Impaired Immunogenicity of Meningococcal Neisserial Surface Protein A in Human Complement Factor H Transgenic Mice

• Published in: Infection and immunity 2016-02, Vol.84 (2), p.452-458
• Main Authors: Lujan, Eduardo, Pajon, Rolando, Granoff, Dan M
• Format: Article
• Language: English
• Subjects: Animals; Bacterial Outer Membrane Proteins - genetics; Bacterial Outer Membrane Proteins - immunology; Bacterial Outer Membrane Proteins - metabolism; Complement Factor H - genetics; Complement Factor H - immunology; Complement Factor H - metabolism; Escherichia coli; Escherichia coli - genetics; Founder Effect; Humans; Immunization; Meningococcal Vaccines - immunology; Mice, Inbred BALB C; Mice, Transgenic; Microbial Immunity and Vaccines; Neisseria meningitidis; Porins - immunology; Recombinant Proteins - immunology; Serum Bactericidal Antibody Assay
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.01267-15

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.