title: Heterogeneity in rhesus macaque complement factor H binding to meningococcal factor H binding protein (FHbp) informs selection of primates to assess immunogenicity of FHbp-based vaccines.
abstract: Neisseria meningitidis causes disease only in humans. An important mechanism underlying this host specificity is the ability of the organism to resist complement by recruiting the complement downregulator factor H (FH) to the bacterial surface. In previous studies, binding of FH to one of the major meningococcal FH ligands, factor H binding protein (FHbp), was reported to be specific for human FH. Here we report that sera from 23 of 73 rhesus macaques (32%) tested had high FH binding to FHbp. Similar to human FH, binding of macaque FH to the meningococcal cell surface inhibited the complement alternative pathway by decreasing deposition of C3b. FH contains 20 domains (or short consensus repeats), with domains 6 and 7 being responsible for binding of human FH to FHbp. DNA sequence analyses of FH domains 6 and 7 from macaques with high or low FH binding showed a polymorphism at residue 352 in domain 6, with Tyr being associated with high binding and His with low binding. A recombinant macaque FH 6,7/Fc fragment with Tyr352 showed higher binding to FHbp than the corresponding fragment with His352. In previous studies in human FH transgenic mice, binding of FH to FHbp vaccines decreased protective antibody responses, and mutant FHbp vaccines with decreased FH binding elicited serum antibodies with greater protective activity. Thus, macaques with high FH binding to FHbp represent an attractive nonhuman primate model to investigate further the effects of FH binding on the immunogenicity of FHbp vaccines.
authors.affiliation: Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California, USA.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Beernink
authors.affiliation: Division of Immunology and Infectious Diseases, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Jutamas
authors.initials: J
authors.lastname: Shaughnessy
authors.affiliation: Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Stefek
authors.affiliation: Division of Immunology and Infectious Diseases, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Ram
authors.affiliation: Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California, USA dgranoff@chori.org.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Granoff
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology* / Q000378:metabolism*; D001426:Bacterial Proteins / Q000276:immunology* / Q000378:metabolism*; D003179:Complement C3b / Q000037:antagonists & inhibitors*; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism*; D008253:Macaca mulatta; D022401:Meningococcal Vaccines / Q000276:immunology*; D009345:Neisseria meningitidis / Q000276:immunology*; D011110:Polymorphism, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D022401:Meningococcal Vaccines; C484699:factor H-binding protein, Neisseria meningitidis; D003179:Complement C3b; D017242:Complement Factor H