Meningococcal Factor H Binding Proteins in Epidemic Strains from Africa: Implications for Vaccine Development

Abstract

BackgroundFactor H binding protein (fHbp) is an important antigen for vaccines against meningococcal serogroup B disease. The protein binds human factor H (fH), which enables the bacteria to resist serum bactericidal activity. Little is known about the vaccine-potential of fHbp for control of meningococcal epidemics in Africa, which typically are caused by non-group B strains.Methodology/Principal FindingsWe investigated genes encoding fHbp in 106 serogroup A, W-135 and X case isolates from 17 African countries. We determined complement-mediated bactericidal activity of antisera from mice immunized with recombinant fHbp vaccines, or a prototype native outer membrane vesicle (NOMV) vaccine from a serogroup B mutant strain with over-expressed fHbp. Eighty-six of the isolates (81%) had one of four prevalent fHbp sequence variants, ID 4/5 (serogroup A isolates), 9 (W-135), or 74 (X) in variant group 1, or ID 22/23 (W-135) in variant group 2. More than one-third of serogroup A isolates and two-thirds of W-135 isolates tested had low fHbp expression while all X isolates tested had intermediate or high expression. Antisera to the recombinant fHbp vaccines were generally bactericidal only against isolates with fHbp sequence variants that closely matched the respective vaccine ID. Low fHbp expression also contributed to resistance to anti-fHbp bactericidal activity. In contrast to the recombinant vaccines, the NOMV fHbp ID 1 vaccine elicited broad anti-fHbp bactericidal activity, and the antibodies had greater ability to inhibit binding of fH to fHbp than antibodies elicited by the control recombinant fHbp ID 1 vaccine.Conclusion/SignificanceNOMV vaccines from mutants with increased fHbp expression elicit an antibody repertoire with greater bactericidal activity than recombinant fHbp vaccines. NOMV vaccines are promising for prevention of meningococcal disease in Africa and could be used to supplement coverage conferred by a serogroup A polysaccharide-protein conjugate vaccine recently introduced in some sub-Saharan countries.

Immunogenicity and safety of investigational vaccine formulations against meningococcal serogroups A, B, C, W, and Y in healthy adolescents

“…For example, isolated epidemic strains from serogroups A, W, and X (a recently identified cause of IMD in Africa, for which no vaccine exists), express fHbp proteins that share significant sequence homology with the fHbp antigen used in the 4CMenB vaccine and, therefore, may be susceptible to the bactericidal activity of 4CMenB-induced antibodies. 28,29 Indeed, results of an analysis of the bactericidal activity of sera from 4CMenB-vaccinated individuals against a panel of serogroup X epidemic strains indicated that 4CMenB may indeed confer protection against strains of this serogroup, and that this protection is likely attributable to fHbp-specific antibody responses. 30 While 4CMenB coverage of non-serogroup B strains has not been studied extensively, the susceptibility of any meningococcal strain to bactericidal antibodies elicited by 4CMenB is dependent upon both the degree of similarity between vaccine antigens and the respective target proteins, as well as the expression level of the target proteins, in each strain.…”

A meningococcal vaccine antigen engineered to increase thermal stability and stabilize protective epitopes

“…We chose FHbp ID 22, as this sequence variant was prevalent in invasive isolates from Africa (14,20) and the immunogenicity of vaccines containing FHbp ID 22 previously had been tested in mice (6,14,16,21). The L130R substitution increased the T m of the N-terminal domain by 7.7°C (Fig.…”

“…FHbp sequence variants in variant group 2 are prevalent among invasive strains in Europe (12) and North America (ID 19) (13) and Africa (ID 22) (14). These two sequence variants were reported to have low thermal stability for the amino-(N-) terminal domain (15,16), whereas FHbp from variant groups 1 and 3 had high thermal stability (15,17,18).…”

Current Trends In Research, Development And Production Of Prophylactic Vaccines: Report of Vaccipharma 2015 Congress

“…Issues to be studied more carefully are duration of protection in various age groups, mucosal immunity and herd protection. Of particular note, a substantial difference in immunogenicity has been observed with recombinant fHbp versus the experimental formulations of native OMV vaccines where fHbp has been included as over-expressed vaccine antigen (NOMV-OEfHbp with 3-6 times the ordinary level found in wild type strains) [89][90][91]. The total amount of fHbp in the two formulations can be more than 100 times different, and the NOMV formulation induces better anti-fHbp immunity than the recombinant vaccine.…”

“…Instead the vaccine can be made tolerable for humans with genetic manipulation of LPS (lpx1-mutants) [89]. Preclinical studies with NOMV vaccines have shown higher protective titres and broader immune responses, resulting in better capacity to kill strains with fHbp variants that are substantially different from the vaccine antigen selected for the vaccine [91,[93][94][95]. These observations served as inspiration for further studies of the OMV-concept and use of NOMV as a "platform" for various other antigens.…”