Impact of Reducing Complement Inhibitor Binding on the Immunogenicity of Native Neisseria meningitidis Outer Membrane Vesicles

Neisseria meningitidis recruits host human complement inhibitors to its surface to down-regulate complement activation and enhance survival in blood. We have investigated whether such complement inhibitor binding occurs after vaccination with native outer membrane vesicles (nOMVs), and limits immunogenicity of such vaccines. To this end, nOMVs reactogenic lipopolysaccharide was detoxified by deletion of the lpxl1 gene (nOMV lpxl1 ). nOMVs unable to bind human complement factor H (hfH) were generated by additional deletions of the genes encoding factor H binding protein (fHbp) and neisserial surface protein A (NspA) (nOMV dis ). Antibody responses elicited in mice with nOMV dis were compared to those elicited with nOMV lpxl1 in the presence of hfH. Results demonstrate that the administration of human fH to mice immunized with fHbp containing OMV lpxl1 decreased immunogenicity against fHbp (but not against the OMV as a whole). The majority of the OMV-induced bactericidal immune response (OMV lpxl1 or OMV dis) was versus PorA. Despite a considerable reduction of hfH binding to nOMV dis , and the absence of the vaccine antigen fHbp, immunogenicity in mice was not different from nOMV lpxl1 , in the absence or presence of hfH (serum bactericidal titers of 1:64 vs 1:128 after one dose in the nOMV dis and nOMV lpxl1 –immunized groups respectively). Therefore, partial inhibition of fH binding did not enhance immunity in this model.