Eculizumab, a humanized anti–complement C5 monoclonal antibody (mAb) for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome, blocks the terminal complement ...pathway required for serum bactericidal activity (SBA). Because treated patients are at >1000-fold increased risk of meningococcal disease, vaccination is recommended; whether vaccination can protect by opsonophagocytic activity in the absence of SBA is not known. Meningococci were added to anticoagulated blood from 12 healthy adults vaccinated with meningococcal serogroup B and serogroup A, C, W, Y vaccines. Bacterial survival was measured after 3-hour incubation in the presence of eculizumab or control complement factor D inhibitor ACH-4471, which blocks the complement alternative pathway (AP) and is in phase 2 development for treatment of PNH. In the absence of inhibitors, colony formation units (CFUs) per milliliter in blood from all 12 immunized subjects decreased from ∼4000 at time 0 to sterile cultures at 3 hours. In the presence of eculizumab, there was a >22-fold increase in geometric mean CFUs per milliliter (90 596 and 114 683 CFU/mL for serogroup B and C strains, respectively; P < .0001 compared with time 0). In the presence of ACH-4471, there was a >12-fold decrease (23 and 331 CFU/mL, respectively; P < .0001). The lack of meningococci killing by blood containing eculizumab resulted from inhibition of release of C5a, a C5 split product needed for upregulation of phagocytosis. The results provide an explanation for the large number of cases of meningococcal disease in immunized patients being treated with eculizumab and suggest that vaccination may provide better protection against meningococcal disease in patients treated with an AP-specific inhibitor.
•Eculizumab, an anti–complement C5 mAb, blocked killing of meningococci by whole blood from healthy immunized adults.•Blocking the AP with ACH-4471, a small molecule in development for PNH, had much less of an effect on meningococcal killing.
No broadly effective vaccines are available for prevention of group B meningococcal disease, which accounts for>50% of all cases. The group B capsule is an autoantigen and is not a suitable vaccine ...target. Outer-membrane vesicle vaccines appear to be safe and effective, but serum bactericidal responses in infants are specific for a porin protein, PorA, which is antigenically variable. To broaden protection, outer-membrane vesicle vaccines have been prepared from>1 strain, from mutants with>1 PorA, or from mutants with genetically detoxified endotoxin and overexpressed desirable antigens, such as factor H binding protein. Also, recombinant protein vaccines such as factor H binding protein, given alone or in combination with other antigens, are in late-stage clinical development and may be effective against the majority of group B strains. Thus, the prospects have never been better for developing vaccines for prevention of meningococcal disease, including that caused by group B strains.
Complement factor H (fH), a molecule that downregulates complement activation, binds to Neisseria meningitidis and increases resistance to serum bactericidal activity. We investigated the species ...specificity of fH binding and the effect of human fH on downregulating rat (relevant for animal models) and rabbit (relevant for vaccine evaluation) complement activation. Binding to N. meningitidis was specific for human fH (low for chimpanzee fH and not detected with fH from lower primates). The addition of human fH decreased rat and rabbit C3 deposition on the bacterial surface and decreased group C bactericidal titers measured with rabbit complement 10- to 60-fold in heat-inactivated sera from human vaccinees. Administration of human fH to infant rats challenged with group B strain H44/76 resulted in an fH dose-dependent increase in CFU/ml of bacteria in blood 8 h later (P < 0.02). At the highest fH dose, 50 μg/rat, the geometric mean number of CFU per ml was higher than that in control animals (1,050 versus 43 P < 0.005). The data underscore the importance of binding of human fH for survival of N. meningitidis in vitro and in vivo. The species specificity of binding of human fH adds another mechanism toward our understanding of why N. meningitidis is strictly a human pathogen.
Abstract Killing of Neisseria meningitidis can result from complement-mediated serum bactericidal activity (SBA) or opsonophagocytosis (OPA), or a combination of the two mechanisms. While SBA titers ...≥1:4 confer protection, recent evidence suggests that this threshold titer may not be required. For example, the incidence of meningococcal disease declines between ages 1 and 4 years without evidence of acquisition of SBA titers ≥1:4. Meningococcal polysaccharide vaccination also elicited OPA and lowered the risk of disease in patients with late complement component deficiencies whose sera did not support SBA. Sera from healthy adults immunized with an outer membrane vesicle vaccine showed OPA killing of N. meningitidis with C6-depleted complement, and whole blood from complement-sufficient non-immunized adults with SBA titers <1:4 also frequently had killing activity. Collectively the data indicate that SBA titers <1:4 and/or vaccine-induced OPA can confer protection against meningococcal disease.
