Characterization of Neisseria meningitidis Isolates That Do Not Express the Virulence Factor and Vaccine Antigen Factor H Binding Protein

Abstract

Neisseria meningitidis remains a leading cause of bacterial sepsis and meningitis. Complement is a key component of natural immunity against this important human pathogen, which has evolved multiple mechanisms to evade complement-mediated lysis. One approach adopted by the meningococcus is to recruit a human negative regulator of the complement system, factor H (fH), to its surface via a lipoprotein, factor H binding protein (fHbp). Additionally, fHbp is a key antigen in vaccines currently being evaluated in clinical trials. Here we characterize strains of N. meningitidis from several distinct clonal complexes which do not express fHbp; all strains were recovered from patients with disseminated meningococcal disease. We demonstrate that these strains have either a frameshift mutation in the fHbp open reading frame or have entirely lost fHbp and some flanking sequences. No fH binding was detected to other ligands among the fHbp-negative strains. The implications of these findings for meningococcal pathogenesis and prevention are discussed.

Recruitment of Factor H as a Novel Complement Evasion Strategy for Blood-Stage Plasmodium falciparum Infection

“…use the CRASP family of proteins, whereas the M-protein family are used by Streptococcus (21). Many of these FH-binding proteins are virulence factors (22,23).…”

Meningococcal Factor H Binding Protein Vaccine Antigens with Increased Thermal Stability and Decreased Binding of Human Factor H

“…Since FHbp variant group 2 is more prevalent than variant group 3 (1, 21) and there is a high degree of cross-protection between them (26,36), these antigens have the potential to provide greater coverage against the majority of prevalent disease-producing strains. The two licensed vaccines contain FHbp as a key antigen, and invasive meningococci lacking an fHbp gene have been identified (37). Since meningococci have redundant mechanisms to bind FH and other complement downregulators (38), inclusion of additional virulence factors that mediate complement evasion may delay the emergence of escape mutants.…”

Role of Factor H Binding Protein in Neisseria meningitidis Virulence and Its Potential as a Vaccine Candidate To Broadly Protect against Meningococcal Disease

“…The importance of fHBP to N. meningitidis is reflected by the detection of the fHBP gene in essentially all MnB strains examined (29,33,37,44). Of 1,263 U.S. and European MnB invasive strains from a prevalence-based study surveyed for surface expression of fHBP, fewer than 2% did not express fHBP levels above the limit of detection as measured using a universal monoclonal antibody, MN86-994-11, that binds to both subfamilies of fHBP (46).…”

“…fHBP confers a benefit for the bacteria in vivo, as binding human factor H protects the bacteria from complement attack (43). A small number of isolates that lack the fHBP gene have been identified (44). These isolates are estimated to represent 0.04% of all the isolates that caused disease in England, Wales, and Northern Ireland over a 35-year period.…”