Predicting the Susceptibility of Meningococcal Serogroup B Isolates to Bactericidal Antibodies Elicited by Bivalent rLP2086, a Novel Prophylactic Vaccine

Abstract

Bivalent rLP2086 (Trumenba), a vaccine for prevention of Neisseria meningitidis serogroup B (NmB) disease, was licensed for use in adolescents and young adults after it was demonstrated that it elicits antibodies that initiate complement-mediated killing of invasive NmB isolates in a serum bactericidal assay with human complement (hSBA). The vaccine consists of two factor H binding proteins (fHBPs) representing divergent subfamilies to ensure broad coverage. Although it is the surrogate of efficacy, an hSBA is not suitable for testing large numbers of strains in local laboratories. Previously, an association between the in vitro fHBP surface expression level and the susceptibility of NmB isolates to killing was observed. Therefore, a flow cytometric meningococcal antigen surface expression (MEASURE) assay was developed and validated by using an antibody that binds to all fHBP variants from both fHBP subfamilies and accurately quantitates the level of fHBP expressed on the cell surface of NmB isolates with mean fluorescence intensity as the readout. Two collections of invasive NmB isolates (n = 1,814, n = 109) were evaluated in the assay, with the smaller set also tested in hSBAs using individual and pooled human serum samples from young adults vaccinated with bivalent rLP2086. From these data, an analysis based on fHBP variant prevalence in the larger 1,814-isolate set showed that >91% of all meningococcal serogroup B isolates expressed sufficient levels of fHBP to be susceptible to bactericidal killing by vaccine-induced antibodies.

Complement and Bacterial Infections: From Molecular Mechanisms to Therapeutic Applications

“…With the advancement of new antibody-discovery technologies (immune receptor identification), we believe that this promises to be a rapidly growing field in the near future. Generation of complement-activating antibodies is also considered important for the protective action of multivalent Neisseria vaccines that trigger the formation of antibodies that kill bacteria via MAC or phagocytosis [64,65]. A potent vaccine candidate in N. meningitidis is factor H-binding protein (fHBP), an outer membraneassociated lipoprotein that recruits factor H and thereby downregulates complement activation.…”

A review of the immunogenicity, safety and current recommendations for the meningococcal serogroup B vaccine, MenB‐FHbp

“…MenB‐FHbp contains two FHbp variants, one each from subfamilies A and B, and is sufficient to provide broad coverage against the diversity of disease‐causing MenB strains; >99% of 650 US strains surveyed by the CDC contain FHbp , and >91% of invasive MenB strains express FHbp at sufficient levels to be susceptible to bactericidal antibodies elicited by the vaccine . MenB‐4C is composed of four protein antigens present in variable percentages of 442 US strains surveyed by the CDC: recombinant FHbp subfamily B fusion protein (53% of strains); recombinant neisserial heparin‐binding antigen fusion protein (NHBA; 83% of strains); recombinant neisserial adhesin A protein (NadA; 2.5% of strains); and outer membrane vesicles containing PorA (5.9% of strains) .…”

Potential benefits of using a multicomponent vaccine for prevention of serogroup B meningococcal disease

“…The level of fHbp expression has been found to be a key determinant of bactericidal susceptibility to anti-fHbp antibodies (Jiang et al, 2010). Pre-clinical studies have indicated that as many as 19% of strains expressing fHbp variant 2 or 3 may not be susceptible to bactericidal killing by MenB-fHbp-induced antibodies because they express insufficient antigen on the cell surface (McNeil et al, 2018). Similarly, protection would not be expected against strains that do not express fHbp.…”