4CMenB vaccine induces elite cross-protective human antibodies that compete with human factor H for binding to meningococcal fHbp

Neisseria meningitidisserogroup B (MenB) is the leading cause of meningococcal meningitis and sepsis in industrialized countries, with the highest incidence in infants and adolescents. Two recombinant protein vaccines that protect against MenB are now available (i.e. 4CMenB and MenB-fHbp). Both vaccines contain the Factor H Binding Protein (fHbp) antigen, which can bind the Human Factor H (fH), the main negative regulator of the alternative complement pathway, thus enabling bacterial survival in the blood. fHbp is present in meningococcal strains as three main variants which are immunologically distinct. Here we sought to obtain detailed information about the epitopes targeted by anti-fHbp antibodies induced by immunization with the 4CMenB multicomponent vaccine. Thirteen anti-fHbp human monoclonal antibodies (mAbs) were identified in a library of over 100 antibody fragments (Fabs) obtained from three healthy adult volunteers immunized with 4CMenB. Herein, the key cross-reactive mAbs were further characterized for antigen binding affinity, complement-mediated serum bactericidal activity (SBA) and the ability to inhibit binding of fH to live bacteria. For the first time, we identified a subset of anti-fHbp mAbs able to elicit human SBA against strains with all three variants and able to compete with human fH for fHbp binding. We present the crystal structure of fHbp v1.1 complexed with human antibody 4B3. The structure, combined with mutagenesis and binding studies, revealed the critical cross-reactive epitope. The structure also provided the molecular basis of competition for fH binding. These data suggest that the fH binding site on fHbp v.1.1 can be accessible to the human immune system upon immunization, enabling elicitation of human mAbs broadly protective against MenB. The novel structural, biochemical and functional data are of great significance because the human vaccine-elicited mAbs are the first reported to inhibit the binding of fH to fHbp, and are bactericidal with human complement. Our studies provide molecular insights into the human immune response to the 4CMenB meningococcal vaccine and fuel the rationale for combined structural, immunological and functional studies when seeking deeper understanding of the mechanisms of action of human vaccines. Author summary Serogroup B meningococcus is a human pathogen causing meningitis and sepsis, especially in infants and adolescents. The recent development of two vaccines (4CMenB, MenB-fHbp) provides an opportunity to reduce disease incidence. One vaccine component is the factor H binding protein (fHbp), which exists in three main variants. On the meningococcal surface, fHbp recruits the human complement-downregulating factor H (fH), allowing the bacterium to evade the host immune system. Analyses of antibodies from vaccinated humans can yield insights into vaccine mechanisms of action. Recently, analyses of the response to 4CMenB vaccination identified thirteen new antibodies able to bind all three fHbp variants. We characterized all 13 antibodies. One of them, 4B3, is the first human antibody reported to effectively mediate bactericidal killing of meningococcal strains expressing each of the three fHbp variants and to compete with human fH for binding to fHbp. We present the three-dimensional structure of 4B3 complexed with fHbp, molecular details that explain how 4B3 can cross-react with all different fHbp variants and why it is so potent. This study provides a deeper understanding of 4CMenB vaccine-induced antibodies, and guidance for the rational design of antigens inducing broadly protective immunity.