Distinct Binding and Immunogenic Properties of the Gonococcal Homologue of Meningococcal Factor H Binding Protein

Abstract

Neisseria meningitidis is a leading cause of sepsis and meningitis. The bacterium recruits factor H (fH), a negative regulator of the complement system, to its surface via fH binding protein (fHbp), providing a mechanism to avoid complement-mediated killing. fHbp is an important antigen that elicits protective immunity against the meningococcus and has been divided into three different variant groups, V1, V2 and V3, or families A and B. However, immunisation with fHbp V1 does not result in cross-protection against V2 and V3 and vice versa. Furthermore, high affinity binding of fH could impair immune responses against fHbp. Here, we investigate a homologue of fHbp in Neisseria gonorrhoeae, designated as Gonococcal homologue of fHbp (Ghfp) which we show is a promising vaccine candidate for N. meningitidis. We demonstrate that Gfhp is not expressed on the surface of the gonococcus and, despite its high level of identity with fHbp, does not bind fH. Substitution of only two amino acids in Ghfp is sufficient to confer fH binding, while the corresponding residues in V3 fHbp are essential for high affinity fH binding. Furthermore, immune responses against Ghfp recognise V1, V2 and V3 fHbps expressed by a range of clinical isolates, and have serum bactericidal activity against N. meningitidis expressing fHbps from all variant groups. Neisseria meningitidis is a major cause of sepsis and meningitis in young children and adolescents. Although vaccines are currently available against several serogroups, a broadly effective vaccine against serogroup B is still needed. Factor H binding protein (fHbp) can bind the human complement regulator factor H (fH) and is an important meningococcal immunogen. fHbp is divided into three variant groups (V1, V2 and V3) and immunisation with V1 fHbp does not elicit cross-protection against meningococcus expressing fHbp V2 or V3, and vice versa. Here, we investigate a homologue of fHbp in Neisseria gonorrhoeae which we named Gonococcal homologue of factor H binding protein (Ghfp). We show that in contrast to fHbp, Ghfp is not expressed on the bacterial surface and is unable to bind to factor H. Surprisingly, we found that antibodies raised against Ghfp have the capacity to mediate protective immunity against N. meningitidis expressing any of the three variant groups of fHbp, and could provide a broadly protective vaccine against N. meningitidis.