An adenoviral-vectored vaccine confers seroprotection against capsular group B meningococcal disease.

Adenoviral-vectored vaccines are licensed for prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus, but, for bacterial proteins, expression in a eukaryotic cell may affect the antigen's localization and conformation or lead to unwanted glycosylation. Here, we investigated the potential use of an adenoviral-vectored vaccine platform for capsular group B meningococcus (MenB). Vector-based candidate vaccines expressing MenB antigen factor H binding protein (fHbp) were generated, and immunogenicity was assessed in mouse models, including the functional antibody response by serum bactericidal assay (SBA) using human complement. All adenovirus-based vaccine candidates induced high antigen-specific antibody and T cell responses. A single dose induced functional serum bactericidal responses with titers superior or equal to those induced by two doses of protein-based comparators, as well as longer persistence and a similar breadth. The fHbp transgene was further optimized for human use by incorporating a mutation abrogating binding to the human complement inhibitor factor H. The resulting vaccine candidate induced high and persistent SBA responses in transgenic mice expressing human factor H. The optimized transgene was inserted into the clinically relevant ChAdOx1 backbone, and this vaccine has now progressed to clinical development. The results of this preclinical vaccine development study underline the potential of vaccines based on genetic material to induce functional antibody responses against bacterial outer membrane proteins.

Anti-Factor H Antibody Reactivity in Young Adults Vaccinated with a Meningococcal Serogroup B Vaccine Containing Factor H Binding Protein.

Meningococcal serogroup B (MenB) vaccines contain recombinant factor H binding protein (FHbp), which can complex with complement factor H (CFH) and thereby risk eliciting anti-FH autoantibodies. While anti-FH antibodies can be present in sera of healthy persons, the antibodies are implicated in autoimmune atypical hemolytic uremic syndrome and C3 glomerulopathies. We immunized 120 students with a MenB vaccine (Bexsero). By enzyme-linked immunosorbent assay (ELISA), there were small increases in serum anti-FH levels at 3 weeks postvaccination (geometric mean optical density at 405 nm [OD405], 0.54 versus 0.51 preimmunization, P ≤ 0.003 for each schedule tested). There was a similar small increase in anti-FH antibody levels in a second historical MenB study of 20 adults with stored paired preimmunization and postimmunization sera (P = 0.007) but not in three other studies of 57 adults immunized with other meningococcal vaccines that did not contain recombinant FHbp (P = 0.17, 0.84, and 0.60, respectively). Thus, humans vaccinated with MenB-4C develop small increases in serum anti-FH antibody reactivity. Although not likely to be clinically important, the data indicate a host response to FH. In the prospective MenB study, three subjects (2.5%) developed higher anti-FH titers postimmunization. The elevated titers returned to baseline within 3 to 4 months, and none of the subjects reported adverse events during the follow-up. Although anti-FH antibodies can decrease FH function, the postimmunization sera with high anti-FH antibody levels did not impair serum FH function as measured using a hemolytic assay. Thus, while additional studies are warranted, there is no evidence that the anti-FH antibodies elicited by MenB-4C are likely to cause anti-FH-mediated autoimmune disorders. (This study has been registered at ClinicalTrials.gov under registration no. NCT02583412.)IMPORTANCE Meningococci are bacteria that cause sepsis and meningitis. Meningococcal species are subdivided into serogroups on the basis of different sugar capsules. Vaccines that target serogroup A, C, Y, and W capsules are safe and highly effective. New serogroup B (MenB) vaccines target a bacterial protein that can bind to a blood protein called complement factor H (FH). While serogroup B vaccines appear to be safe and effective, there is a theoretical risk that immunization with a bacterial protein that binds host FH might elicit anti-FH autoantibodies. Autoantibodies to FH have been detected in healthy persons but in rare cases can cause certain autoimmune diseases. We found small and/or transient increases in serum antibody to FH after MenB immunization. While no serious adverse events were reported in the subjects with elevated anti-FH titers, since onset of autoimmune disease is a rare event and may occur months or years after vaccination, additional, larger studies are warranted.

Enhanced protective antibody to a mutant meningococcal factor H-binding protein with low-factor H binding.

Meningococcal factor H-binding protein (FHbp) is an antigen in 2 serogroup B meningococcal vaccines. FHbp specifically binds human and some nonhuman primate complement FH. To investigate the effect of binding of FH to FHbp on protective antibody responses, we immunized infant rhesus macaques with either a control recombinant FHbp antigen that bound macaque FH or a mutant antigen with 2 amino acid substitutions and >250-fold lower affinity for FH. The mutant antigen elicited 3-fold higher serum IgG anti-FHbp titers and up to 15-fold higher serum bactericidal titers than the control FHbp vaccine. When comparing sera with similar IgG anti-FHbp titers, the antibodies elicited by the mutant antigen gave greater deposition of complement component C4b on live meningococci (classical complement pathway) and inhibited binding of FH, while the anti-FHbp antibodies elicited by the control vaccine enhanced FH binding. Thus, the mutant FHbp vaccine elicited an anti-FHbp antibody repertoire directed at FHbp epitopes within the FH binding site, which resulted in greater protective activity than the antibodies elicited by the control vaccine, which targeted FHbp epitopes outside of the FH combining site. Binding of a host protein to a vaccine antigen impairs protective antibody responses, which can be overcome with low-binding mutant antigens.