the effect of human factor h on immunogenicity of meningococcal native outer membrane vesicle vaccines with over-expressed factor h binding protein人为因素的影响h脑膜炎球菌本地外膜泡疫苗的免疫原性与vegf结合蛋白因子h.pdf

The Effect of Human Factor H on Immunogenicity of Meningococcal Native Outer Membrane Vesicle Vaccines with Over-Expressed Factor H Binding Protein 1 2 1 1 2 Peter T. Beernink , Jutamas Shaughnessy , Rolando Pajon , Emily M. Braga , Sanjay Ram , Dan M. Granoff1* 1 Center for Immunobiology and Vaccine Development, Children’s Hospital Oakland Research Institute, Oakland, California, United States of America, 2 Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America Abstract The binding of human complement inhibitors to vaccine antigens in vivo could diminish their immunogenicity. A meningococcal ligand for the complement down-regulator, factor H (fH), is fH-binding protein (fHbp), which is specific for human fH. Vaccines containing recombinant fHbp or native outer membrane vesicles (NOMV) from mutant strains with over-expressed fHbp are in clinical development. In a previous study in transgenic mice, the presence of human fH impaired the immunogenicity of a recombinant fHbp vaccine. In the present study, we prepared two NOMV vaccines from mutant group B strains with over-expressed wild-type fHbp or an R41S mutant fHbp with no detectable fH binding. In wild-type mice in which mouse fH did not bind to fHbp in either vaccine, the NOMV vaccine with wild-type fHbp elicited 2-fold higher serum IgG anti-fHbp titers (P = 0.001) and 4-fold higher complement-mediated bactericidal titers against a PorA- heterologous strain than the NOMV with the mutant fHbp (P = 0.003). By adsorption, the bactericidal antibodies were shown to be directed at fHbp. In transgenic mice i