Enhanced protective antibody to a mutant meningococcal factor H-binding protein with low-factor H binding

Abstract

Meningococcal factor H-binding protein (FHbp) is an antigen in 2 serogroup B meningococcal vaccines. FHbp specifically binds human and some nonhuman primate complement FH. To investigate the effect of binding of FH to FHbp on protective antibody responses, we immunized infant rhesus macaques with either a control recombinant FHbp antigen that bound macaque FH or a mutant antigen with 2 amino acid substitutions and >250-fold lower affinity for FH. The mutant antigen elicited 3-fold higher serum IgG anti-FHbp titers and up to 15-fold higher serum bactericidal titers than the control FHbp vaccine. When comparing sera with similar IgG anti-FHbp titers, the antibodies elicited by the mutant antigen gave greater deposition of complement component C4b on live meningococci (classical complement pathway) and inhibited binding of FH, while the anti-FHbp antibodies elicited by the control vaccine enhanced FH binding. Thus, the mutant FHbp vaccine elicited an anti-FHbp antibody repertoire directed at FHbp epitopes within the FH binding site, which resulted in greater protective activity than the antibodies elicited by the control vaccine, which targeted FHbp epitopes outside of the FH combining site. Binding of a host protein to a vaccine antigen impairs protective antibody responses, which can be overcome with low-binding mutant antigens.

Eliminating Factor H-Binding Activity of Borrelia burgdorferi CspZ Combined with Virus-Like Particle Conjugation Enhances Its Efficacy as a Lyme Disease Vaccine

“…Eliminating the ability of CspZ to bind FH exposes the FH-binding site and, therefore, may increase the ability of the epitopes close to/within this site to induce bactericidal antibodies. In fact, immunization with point mutants of a Neisseria meningitidis FH-binding protein fHbp with reduced FH-binding activity induces greater levels of bactericidal antibodies in vaccinated human FH-transgenic mice and in non-human primates than immunization with wild-type fHbp ( 19 , 42 – 45 ). This reduction in immunogenicity as a result of binding to host proteins thus is not restricted to FH-binding molecules ( 46 ).…”

Hijacking Complement Regulatory Proteins for Bacterial Immune Evasion

“…However, other reports have shown that the binding of host molecules to vaccine targets can result in the induction of the antibodies directed against parts of the vaccine target that are not involved in the binding to the complement regulatory protein. This phenomenon can be overcome by the use of mutated bacterial proteins that are no longer able to bind their host target protein (Rossi et al, 2013; Zariri et al, 2013; Costa et al, 2014; Granoff et al, 2016). Therefore, the use of mutated complement evasion molecules that no longer bind to their host target proteins should be considered in the design of microbial vaccines that aim to elicit antibodies that block binding of the host complement regulator to the pathogen.…”

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

“…Some antibodies also inhibit the binding of human complement factor H (fH) to the bacteria, rendering them more susceptible to complement 12 . While some antibodies to fHbp elicited in mice inhibited the binding of fH to the bacterial surface 12 , 13 , the antibodies elicited in rhesus macaques 14 , 15 or humans 16 generally did not inhibit binding of fH. This difference may result from the inability of murine fH to bind fHbp 16 , in contrast to human fH that binds fHbp, such that the dynamics of epitope exposure, dependent on fH binding, are likely different when immunizing mice and humans.…”