Bactericidal antibody responses induced by meningococcal recombinant chimeric factor H-binding protein vaccines.
Factor H-binding protein (fHbp) is a novel meningococcal vaccine candidate that elicits serum antibodies that activate classical complement pathway bacteriolysis and also inhibit binding of the complement down-regulatory protein, factor H, to the bacterial surface. One limitation of fHbp as a vaccine candidate is antigenic variability, since antibodies to fHbp in the variant 1 (v.1) antigenic group do not protect against strains expressing v.2 or v.3 proteins, and vice versa. We have identified amino acid residues of epitopes recognized by bactericidal anti-fHbp monoclonal antibodies prepared against fHbp from each of the variant groups. One epitope expressed by nearly all v.1 proteins mapped to the B domain, while epitopes expressed by fHbp v.2 or v.3 mapped to the C domain. The results provided the rationale for engineering chimeric fHbp molecules containing the A domain (which is conserved across all variant groups), a portion of the B domain of a v.1 protein, and the carboxyl-terminal portion of the B domain and the C domain of a v.2 protein. By enzyme-linked immunosorbent assay, the resulting recombinant chimeric proteins expressed epitopes from all three variant groups. In mice, the chimeric vaccines elicited serum antibodies with bactericidal activity against a panel of genetically diverse strains expressing fHbp v.1, v.2, or v.3. The data demonstrate the feasibility of preparing a meningococcal vaccine from a single recombinant protein that elicits broad bactericidal activity, including group B strains, which account for 50 percent of cases of meningococcal disease and for which there currently is no broadly protective vaccine.
Beernink
Peter T
PT
Center for Immunobiology and Vaccine Development, Children's Hospital Oakland Research Institute, Oakland, California, USA.
Granoff
Dan M
DM
D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis* / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D000942:Antigens, Bacterial / Q000276:immunology*; D001426:Bacterial Proteins / Q000276:immunology*; D017242:Complement Factor H / Q000276:immunology; D000939:Epitopes / Q000378:metabolism; D005260:Female; D008589:Meningococcal Infections / Q000276:immunology*; D022401:Meningococcal Vaccines / Q000276:immunology*; D051379:Mice; D008958:Models, Molecular; D009345:Neisseria meningitidis / Q000276:immunology*; D011487:Protein Conformation; D015202:Protein Engineering; D011951:Receptors, Complement / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology
D000907:Antibodies, Bacterial; D000911:Antibodies, Monoclonal; D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D000939:Epitopes; D022401:Meningococcal Vaccines; D011951:Receptors, Complement; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; C488465:antigen 1870, Neisseria meningitidis; C484699:factor H-binding protein, Neisseria meningitidis; D017242:Complement Factor H