Frequency of factor H-binding protein modular groups and susceptibility to cross-reactive bactericidal activity in invasive meningococcal isolates

Abstract

Meningococcal factor H binding protein (fHbp) is a promising vaccine candidate that elicits serum bactericidal antibodies in humans. Based on sequence variability of the entire protein, fHbp has been divided into three variant groups or two sub-families. We recently reported that the fHbp architecture was modular, consisting of five variable segments, each encoded by genes from one of two lineages. Based on combinations of segments from different lineages, all 70 known fHbp sequence variants could be classified into one of six modular groups. In this study, we analyzed sequences of 172 new fHbp variants that were available from public databases. All but three variants could be classified into one of the six previously described modular groups. Among systematically collected invasive group B isolates from the U.S. and Europe, modular group I overall was most common (60%) but group IV (natural chimeras) accounted for 23% of UK isolates and <1% of U.S. isolates (P<0.0001). Mouse antisera to recombinant fHbp from each of the modular groups showed modular group-specific bactericidal activity against strains with low fHbp expression but had broader activity against strains with higher fHbp expression. Thus both modular group and relative expression of fHbp affected strain susceptibility to anti-fHbp bactericidal activity. The results confirmed the modular architecture of fHbp and underscored its importance for the design of broadly protective group B vaccines in different regions.

A meningococcal vaccine antigen engineered to increase thermal stability and stabilize protective epitopes

“…We chose FHbp ID 22, as this sequence variant was prevalent in invasive isolates from Africa (14,20) and the immunogenicity of vaccines containing FHbp ID 22 previously had been tested in mice (6,14,16,21). The L130R substitution increased the T m of the N-terminal domain by 7.7°C (Fig.…”

“…For single-cycle kinetics, ∼500 RUs of murine anti-FHbp MAbs were captured, and five concentrations (1-100 nM or 3.16-316 nM) of FHbp analyte were injected. The MAbs used were JAR 4 (22,35), JAR 41 (23), and JAR 31 (6). For measuring affinity of FH for FHbp, a goat anti-human FH antibody (Complement Technologies) that had been affinity purified was amine coupled to a CM5 chip.…”

“…One of the two licensed vaccines contains an FHbp sequence from variant groups 1 and 3 and was shown to elicit broad protective immunity against genetically diverse meningococcal strains (3,5,6). The second licensed vaccine contains FHbp in variant group 1 and three other antigens capable of eliciting protective antibodies (7,8).…”

Bexsero

“…There is also mounting evidence of the critical relationship between fHbp expression levels in the outer membrane and susceptibility to anti-fHbp antibodies, with strains expressing low levels of fHbp being resistant to killing by antifHbp cross-protective antibodies. 43 Last but not least, a small number of isolates from meningococcal disease cases have been found not to express fHbp at all, although the epidemiological impact of such strains is probably low at present. 44,45 Cost effectiveness.…”

“…Based on analysis of amino acid sequence variants, fHbp antigens have been subdivided into two subfamilies (A or B), 27 three variant groups (v1, v2, and v3), 48 or six major modular groups (I to VI). 43,49 Sub-family A includes variant groups 2 and 3 (modular groups II, III, V and VI). Sub-family B includes variant 1 (modular groups I and IV) sequences.…”