Date Published: August 1, 2013
Publisher: Public Library of Science
Author(s): Ilse Jongerius, Hayley Lavender, Lionel Tan, Nicola Ruivo, Rachel M. Exley, Joseph J. E. Caesar, Susan M. Lea, Steven Johnson, Christoph M. Tang, Xavier Nassif.
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.
The Gram negative bacterium Neisseria meningitidis is part of the normal human nasopharyngeal flora in up to 40% of healthy individuals ,  and a leading cause of sepsis and meningitis worldwide, with a case fatality rate from septicaemia of approximately 10% , . Because of the non-specific early symptoms and rapid progression of meningococcal disease, there is an urgent need to develop vaccines to protect individuals from this important infection , . N. meningitidis is classified into 12 different serogroups based on its polysaccharide capsule, although only six serogroups are responsible for the majority of disease. Currently there are vaccines based on the polysaccharide capsule of four of these serogroups (i.e. A, C, W, and Y) . However, the capsule of serogroup B N. meningitidis (MenB) is structurally identical to a modification of a cell adhesion molecule present in the foetal brain, and is thus weakly immunogenic and could induce autoimmunity if used as a vaccine . Vaccines based on outer membrane vesicles have proven to be effective against MenB but only in combating epidemic disease caused by a single clone ; the most effective approach to produce a broadly protective vaccine against all N. meningitidis serogroups (including MenB) will be the use of protein based vaccines .
N. meningitidis and N. gonorrhoeae are two human specific, closely related pathogens that inhabit distinct niches in the body. N. gonorrhoeae causes sexually transmitted infections predominantly affecting the mucous membranes of the genito-urinary tract, while N. meningitidis colonises the nasopharynx . Despite sharing many similarities of the genetic level, these bacteria employ entirely different mechanisms to evade immune responses, and in particular, to avoid complement activation on their surface . For example, disease isolates of N. meningitidis express a polysaccharide capsule which is essential for high-level serum resistance , while N. gonorrhoeae is not encapsulated. Instead sialylation of lipopolysaccharide markedly promotes complement resistance in the gonococcus  but this has less impact on N. meningitidis.