012),3 and the rate of disease in the USA fell to less than 0·15 cases per 100 000 population in 2012 (ten times less than in the UK).4 Meningitis and septicaemia caused by this organism can be treated with antibiotics, but because of the rapid progression of the illness, early diagnosis is essential for successful treatment. Because early diagnosis is rarely achieved, immunisation is the only rational approach to reduce disease burden and serious outcomes of infection.

N meningitidis can be classified into 12 serogroups on the basis of capsular polysaccharide structure. Prophylactic vaccines based on these capsular polysaccharides, either alone or after chemical conjugation to a protein carrier, are available against the A, C, W, and Y serogroups. Disease caused by serogroup C meningococci has been almost entirely eradicated from countries where conjugate vaccines have been included in highly effective routine immunisation schedules—eg, in Australia,5 Ireland,6 and England and Wales7 (figure 1)—showing the remarkable effectiveness of these vaccines as a result of both direct protection of vaccinated individuals and induction of herd immunity. Most cases of meningococcal infection and septicaemia in high-income countries are now caused by serogroup B meningococci, for which no vaccine is in use. A protein–polysaccharide conjugate vaccine against serogroup B meningococci could not be developed because the capsular polysaccharide as is used in vaccines for other serogroups8 is identical to polysialic acid on many human cells,9 making the vaccine poorly immunogenic and potentially capable of eliciting production of autoantibodies.10

Another approach that has yielded some success in the development of vaccines against serogroup B meningococci is the exploitation of outer-membrane vesicles, which are released from the surface of Gram-negative bacteria during growth and can be extracted at high yield with detergents for use in a vaccine.11 These vesicles are immunogenic because they contain endogenous surface-exposed proteins (eg, the trimeric transmembrane porin protein [PorA], which is the main target of immune response against these outer-membrane vesicles12).

Vaccines based on outer-membrane vesicles have been used effectively for several decades to control regional and national outbreaks of meningococcal disease (eg, the epidemic of serogroup B meningococcal disease that occurred in New Zealand in 1991–2007).13 However, the ability of a vaccine based on outer-membrane vesicles made from a single strain of serogroup B meningococci to protect against endemic disease is limited by the strain specificity of antibodies against PorA.14 PorA is a very diverse protein because of the presence of hypervariable regions on the eight surface-exposed loops that are under immune selection;15 antibodies against one variant do not protect against meningococci expressing a different variant. The prevalence of particular variants changes over time and across geographical regions,16 and as many as nine different serosubtypes of PorA might be needed for a vaccine to cover about 75% of isolates in any one country.17 Up to now, multivalent vaccines based on outer-membrane vesicles containing up to nine serosubtypes of PorA have been produced in an attempt to achieve broad, cross-protective immune responses, but none have yet been licensed.18, 19, 20, 21, 22

In an alternative approach, by prediction of surface-exposed antigenic structures from the bacterial genome (so-called reverse vaccinology), proteins have been identified for inclusion in a new vaccine—the four component meningococcal serogroup B vaccine (4CMenB; Bexsero, Novartis Vaccines, Siena, Italy). The licensure of 4CMenB by the European Commission in January, 2013, for use in the European Union in people older than 2 months,23 was one of the most important advances for public health in Europe in the past decade. As a result, the Department of Health's Joint Committee on Vaccination and Immunisation has been considering the use of the vaccine in the UK since 2011.

However, although the vaccine has shown acceptable immunogenicity and safety in trials,24, 25, 26 no data about vaccine efficacy exist because the sample size needed to show this effect is too large to contemplate in a formal clinical trial, and the crucial questions about herd immunity cannot be easily addressed without a high-uptake programme. As a result, the potential of the 4CMenB vaccine is based on assumptions derived mostly from in-vitro findings about immunogenicity and experience with outer-membrane-vesicle vaccines.

In this Review we aim to provide an overview of the vaccine's development and composition, summarise and assess the uncertainties surrounding the use of 4CMenB, and emphasise the need for careful assessment of any future programmes.

Section snippets

Development

The 4CMenB vaccine was developed by reverse vaccinology—ie, searching of the complete meningococcal genome in silico for genes predicted to encode proteins that are either exposed on the pathogen's surface or secreted, and are therefore accessible to antibodies. Several potential vaccine candidates were identified with this technique,27 including three proteins selected for inclusion in the 4CMenB vaccine: factor H binding protein (fHbp), neisserial adhesion A (NadA), and neisserial heparin

Estimation of protective immunity and vaccine coverage

Estimation of the amount of protection from any potential vaccine against serogroup B meningococci is difficult, and is especially complex for the multi-component vaccine 4CMenB. With only 614 laboratory confirmed cases of invasive disease in the UK between July, 2011, and June, 2012,3 serogroup B meningococcal disease is a rare but very serious illness. Statistically significant data about the amount of protection that can be achieved by vaccination for a disease affecting as few as 1–2 per

SBA assay

In the SBA assay, bactericidal activity is characterised in vitro by measurement of the complement-mediated killing of meningococci by antibodies in serum samples from vaccinated individuals, in the presence of exogenous complement (figure 3). Although complement from baby rabbit serum can be readily standardised and is used in the assay for serogroup C meningococcal disease, it does not contain human factor H and therefore generally produces higher titres than does human complement. For this

The meningococcal antigen typing system

Although the SBA assay provides information about the ability of a vaccinee's blood to kill meningococci in vitro, it does not provide information about the individual contribution of each of the vaccine's components to antibody response. The meningococcal antigen typing system was developed by Donnelly and colleagues42 in 2010 in an attempt to provide an assay that combines assessment of the quality (antigenicity) and quantity (level of expression) of antigens on the bacterial surface with

