A Meningococcal Factor H Binding Protein Mutant That Eliminates Factor H Binding Enhances Protective Antibody Responses to Vaccination

Abstract

Certain pathogens recruit host complement inhibitors such as factor H (fH) to evade the immune system. Microbial complement inhibitor-binding molecules can be promising vaccine targets by eliciting antibodies that neutralize this microbial defense mechanism. One such antigen, meningococcal fH-binding protein (fHbp), was used in clinical trials before the protein was discovered to bind fH. The potential effect of fH binding on vaccine immunogenicity had not been assessed in experimental animals because fHbp binds human fH specifically. In this study, we developed a human fH transgenic mouse model. Transgenic mice immunized with fHbp vaccine had 4- to 8-fold lower serum bactericidal antibody responses than control mice whose native fH did not bind the vaccine. In contrast, antibody responses were unimpaired in transgenic mice immunized with a control meningococcal group C polysaccharide-protein conjugate vaccine. In transgenic mice, immunization with an fH non-binding mutant of fHbp elicited antibodies with higher bactericidal activity than fHbp vaccination itself. Antibodies elicited by the mutant fHbp more effectively blocked fH binding to wild-type fHbp than antibodies elicited by fHbp that bound fH. Thus, a mutant fHbp vaccine that does not bind fH, but which retains immunogenicity, is predicted to be superior in humans than an fHbp vaccine that binds human fH. In the case of mutant fHbp vaccination, the resultant antibody responses may be directed more at epitopes in or near the fH-binding site, which result in greater complement-mediated serum bactericidal activity; these epitopes may be obscured when human fH is bound to the wild-type fHbp vaccine.

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

“…Binding of human FH decreases FHbp immunogenicity (24)(25)(26), and FHbp mutants with decreased binding of FH elicit higher protective antibody responses in human FH transgenic mice (16,24,27). Because R130 is an FH binding residue in variant group 1 proteins (28), we tested binding of human FH to the doublemutant FHbp.…”

“…FHbp mutants with decreased binding of human FH were shown to have enhanced immunogenicity in human FH transgenic mice (15,16,24,27). The stabilized double-mutant FHbp had approximately sevenfold lower affinity for human FH than the WT FHbp (Fig.…”

Bexsero

“…Since the formulation of Bexsero, subsequent research has suggested ways of producing more effective MenB vaccines, e.g., the use of fHbp modified so that it does not bind human factor H, 64,65 the removal of potential blocking antibodies, 66 or the use of engineered nOMVs with lower toxicity and overexpressing selected antigens. Thus the vaccine may be reformulated to improve protection provided.…”

Role of Factor H Binding Protein in Neisseria meningitidis Virulence and Its Potential as a Vaccine Candidate To Broadly Protect against Meningococcal Disease

“…It has also been suggested that binding of fH to the fHBP in the vaccine might reduce the availability of epitopes during the immunization process. This was evaluated in a recent study by Beernink et al, who assessed the immunogenicity of fHBP-based vaccines in human fH transgenic mice that were immunized with fHBP or a mutant fHBP that eliminated fH binding (76). Though there was no statistically significant difference in SBA responses between the two vaccines, a logarithmic regression looked at the effect of the concentration of human factor H on immunogenicity and found that at high fH concentrations, the mutant vaccine generated slightly higher bactericidal responses.…”