Nonfunctional variant 3 factor H binding proteins as meningococcal vaccine candidates

Stijn van der Veen, Steven Johnson, Ilse Jongerius, Talat Malik, Alessia Genovese, Laura Santini, David Staunton, Rafael L. Ufret-Vincenty, Matthew C. Pickering, Susan M. Lea, Christoph M. Tang

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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, fHbpT286A and fHbpE313A, 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 fHbpT286A, and V3 fHbpE313A, 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 nextgeneration vaccines containing nonfunctional V3 fHbps.

Original languageEnglish (US)
Pages (from-to)1157-1163
Number of pages7
JournalInfection and immunity
Volume82
Issue number3
DOIs
StatePublished - Mar 2014

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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