Use of expanded Neisseria meningitidis serogroup B panels with the serum bactericidal antibody assay for the evaluation of meningococcal B vaccine effectiveness

ABSTRACT

Introduction

Neisseria meningitidis serogroup B (NmB) antigens are inherently diverse with variable expression among strains. Prediction of meningococcal B (MenB) vaccine effectiveness therefore requires an assay suitable for use against large panels of epidemiologically representative disease-causing NmB strains. Traditional serum bactericidal antibody assay using exogenous human complement (hSBA) is limited to the quantification of MenB vaccine immunogenicity on a small number of indicator strains.

Areas covered

Additional and complementary methods for assessing strain coverage developed previously include the Meningococcal Antigen Typing System (MATS), Meningococcal Antigen Surface Expression (MEASURE) assay, and genotyping approaches, but these do not estimate vaccine effectiveness. We provide a narrative review of these methods, highlighting a more recent approach involving the hSBA assay in conjunction with expanded NmB strain panels: hSBA assay using endogenous complement in each vaccinated person’s serum (enc-hSBA) against a 110-strain NmB panel and the traditional hSBA assay against 14 (4 + 10) NmB strains.

Expert opinion

The enc-hSBA is a highly standardized, robust method that can be used in clinical trials to measure the immunological effectiveness of MenB vaccines under conditions that mimic real-world settings as closely as possible, through the use of endogenous complement and a diverse, epidemiologically representative panel of NmB strains.

Plain Language Summary

Meningococcal disease refers to illnesses caused by the bacterium Neisseria meningitidis (meningococcus), including infections of the brain lining and spinal cord (meningitis) and bloodstream (septicemia). It is rare but often severe and can be deadly. Invasive meningococcal disease can be prevented through vaccination. Nearly all cases are caused by six serogroups (types) of meningococci, including meningococcal serogroup B. Vaccines are available against meningococcal serogroup B but, because of the uncommonness of the disease, standard clinical trials could not be performed to prove these vaccines are effective. Instead, an indirect measure, called the ‘hSBA assay' (serum bactericidal antibody assay using human complement), is used to measure the ability of vaccines to provide protection against specific N. meningitidis strains that have antigens (substances that cause the immune system to react) sharing characteristics with components of the vaccines. However, meningococcal serogroup B strains are diverse in the genetic composition and expression of vaccine antigens. Hence, a large number of N. meningitidis serogroup B strains would have to be tested to make sure that the vaccine is effective against these strains. This is not feasible using the traditional hSBA assay, which requires a human complement (a protein system, which is part of the immune system) that has not come from the vaccinated person and is difficult and time-consuming to source. Recently, an alternative hSBA assay was developed that uses the complement present in each vaccinated person’s blood (endogenous complement) and which overcomes these challenges. By allowing testing against a broad panel of N. meningitidis serogroup B strains, this new assay may enable a more accurate estimation of the effectiveness of vaccines against serogroup B meningococci.

KEYWORDS:

• 4CMenB
• complement
• invasive meningococcal disease
• MenB-FHbp
• Neisseria meningitidis
• serum bactericidal antibody assay
• vaccine
• vaccine effectiveness

Article highlights

• Accurate prediction of meningococcal serogroup B (MenB) vaccine coverage is challenging with the traditional human complement serum bactericidal antibody (hSBA) assay because of diversity in both the genetic features and level of expression of vaccine antigens across Neisseria meningitidis serogroup B (NmB) strains.

• Different methods exist to predict MenB vaccine strain coverage, including the Meningococcal Antigen Typing System (MATS), Meningococcal Antigen Surface Expression (MEASURE) assay, and genetic tools, such as genetic MATS (gMATS), but these do not take into account the synergistic effect of antibodies against multiple antigens and tend to provide an overly conservative estimate for multicomponent MenB vaccines.

• To complement these tools, two methods have been developed to assess MenB vaccine effectiveness in a clinical trial setting and thus comprehensively evaluate the effectiveness of MenB vaccines. These measure serum bactericidal activity against a large panel of epidemiologically representative NmB strains: hSBA assay using endogenous complement in each vaccinated person’s serum (enc-hSBA) against a 110-strain NmB panel and traditional hSBA (which uses exogenous complement) against 14 (4 + 10) NmB strains.

• The enc-hSBA assay, which provides an assessment of the killing activity of sera from recipients of MenB-containing vaccines, was qualified using 110 invasive strains representing, with their repertoire of antigen genotypes, ~89% of the strains circulating globally, 87% in Europe, 95% in the United States, 90% in Canada, and 97% in Australia.

• The traditional hSBA 4 + 10 approach is a quantitative measure of killing activity of the bivalent MenB-FHbp vaccine and was qualified against four primary and 10 additional NmB strains selected following evaluation of factor H-binding protein (fHbp) sequence diversity and expression. The four primary strains represent ~42% and the 10 additional strains represent ~38% of circulating strains in the United States and Europe (~80% combined).

• The hSBA assay against expanded NmB strain panels helps account for the diversity of circulating strains in vaccine effectiveness assessments. With a broad panel of diverse strains and the vaccinee’s own (endogenous) complement, the enc-hSBA assay aims to measure the immunological effectiveness of MenB-containing vaccines in clinical trials, under conditions that are as close as possible to real-world settings.

Declaration of interest

V Abitbol, A Andani, S Preiss, A Muzzi, L Serino, and W-Y Sohn are employed by GSK and hold shares in GSK. RB performs contract research on behalf of UKHSA for GSK, Pfizer, and Sanofi Pasteur. F Martinon-Torres reports payments to his institution from AstraZeneca, Biofabri, Seqirus, Sanofi Pasteur, MSD, Merck, Pfizer, Roche, Regeneron, Janssen, MedImmune, Novavax, Novartis, and GSK, outside the submitted work. F Martinon-Torres also reports payments made to him from Pfizer, Sanofi Pasteur, MSD, Biofabri, Seqirus, Janssen, and GSK, outside the submitted work. 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 material discussed in the manuscript apart from those disclosed.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they are an employee of GSK that has a commercial vaccine on MenB. Due to this conflict of interest, an additional peer reviewer was secured in order to ensure there were two further reviewers with no conflict of interest.

Author contributions

All authors substantially contributed to the conception and design of this review article and to the interpretation of the relevant literature and the development of the manuscript. All authors gave final approval before submission.

Acknowledgments

The authors thank Business & Decision Life Sciences platform for editorial assistance and manuscript coordination, on behalf of GSK. Joanne Knowles (independent medical writer, on behalf of GSK) provided medical writing support. This work was presented previously at the 41st Annual Meeting of the European Society of Paediatric Infectious Diseases (ESPID), May 8–12, 2023.

Trademark statement

Bexsero and Menveo are trademarks owned by or licensed to GSK. Trumenba and Nimenrix are trademarks of Pfizer.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

GlaxoSmithKline Biologicals SA was the funding source and took in charge all costs associated with the development and publication of this manuscript.