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Review
, 13 (2), 255-265

Meningococcal Serogroup B Vaccines: Estimating Breadth of Coverage

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Review

Meningococcal Serogroup B Vaccines: Estimating Breadth of Coverage

Robert G K Donald et al. Hum Vaccin Immunother.

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.

Keywords: Neisseria meningitidis; Trumenba®; bivalent rLP2086; breadth of coverage; factor H binding protein; serogroup B.

Figures

Figure 1.
Figure 1.
Serum bactericidal assay with human complement. Figure adapted from Ghandi, et al. Postgraduate Medicine, 2016.
Figure 2.
Figure 2.
Phylogenetic relationship of different fHBP subgroups in the extended MenB SBA strain pool. Representation of the phylogeny of fHBP is based on a clustalW alignment and drawn with MEGA 4.2. The relative phylogenetic position of subfamily A and B fHBP variants, as well as the 6 major subgroups of fHBP, are outlined. The phylogenetic position of fHBP variants expressed by the 4 primary and 10 secondary SBA test strains, as well as 2 vaccine variants, is highlighted. The numbers beneath each of the fHBP subgroups represent the number of isolates, number of unique fHBP variants, and average amino acid percent identity from the respective subgroups. The scale bar represents phylogenetic distance based on the deduced fHBP protein sequence. Phylogenetic relationship of MenB fHBP variants first described by Murphy, et al. J Infect Dis. 2009.
Figure 3.
Figure 3.
Activity of rLP2086 immune sera against fHBP B133 isolates in exploratory hSBAs. Isolates tested were from the University E outbreak (PMB5543 and PMB5544) and from the Netherlands (PMB5507). Sera are from 15 subjects vaccinated with bivalent rLP2086. Sera were collected before vaccination, after the first vaccination (PD1), after the second vaccination (PD2), and after the third vaccination (PD3). Responder rates based on individual titers ≥1:4 are indicated. Open rectangles represent geometric mean titers with 95% CIs (error bars). fHBP = factor H binding protein; hSBA = serum bactericidal assay using human complement; PD = postdose.
Figure 4.
Figure 4.
MATS assay. Bacteria are grown overnight. A bacterial suspension is grown to a specific OD and detergent is added to the suspension to extract the capsule and expose the antigens. Serial dilutions of the extract are tested by ELISA. fHBP, NHBA, and NadA coverage is assessed by defining a relative potency of the tested strain versus a reference strain for each antigen and then extrapolating a relative potency to a positive bactericidal threshold. PCR genotyping is used to identify PorA. ELISA = enzyme-linked immunosorbent assay; fHBP = factor H binding protein; MATS = Meningococcal Antigen Typing System; NadA = Neisserial adhesin A; NHBA = Neisserial heparin binding antigen; OD = optical density; PCR = polymerase chain reaction; PorA = porin A.
Figure 5.
Figure 5.
MEASURE assay. Bacteria are grown overnight using standard hSBA procedures. Bacteria are then stained using a 3-step antibody staining method. Flow cytometry is used to selectively quantify the concentration of surface-expressed fHBP. fHBP = factor H binding protein; hSBA = serum bactericidal assay using human complement; MEASURE = Meningococcal Antigen Surface Expression; OD = optical density.

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References

    1. Rosenstein NE, Fischer M, Tappero JW.. Meningococcal vaccines. Infect Dis Clin North Am 2001; 15(1):155-169; PMID:11301813; http://dx.doi.org/10.1016/S0891-5520(05)70273-7 - DOI - PubMed
    1. Cohn AC, MacNeil JR, Clark TA, Ortega-Sanchez IR, Briere EZ, Meissner HC, Baker CJ, Messonnier NE, Centers for Disease Control and Prevention .. Prevention and control of meningococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2013; 62:1-28; PMID:23515099 - PubMed
    1. Centers for Disease Control and Prevention Meningococcal disease: technical & clinical information. Available at: http://www.cdc.gov/meningococcal/clinical-info.html. Accessed July13, 2015.
    1. Pace D, Pollard AJ.. Meningococcal disease: clinical presentation and sequelae. Vaccine 2012; 30 Suppl 2: B3-9; PMID:22607896; http://dx.doi.org/10.1016/j.vaccine.2011.12.062 - DOI - PubMed
    1. Harrison OB, Claus H, Jiang Y, Bennett JS, Bratcher HB, Jolley KA, Corton C, Care R, Poolman JT, Zollinger WD, et al. Description and nomenclature of Neisseria meningitidis capsule locus. Emerg Infect Dis 2013; 19:566-573; PMID:23628376; http://dx.doi.org/10.3201/eid1904.111799 - DOI - PMC - PubMed

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