title: Impaired Immunogenicity of Meningococcal Neisserial Surface Protein A in Human Complement Factor H Transgenic Mice.
abstract: Neisserial surface protein A (NspA) is a highly conserved outer membrane protein previously investigated as a meningococcal vaccine candidate. Despite eliciting serum bactericidal activity in mice, a recombinant NspA vaccine failed to elicit serum bactericidal antibodies in a phase 1 clinical trial in humans. The discordant results may be explained by the recent discovery that NspA is a human-specific ligand of the complement inhibitor factor H (FH). Therefore, in humans but not mice, NspA would be expected to form a complex with FH, which could impair human anti-NspA protective antibody responses. To investigate this question, we immunized human FH transgenic BALB/c mice with three doses of recombinant NspA expressed in Escherichia coli microvesicles, with each dose being separated by 3 weeks. Three of 12 (25%) transgenic mice and 13 of 14 wild-type mice responded with bactericidal titers of ≥1:10 in postimmunization sera (P = 0.0008, Fisher's exact test). In contrast, human FH transgenic and wild-type mice immunized with a control meningococcal native outer membrane vesicle vaccine had similar serum bactericidal antibody responses directed at PorA, which is not known to bind human FH, and a mutant factor H binding protein (FHbp) antigen with a >50-fold lower level of FH binding than wild-type FHbp antigen binding.Thus, human FH can impair anti-NspA serum bactericidal antibody responses, which may explain the poor immunogenicity of the NspA vaccine previously tested in humans. A mutant NspA vaccine engineered to have decreased binding to human FH may increase protective antibody responses in humans.
authors.affiliation: Center for Immunobiology and Vaccine Development, UCSF Benioff Children's Hospital Oakland Research Institute, Oakland, California, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Lujan
authors.affiliation: Center for Immunobiology and Vaccine Development, UCSF Benioff Children's Hospital Oakland Research Institute, Oakland, California, USA.
authors.forename: Rolando
authors.initials: R
authors.lastname: Pajon
authors.affiliation: Center for Immunobiology and Vaccine Development, UCSF Benioff Children's Hospital Oakland Research Institute, Oakland, California, USA dgranoff@chori.org.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Granoff
mesh_terms: D000818:Animals; D001425:Bacterial Outer Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics; D018703:Founder Effect; D006801:Humans; D007114:Immunization; D022401:Meningococcal Vaccines / Q000276:immunology; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018272:Porins / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology; D058248:Serum Bactericidal Antibody Assay
chemical_list: D001425:Bacterial Outer Membrane Proteins; C493495:CFH protein, human; D022401:Meningococcal Vaccines; C105506:NspA protein, Neisseria; D018272:Porins; D011994:Recombinant Proteins; C057699:porin protein, Neisseria; D017242:Complement Factor H