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Published on: February 14, 2011
A meningococcal factor H binding protein mutant that eliminates factor H binding enhances protective antibody
Peter T Beernink1, Jutamas Shaughnessy, Emily M Braga
1Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
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 Abs that neutralize this microbial defense mechanism. One such Ag, meningococcal factor H-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 Ab responses than those of control mice whose native fH did not bind the vaccine. In contrast, Ab responses were unimpaired in transgenic mice immunized with a control meningococcal group C polysaccharide-protein conjugate vaccine. In transgenic mice, immunization with an fH nonbinding mutant of fHbp elicited Abs with higher bactericidal activity than that of fHbp vaccination itself. Abs elicited by the mutant fHbp more effectively blocked fH binding to wild-type fHbp than Abs elicited by fHbp that bound fH. Thus, a mutant fHbp vaccine that does not bind fH but that retains immunogenicity is predicted to be superior in humans to an fHbp vaccine that binds human fH. In the case of mutant fHbp vaccination, the resultant Ab 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.
Insights
A novel mouse model revealed that meningococcal factor H-binding protein (fHbp) vaccines binding factor H (fH) elicit weaker antibody responses. A mutant fHbp vaccine, unable to bind fH, shows superior immunogenicity and bactericidal activity.
Area of Science:
- Immunology
- Vaccinology
- Microbial Pathogenesis
Background:
- Pathogens evade immune responses by recruiting host complement inhibitors like factor H (fH).
- Meningococcal factor H-binding protein (fHbp) is a vaccine candidate that binds human fH, potentially impacting immunogenicity.
- Previous studies lacked animal models to assess the effect of fH binding on fHbp vaccine efficacy.
Purpose of the Study:
- To investigate the impact of factor H (fH) binding on the immunogenicity of meningococcal factor H-binding protein (fHbp) vaccines.
- To evaluate a novel human fH transgenic mouse model for assessing fHbp vaccine efficacy.
- To compare the immunogenicity and bactericidal activity of wild-type fHbp and an fH non-binding mutant fHbp vaccine.
Main Methods:
- Development of a human factor H (fH) transgenic mouse model.
- Immunization of transgenic mice with fHbp vaccine, fH non-binding mutant fHbp vaccine, and a control meningococcal group C conjugate vaccine.
- Measurement of serum bactericidal antibody (SBA) responses and assessment of antibody-mediated blocking of fH binding to fHbp.
Main Results:
- Mice immunized with fHbp vaccine showed significantly lower serum bactericidal antibody responses compared to controls.
- Immunization with an fH non-binding mutant fHbp vaccine elicited antibodies with higher bactericidal activity.
- Antibodies from mutant fHbp vaccination more effectively blocked fH binding to fHbp than those from wild-type fHbp vaccination.
Conclusions:
- Factor H (fH) binding to meningococcal factor H-binding protein (fHbp) vaccine reduces antibody responses and bactericidal activity.
- A mutant fHbp vaccine that does not bind fH is predicted to be superior for human vaccination.
- Targeting fH binding sites may enhance vaccine-induced immune responses and complement-mediated bactericidal activity.
