title: Meningococcal factor H-binding protein vaccines with decreased binding to human complement factor H have enhanced immunogenicity in human factor H transgenic mice.
abstract: Factor H-binding protein (fHbp) is a component of a meningococcal vaccine recently licensed in Europe for prevention of serogroup B disease, and a second vaccine in clinical development. The protein specifically binds human factor H (fH), which down-regulates complement activation and enhances resistance to bactericidal activity. There are conflicting data from studies in human fH transgenic mice on whether binding of human fH to fHbp vaccines decreases immunogenicity, and whether mutant fHbp vaccines with decreased fH binding have enhanced immunogenicity. fHbp can be classified into two sub-families based on sequence divergence and immunologic cross-reactivity. Previous studies of mutant fHbp vaccines with low fH binding were from sub-family B, which account for approximately 60% of serogroup B case isolates. In the present study, we evaluated the immunogenicity of two mutant sub-family A fHbp vaccines containing single substitutions, T221A or D211A, which resulted in 15- or 30-fold lower affinity for human fH, respectively, than the corresponding control wild-type fHbp vaccine. In transgenic mice with high serum concentrations of human fH, both mutant vaccines elicited significantly higher IgG titers and higher serum bactericidal antibody responses than the control fHbp vaccine that bound human fH. Thus, mutations introduced into a sub-family A fHbp antigen to decrease fH binding can increase protective antibody responses in human fH transgenic mice. Collectively the data suggest that mutant fHbp antigens with decreased fH binding will result in superior vaccines in humans.
authors.affiliation: Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Rossi
authors.forename: Dan M
authors.initials: DM
authors.lastname: Granoff
authors.forename: Peter T
authors.initials: PT
authors.lastname: Beernink
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood*; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D001770:Blood Bactericidal Activity; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D022401:Meningococcal Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology; D011485:Protein Binding
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D007074:Immunoglobulin G; D022401:Meningococcal Vaccines; D050505:Mutant Proteins; C484699:factor H-binding protein, Neisseria meningitidis
keywords: Animal model; Bactericidal; Mutant fHbp vaccine; Sub-family A; Variant group 2; fH; fHbp
references.citation: Lancet Infect Dis. 2012 Aug;12(8):597-607
references.pmid: 22569484
references.citation: J Immunol. 1998 May 15;160(10):5028-36
references.pmid: 9590252
references.citation: Mol Immunol. 2009 May;46(8-9):1647-53
references.pmid: 19286260
references.citation: Clin Vaccine Immunol. 2006 Jul;13(7):758-63
references.pmid: 16829612
references.citation: Clin Vaccine Immunol. 2013 Aug;20(8):1099-107
references.pmid: 23740919
references.citation: J Biol Chem. 2009 Mar 27;284(13):8738-46
references.pmid: 19103601
references.citation: Infect Immun. 2004 Apr;72(4):2088-100
references.pmid: 15039331
references.citation: Infect Immun. 2012 Aug;80(8):2667-77
references.pmid: 22615247
references.citation: Vaccine. 2010 Feb 25;28(9):2122-9
references.pmid: 20044056
references.citation: Vaccine. 2010 Aug 23;28(37):6086-93
references.pmid: 20619376
references.citation: J Immunol. 2011 Mar 15;186(6):3606-14
references.pmid: 21325619
references.citation: Infect Immun. 2008 Sep;76(9):4232-40
references.pmid: 18591239
references.citation: PLoS Pathog. 2012;8(5):e1002688
references.pmid: 22589720
references.citation: J Infect Dis. 2013 Aug 15;208(4):627-36
references.pmid: 23715659
references.citation: J Infect Dis. 2008 Apr 1;197(7):1053-61
references.pmid: 18419542
references.citation: Vaccine. 2008 Dec 30;26 Suppl 8:I113-7
references.pmid: 19388175
references.citation: Vaccine. 2011 Jun 24;29(29-30):4739-44
references.pmid: 21571026
references.citation: J Exp Med. 2003 Mar 17;197(6):789-99
references.pmid: 12642606
references.citation: Pediatr Infect Dis J. 2012 Oct;31(10):1061-8
references.pmid: 22718089
references.citation: Infect Immun. 2011 Sep;79(9):3751-9
references.pmid: 21708990
references.citation: J Infect Dis. 2009 May 1;199(9):1360-8
references.pmid: 19302008
references.citation: PLoS Pathog. 2012;8(10):e1002981
references.pmid: 23133374
references.citation: Invest Ophthalmol Vis Sci. 2009 Dec;50(12):5818-27
references.pmid: 19661236
references.citation: Vox Sang. 2007 Apr;92(3):206-12
references.pmid: 17348869
references.citation: Invest Ophthalmol Vis Sci. 2010 Nov;51(11):5878-87
references.pmid: 20538999
references.citation: Infect Immun. 2009 Feb;77(2):764-9
references.pmid: 19047406
references.citation: Pediatr Infect Dis J. 2013 Apr;32(4):372-3
references.pmid: 23263177
references.citation: J Infect Dis. 2009 Aug 1;200(3):379-89
references.pmid: 19534597
references.citation: PLoS Negl Trop Dis. 2011 Sep;5(9):e1302
references.pmid: 21909444
references.citation: Invest Ophthalmol Vis Sci. 2008 May;49(5):1983-90
references.pmid: 18436830