Potential effect

By extrapolation from existing data for the outer-membrane-vesicle component, SBA data provide convincing evidence that the 4CMenB vaccine will prevent some cases of meningococcal disease in the UK, because about 40% of the UK isolates of serogroup B meningococci submitted to the Meningitis Research Foundation's Meningococcus Genome Library in 2012 belonged to the ST-41/44 clonal complex from which vaccine outer-membrane vesicles are derived. However, because predictions of the potential

Conclusions

The development of 4CMenB by reverse vaccinology has allowed important progress to be made towards the goal of controlling meningococcal disease. With the recent licensing of the 4CMenB vaccine for use in the European Union, there is for the first time a possibility of implementation of a vaccine that could prevent a proportion of cases of this important childhood disease. The recommendation by the Joint Committee on Vaccination and Immunisation published in March, 2014, for implementation of

Search strategy and selection criteria

We searched PubMed and Web of Knowledge with the search terms “(Neisseria meningitidis OR meningococcus OR meningococcal disease) AND vaccine AND (Serogroup B OR Serotype B)”. Articles published in English from November, 1999, to December, 2013, were selected with emphasis given to papers published after January, 2009. Further studies were identified from the reference lists of the articles identified by the search.

References (81)

  • S Bambini et al.

    Distribution and genetic variability of three vaccine components in a panel of strains representative of the diversity of serogroup B meningococcus

    Vaccine

    (2009)
  • JW Marsh et al.

    Diversity of factor H-binding protein in Neisseria meningitidis carriage isolates

    Vaccine

    (2011)
  • DM Vu et al.

    Cooperative serum bactericidal activity between human antibodies to meningococcal factor H binding protein and neisserial heparin binding antigen

    Vaccine

    (2011)
  • T Vesikari et al.

    Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials

    Lancet

    (2013)
  • P Richmond et al.

    Safety and immunogenicity of a new Neisseria meningitidis serogroup C-tetanus toxoid conjugate vaccine in healthy adults

    Vaccine

    (1999)
  • R Arnold et al.

    Effectiveness of a vaccination programme for an epidemic of meningococcal B in New Zealand

    Vaccine

    (2011)
  • HQ Jiang et al.

    Broad vaccine coverage predicted for a bivalent recombinant factor H binding protein based vaccine to prevent serogroup B meningococcal disease

    Vaccine

    (2010)
  • U Vogel et al.

    Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment

    Lancet Infect Dis

    (2013)
  • E Hong et al.

    Could the multicomponent meningococcal serogroup B vaccine (4CMenB) control Neisseria meningitidis capsular group X outbreaks in Africa?

    Vaccine

    (2013)
  • G Frosi et al.

    Bactericidal antibody against a representative epidemiological meningococcal serogroup B panel confirms that MATS underestimates 4CMenB vaccine strain coverage

    Vaccine

    (2013)
  • E Miller et al.

    Planning, registration, and implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: a success story

    Vaccine

    (2001)
  • H Christensen et al.

    Introducing vaccination against serogroup B meningococcal disease: an economic and mathematical modelling study of potential impact

    Vaccine

    (2013)
  • MD Snape et al.

    The challenge of post-implementation surveillance for novel meningococcal vaccines

    Vaccine

    (2012)
  • Invasive meningococcal infections laboratory reports, England and Wales by capsular group & epidemiological year, 1998/99–2011/12, 14/09/2012

  • Active Bacterial Core Surveillance (ABCs) report—emerging infections program network: Neisseria meningitidis, 2012-provisional

  • Australian meningococcal surveillance programme annual reports, 1998–2012

  • Meningococcal disease annual report

    (2011)
  • Invasive meningococcal C infections laboratory reports, England and Wales by age group & epidemiological year, 1998/99–2011/12, 14/09/2012

  • I Goldschneider et al.

    Human immunity to the meningococcus. I. The role of humoral antibodies

    J Exp Med

    (1969)
  • J Häyrinen et al.

    Antibodies to polysialic acid and its N-propyl derivative: binding properties and interaction with human embryonal brain glycopeptides

    J Infect Dis

    (1995)
  • TJ Beveridge

    Structures of gram-negative cell walls and their derived membrane vesicles

    J Bacteriol

    (1999)
  • DR Martin et al.

    The VR2 epitope on the PorA P1.7-2,4 protein is the major target for the immune response elicited by the strain-specific group B meningococcal vaccine MeNZB

    Clin Vaccine Immunol

    (2006)
  • ER van der Voort et al.

    Specificity of human bactericidal antibodies against PorA P1.7,16 induced with a hexavalent meningococcal outer membrane vesicle vaccine

    Infect Immun

    (1996)
  • JE Russell et al.

    PorA variable regions of Neisseria meningitidis

    Emerg Infect Dis

    (2004)
  • CT Sacchi et al.

    Diversity and prevalence of PorA types in Neisseria meningitidis serogroup B in the United States, 1992–1998

    J Infect Dis

    (2000)
  • AS Anderson et al.

    New frontiers in meningococcal vaccines

    Expert Rev Vaccines

    (2011)
  • P Van Der Ley et al.

    Construction of a multivalent meningococcal vaccine strain based on the class 1 outer membrane protein

    Infect Immun

    (1992)
  • European Medicines Agency recommends approval of first vaccine for meningitis B, 2012

  • D Toneatto et al.

    The first use of an investigational multicomponent meningococcal serogroup B vaccine (4CMenB) in humans

    Hum Vaccin

    (2011)
  • N Gossger et al.

    Immunogenicity and tolerability of recombinant serogroup B meningococcal vaccine administered with or without routine infant vaccinations according to different immunization schedules: a randomized controlled trial

    JAMA

    (2012)
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