title: Nonfunctional variant 3 factor H binding proteins as meningococcal vaccine candidates.
abstract: Neisseria meningitidis is a human-specific pathogen and leading cause of meningitis and septicemia. Factor H binding protein (fHbp), a virulence factor which protects N. meningitidis from innate immunity by binding the human complement regulator factor H (fH) with high affinity, is also a key antigen in vaccines being developed to prevent meningococcal disease. fHbp can be divided into three variant groups (V1, V2, and V3) that elicit limited immunological cross-reactivity. The interaction of fH with fHbp could impair the immunogenicity of this antigen by hindering access to the antigenic epitopes in fHbp, providing the rationale for the development of nonfunctional fHbps as vaccine candidates. Here, we characterized the two nonfunctional V3 fHbps, fHbp(T286A) and fHbp(E313A), which each contains a single amino acid substitution that leads to a marked reduction in affinity for fH without affecting the folding of the proteins. The immunogenicity of the nonfunctional fHbps was assessed in transgenic mice expressing a single chimeric fH containing domains of human fH involved in binding to fHbp. No differences in anti-V3 fHbp antibody titers were elicited by the wild-type V3 fHbp, V3 fHbp(T286A), and V3 fHbp(E313A), demonstrating that the nonfunctional fHbps retain their immunogenicity. Furthermore, the nonfunctional V3 fHbps elicit serum bactericidal activity that is equivalent to or higher than that observed with the wild-type protein. Our findings provide the basis for the rational design of next-generation vaccines containing nonfunctional V3 fHbps.
authors.affiliation: Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
authors.forename: Stijn
authors.initials: S
authors.lastname: van der Veen
authors.forename: Steven
authors.initials: S
authors.lastname: Johnson
authors.forename: Ilse
authors.initials: I
authors.lastname: Jongerius
authors.forename: Talat
authors.initials: T
authors.lastname: Malik
authors.forename: Alessia
authors.initials: A
authors.lastname: Genovese
authors.forename: Laura
authors.initials: L
authors.lastname: Santini
authors.forename: David
authors.initials: D
authors.lastname: Staunton
authors.forename: Rafael L
authors.initials: RL
authors.lastname: Ufret-Vincenty
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Pickering
authors.forename: Susan M
authors.initials: SM
authors.lastname: Lea
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Tang
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D000942:Antigens, Bacterial / Q000235:genetics / Q000276:immunology*; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D008589:Meningococcal Infections / Q000276:immunology*; D022401:Meningococcal Vaccines / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009345:Neisseria meningitidis / Q000235:genetics / Q000276:immunology*; D011485:Protein Binding / Q000235:genetics / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D000939:Epitopes; D022401:Meningococcal Vaccines; C484699:factor H-binding protein, Neisseria meningitidis