Outbreaks of meningococcal B infection and the 4CMenB vaccine: historical and future perspectives

Abstract

Strains of Neisseria meningitidis serogroup B (MenB) causing invasive meningococcal disease are genetically diverse; however, only a small number of hyperinvasive lineages (CC32, CC41/44, CC269 and CC162) have dominated during the global spread over the past 50 years. Since the mid-1970s, major outbreaks and hyperendemic disease have been reported in Norway, Cuba, France, Canada, New Zealand (and elsewhere), most recently in the USA. We characterized the epidemiology of these MenB outbreaks and their associated clonal complexes and retrospectively assessed the potential coverage offered by the 4CMenB vaccine, a four-component vaccine developed to help confer protection against a broad range of meningococcal B strains causing disease. Of 21 isolates from four clonal complexes evaluated using both human Serum Bactericidal Assay and the Meningococcal Antigen Testing System, coverage ranged from 67 to 100%. 4CMenB shows good potential as a candidate vaccine to be used in the control of new MenB outbreaks globally.

Keywords:

• 4CMenB
• coverage
• epidemiology
• invasive meningococcal disease
• Neisseria meningitidis, serogroup B
• outbreaks
• vaccine

Acknowledgements

We would like to thank the following people for providing strains: L Mayer, CDC, Atlanta, United States; R Borrow, Health Protection Agency, Public Health Laboratory, Manchester, United Kingdom; G Tzanakaky, National Meningitis Reference Laboratory National School of Public Health, Athens, Greece; DA Caugant, NIPH, Oslo, Norway; DR Martin, Institute of Environmental Science and Research, Porirua, New Zealand; R Moxon, University of Oxford, UK; MK Taha, Institute Pasteur, Paris, France. We would also like to thank, our colleagues M Pizza, J Wassil, M Moschioni, P Watson and G Wilkinson for their critical appraisal of the manuscript, and G Corsi for his assistance with the artwork (Figure 1).

Financial & competing interests disclosure

The authors are employees of Novartis Vaccines. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Outbreaks of serogroup B invasive meningococcal disease have been recognized worldwide since serotyping of isolates was first developed in the 1970s. Disease-causing serogroup B strains are genetically diverse, but a small number of hyperinvasive lineages (CC32, CC41/44, CC269 and CC162) have dominated during global spread over the past 40 years.

• Serogroup B outbreaks are often characterized by a moderate rise in disease incidence, but epidemics can last decades. In response, some countries have developed and tested outbreak strain-specific outer membrane vesicle (OMV) vaccines. Though often effective, these vaccines have the disadvantage that they take time to develop, test and authorize and are poorly immunogenic to heterologous strains. Two protein-based vaccines have recently been developed to help confer protection against a broad range of meningococcal B strains causing disease: 4CMenB (Bexsero^®, Novartis Vaccines) and rLP2086 (Trumenba^®, Pfizer Inc.).

• In this paper, we review the 4CMenB vaccine, which is formulated with three major recombinant proteins typically expressed by serogroup B: factor H-binding protein, Neisserial heparin-binding antigen and Neisseria Adhesin A, combined with bacterial OMV derived from the New Zealand outbreak strain NZ98/254.

• We characterized the epidemiology of the major MenB outbreaks worldwide that have occurred over the last 40 years (in Norway, Cuba, Canada, USA, France and elsewhere) and their associated clonal complexes, and retrospectively evaluated the coverage offered by 4CMenB of the outbreak strains. Of 21 strains from four clonal complexes evaluated using both human serum bactericidal assay (hSBA) and the meningococcal antigen testing system (MATS), coverage ranged from 67% to 100%.

• Direct evidence of vaccine safety and efficacy of 4CMenB, and of the indirect effects of immunization on nasopharyngeal carriage and herd immunity, are not yet available. There was no evidence of serious adverse events associated with the vaccine after almost 45,000 first dose vaccinations were administered in Québec, Canada.

• Based on retrospective coverage of outbreak strains reported here (most recently in two university outbreaks in the USA in 2013) and immunogenicity data suggesting >90% protection in adolescents within 1 month of a single dose, 4CMenB shows good potential as a candidate vaccine to be used in the control of new MenB outbreaks.