Crystal structure reveals vaccine elicited bactericidal human antibody targeting a conserved epitope on meningococcal fHbp

Abstract

Data obtained recently in the United Kingdom following a nationwide infant immunization program against serogroup B Neisseria meningitidis (MenB) reported >80% 4CMenB vaccine-mediated protection. Factor H-binding protein (fHbp) is a meningococcal virulence factor and a component of two new MenB vaccines. Here, we investigated the structural bases underlying the fHbp-dependent protective antibody response in humans, which might inform future antigen design efforts. We present the co-crystal structure of a human antibody Fab targeting fHbp. The vaccine-elicited Fab 1A12 is cross-reactive and targets an epitope highly conserved across the repertoire of three naturally occurring fHbp variants. The free Fab structure highlights conformational rearrangements occurring upon antigen binding. Importantly, 1A12 is bactericidal against MenB strains expressing fHbp from all three variants. Our results reveal important immunological features potentially contributing to the broad protection conferred by fHbp vaccination. Our studies fuel the rationale of presenting conserved protein epitopes when developing broadly protective vaccines.

Cocrystal structure of meningococcal factor H binding protein variant 3 reveals a new crossprotective epitope recognized by human mAb 1E6

“…Giuliani et al (41) restricted the epitope localization of 1 crossreactive anti-fHbp mAb 1G3 to short fragments of fHbp v1 by hydrogen-deuterium exchange–MS, whereas López-Sagaseta et al (18) were able to fully characterize at high resolution, by X-ray crystallography, the first human antibody, the 1A12, identifying the epitope on fHbp v1. Fab 1A12 targets exclusively the C-terminal β-barrel, whereas the Fab 1E6 mainly binds the N-terminal region on the opposite side compared to the binding site for hfH ( Fig.…”

“…The C-terminal domain adopts a canonical 8-stranded β-barrel conformation, whereas the fHbp N-terminal domain shows a more unusual taco-shaped β-barrel fold characterized by higher intrinsic flexibility. Differential scanning calorimetry profiles showed independent unfolding of the 2 barrels (17–19). The C-terminal β-barrel melts at temperatures above 80°C in all 3 variants; in contrast, the N-terminal β-barrel exhibits highly variable melting temperatures at 70°C in v1, 61°C in v3, and at 37°C in v2 (20).…”

“…To date, several anti-fHbp monoclonal antibodies were described, but probably due to the high amino acid sequence variability, the majority of them are variant-specific (14, 32–37). However, a few anti-fHbp antibodies that were able to recognize more than 1 variant were reported (18, 38–40). …”

“…The resulting panel of 10 anti-fHbp antibody fragments (Fabs) was analyzed by 2 different research groups, and both teams found 2 anti-fHbp antibodies (1A12 and 1G3) to be crossreactive with the 3 main fHbp variants (41, 42). Moreover, the crystal structure of one of these (1A12) in complex with fHbp v1 was determined, revealing a conserved epitope localized exclusively on the C-terminal β-barrel (18, 41). …”

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

“…Interestingly, 4CMenB vaccine, containing variant 1 fHbp, was also able to induce monoclonal antibodies that were cross-bactericidal against the three variant, as in the case of the 1A12 antibody that targets an epitope highly conserved across the three fHbp variant [83].…”