Meningococcal serogroup B vaccines: Estimating breadth of coverage

Abstract

Neisseria meningitidis serogroup B (MenB) is an important cause of invasive meningococcal disease. The development of safe and effective vaccines with activity across the diversity of MenB strains has been challenging. While capsular polysaccharide conjugate vaccines have been highly successful in the prevention of disease due to meningococcal serogroups A, C, W, and Y, this approach has not been possible for MenB owing to the poor immunogenicity of the MenB capsular polysaccharide. Vaccines based on outer membrane vesicles have been successful in the prevention of invasive MenB disease caused by the single epidemic strain from which they were derived, but they do not confer broad protection against diverse MenB strains. Thus, alternative approaches to vaccine development have been pursued to identify vaccine antigens that can provide broad protection against the epidemiologic and antigenic diversity of invasive MenB strains. Human factor H binding protein (fHBP) was found to be such an antigen, as it is expressed on nearly all invasive disease strains of MenB and can induce bactericidal responses against diverse MenB strains. A bivalent vaccine (Trumenba®, MenB-FHbp, bivalent rLP2086) composed of equal amounts of 2 fHBP variants from each of the 2 immunologically diverse subfamilies of fHBP (subfamilies A and B) was the first MenB vaccine licensed in the United States under an accelerated approval pathway for prevention of invasive MenB disease. Due to the relatively low incidence of meningococcal disease, demonstration of vaccine efficacy for the purposes of licensure of bivalent rLP2086 was based on vaccine-elicited bactericidal activity as a surrogate marker of efficacy, as measured in vitro by the serum bactericidal assay using human complement. Because bacterial surface proteins such as fHBP are antigenically variable, an important component for evaluation and licensure of bivalent rLP2086 included stringent criteria for assessment of breadth of coverage across antigenically diverse and epidemiologically important MenB strains. This review describes the rigorous approach used to assess broad coverage of bivalent rLP2086. Alternative nonfunctional assays proposed for assessing vaccine coverage are also discussed.

Variant Signal Peptides of Vaccine Antigen, FHbp, Impair Processing Affecting Surface Localization and Antibody-Mediated Killing in Most Meningococcal Isolates

“…Altering the vaccine to contain uncleaved, non-lipidated FHbp should improve its target specificity. It is unknown to the public which reference strains are used in Pfizer's MEASURE assay (Meningococcal Antigen Surface Expression) (Donald et al, 2017) as standards for quantifying FHbp surface abundance on test isolates in order to predict vaccine coverage. With knowledge of the prevalence of 4 SP classes for FHbp -the majority of isolates expressing non-class 1, the choice of reference strains should be re-considered to ensure sufficient representation across these classes.…”

Meningococcal factor H binding protein as immune evasion factor and vaccine antigen

“…Cartoon was generated with PYMOL software. subfamily/variant specific, with limited immunologic protection across variants/subfamilies [61].…”

A physician’s guide to the 2-dose schedule of MenB-FHbp vaccine

“…Vaccine-elicited protection against meningococcal infection is evaluated by the in vitro serum bactericidal assay using human complement (hSBA), which measures antibody and complement-mediated killing of meningococcal test strains. 26 An hSBA titer (i.e., the highest serum dilution that kills ≥50% of test bacteria 26 ) of ≥1:4 is widely accepted by the US FDA and other regulators as a correlate of protection against IMD, [27][28][29][30] and has been used for licensure of MenACWY, MenB, and other meningococcal vaccines. 5,18,19,21 The hSBA titer for protein- • At risk during an outbreak attributed to a vaccine serogroup • Are microbiologists routinely exposed to Neisseria meningitidis based vaccines is influenced by antigen sequence variation and surface protein expression level in circulating meningococcal strains.…”

“…5,18,19,21 The hSBA titer for protein- • At risk during an outbreak attributed to a vaccine serogroup • Are microbiologists routinely exposed to Neisseria meningitidis based vaccines is influenced by antigen sequence variation and surface protein expression level in circulating meningococcal strains. 26 Therefore, choice of test strains for use in hSBAs to determine breadth of coverage is critical for MenB vaccines.…”

“…Antibody response to MenB vaccines is affected by the degree of match between the vaccine antigens and circulating pathogenic strains, immunogenicity of vaccine antigen(s), and immune responses of the vaccinated individual. The sub-capsular proteins in MenB vaccines have multiple sequence variants and have differing surface expression levels on circulating pathogenic strains, 26 both of which affect the bactericidal activity of vaccineelicited antibodies. Therefore, to demonstrate broad protective coverage while targeting an antigen that has variability, it is essential to evaluate each MenB vaccine by hSBA against a panel of diverse strains that differ from the vaccine antigen and are epidemiologically representative (i.e., outbreak and nonoutbreak/endemic strains).…”