title: Design of meningococcal factor H binding protein mutant vaccines that do not bind human complement factor H.
abstract: Meningococcal factor H binding protein (fHbp) is a human species-specific ligand for the complement regulator, factor H (fH). In recent studies, fHbp vaccines in which arginine at position 41 was replaced by serine (R41S) had impaired fH binding. The mutant vaccines elicited bactericidal responses in human fH transgenic mice superior to those elicited by control fHbp vaccines that bound human fH. Based on sequence similarity, fHbp has been classified into three variant groups. Here we report that although R41 is present in fHbp from variant groups 1 and 2, the R41S substitution eliminated fH binding only in variant group 1 proteins. To identify mutants in variant group 2 with impaired fH binding, we generated fHbp structural models and predicted 63 residues influencing fH binding. From these, we created 11 mutants with one or two amino acid substitutions in a variant group 2 protein and identified six that decreased fH binding. Three of these six mutants retained conformational epitopes recognized by all six anti-fHbp monoclonal antibodies (MAbs) tested and elicited serum complement-mediated bactericidal antibody titers in wild-type mice that were not significantly different from those obtained with the control vaccine. Thus, fHbp amino acid residues that affect human fH binding differ across variant groups. This result suggests that fHbp sequence variation induced by immune selection also affects fH binding motifs via coevolution. The three new fHbp mutants from variant group 2, which do not bind human fH, retained important epitopes for eliciting bactericidal antibodies and may be promising vaccine candidates.
authors.affiliation: Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California, USA.
authors.forename: Rolando
authors.initials: R
authors.lastname: Pajon
authors.forename: Peter T
authors.initials: PT
authors.lastname: Beernink
authors.forename: Dan M
authors.initials: DM
authors.lastname: Granoff
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001120:Arginine; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D017242:Complement Factor H / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D008589:Meningococcal Infections / Q000517:prevention & control*; D022401:Meningococcal Vaccines / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D009345:Neisseria meningitidis / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D012694:Serine; D014614:Vaccines, Synthetic / Q000276:immunology / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; C493495:CFH protein, human; D022401:Meningococcal Vaccines; D014614:Vaccines, Synthetic; D012694:Serine; D017242:Complement Factor H; D001120:Arginine