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.
Highlights
Data obtained recently in the United Kingdom following a nationwide infant immunization program against serogroup B Neisseria meningitidis (MenB) reported >80% 4CMenB vaccinemediated protection
Surface plasmon resonance (SPR) was used to determine the kinetics for immobilized monoclonal antibodies (mAbs) 1A12 binding to solution phase Factor H-binding protein (fHbp) antigens representative of the three different variant groups: fHbp var1.1; fHbp var2.16; and fHbp var3.45
We determined the crystal structure of fHbp var1.1 bound to the Fab fragment of a vaccine-elicited human mAb, 1A12
Summary
Data obtained recently in the United Kingdom following a nationwide infant immunization program against serogroup B Neisseria meningitidis (MenB) reported >80% 4CMenB vaccinemediated protection. Detailed epitope-mapping studies of anti-fHbp mAbs have been performed using nuclear magnetic resonance spectroscopy[18,22], hydrogen-deuterium exchange followed by mass spectrometry[21,24], and by X-ray crystallography[24,25] The latter studies recently defined a mechanism by which two murine antifHbp antibodies (mAbs JAR5 and 12C1) may synergize to elicit complement-mediated bactericidal activity[25,26]. Both mAbs target epitopes that overlap with the fH-binding site[24,25], revealing the structural basis for their inhibition of fH binding.
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