The meningococcal 4CMenB vaccine (Bexsero; Novartis) contains four antigens that can elicit serum bactericidal activity, one of which is factor H (FH)-binding protein (FHbp). FHbp specifically binds ...human complement FH. When humans are immunized, FHbp is expected to form a complex with FH, which could affect immunogenicity and safety. Wild-type mice (whose FH does not bind to FHbp) and human FH transgenic mice were immunized with three doses of 4CMenB, and their responses were compared. There were no significant differences between the serum bactericidal responses of transgenic and wild-type mice to strains with all of the antigens mismatched for 4CMenB except PorA or NadA. In contrast, against a strain mismatched for all of the antigens except FHbp, the transgenic mice had 15-fold weaker serum bactericidal antibody responses (P = 0.0006). Binding of FH downregulates complement. One explanation for the lower anti-FHbp serum bactericidal activity in the transgenic mice is that their postimmunization serum samples enhanced the binding of FH to FHbp, whereas the serum samples from the wild-type mice inhibited FH binding. Control antiserum from transgenic mice immunized with a low-FH-binding mutant FHbp (R41S) vaccine inhibited FH binding. Two 4CMenB-vaccinated transgenic mice developed serum IgM autoantibodies to human FH. Thus, human FH impairs protective serum anti-FHbp antibody responses, in part by skewing the antibody repertoire to FHbp epitopes outside the FH binding site. FHbp vaccines that bind FH may elicit FH autoantibodies. Mutant FHbp antigens with low FH binding could improve protection and, potentially, vaccine safety in humans.
Two serogroup B meningococcal vaccines contain a novel antigen called factor H (FH)-binding protein (FHbp). FHbp specifically binds human FH, a plasma protein that downregulates complement. One vaccine (4CMenB; Novartis) is licensed in Europe, Canada, and Australia. When humans are immunized, FHbp can complex with FH. We compared the immunogenicity of 4CMenB vaccine in wild-type mice, whose own FH does not bind to FHbp, and human FH transgenic mice. Transgenic mice had respective antibody responses similar to those of wild-type mice to 4CMenB antigens that do not bind FH. However, the protective antibody responses of the transgenic mice to FHbp were impaired, largely because the antibodies did not inhibit but rather enhanced the binding of FH to FHbp. Two transgenic mice developed serum IgM autoantibodies to FH. Mutant FHbp antigens with low FH binding likely will elicit greater protection in humans than FHbp vaccines that bind FH and have a lower risk of FH autoantibodies.
Meningococcal outer membrane vesicle (OMV) vaccines are prepared with detergents to remove endotoxin, which also remove desirable antigens such as factor H binding protein (FHbp). Native OMV (NOMV) ...vaccines with genetically attenuated endotoxin do not require detergent treatment and elicit broader serum bactericidal antibody (SBA) responses than OMV or recombinant FHbp (rFHbp) vaccines.
We measured human complement-mediated SBA responses in mice immunized with NOMV with overexpressed FHbp subfamily B (NOMV-FHbp), NOMV with FHbp genetically inactivated (NOMV-KO), and/or a control rFHbp vaccine against meningococcal and gonococcal strains.
Despite having 36-fold less FHbp per dose, the NOMV-FHbp vaccine elicited a ≥3-fold higher serum IgG anti-FHbp geometric mean titer than control vaccines containing rFHbp (P ≤ .003). Against 2 meningococcal outbreak strains with mismatched PorA and heterologous FHbp subfamily B sequence variants, the NOMV-FHbp vaccine produced ≥30-fold higher SBA titers than control vaccines. Mice immunized with NOMV-FHbp and NOMV-KO vaccines also elicited SBA against a gonococcal strain (P < .0001 vs the adjuvant-only control group). In contrast, 2 licensed meningococcal serogroup B vaccines, including one containing detergent-extracted OMV, did not produce gonococcal SBA in humans.
A meningococcal NOMV vaccine elicits SBA against gonococci and with overexpressed FHbp elicits SBA against meningococci.
Patients receiving eculizumab have an increased risk for meningococcal disease, but most reported cases are attributable to encapsulated meningococcal strains. We describe a case in which a ...nongroupable meningococcal strain, which rarely causes disease in healthy persons, caused fatal disease in an eculizumab recipient despite meningococcal vaccination.
Background. MenB-4C is a recently licensed meningococcal serogroup B vaccine. For vaccine licensure, short-term efficacy was inferred from serum bactericidal antibody (SBA) titers against 3 ...antigen-specific indicator strains, which are not necessarily representative of US disease-causing strains. Methods. A total of 4923 students were immunized with MenB-4C in response to an outbreak at a university. Serum samples were obtained at 1.5–2 months from 106 students who received the recommended 2 doses and 52 unvaccinated students. Follow-up serum samples were obtained at 7 months from 42 vaccinated and 24 unvaccinated participants. SBA was measured against strains from 4 university outbreaks. Results. At 1.5–2 months, the proportion of immunized students with protective titers ≥1:4 against an isolate from the campus outbreak was 93% (95% confidence interval CI, 87%–97%) vs 37% (95% CI, 24%–51%) in unvaccinated students. The proportion with protective titers against strains from 3 other university outbreaks was 73% (95% CI, 62%–82%) vs 26% (95% CI, 14%–41%) in unvaccinated; 71% (95% CI, 61%–79%) vs 19% (95% CI, 10%–33%) in unvaccinated; and 53% (95% CI, 42%–64%) vs 9% (95% CI, 3%–22%) in unvaccinated (P < .0001 for each strain). At 7 months, the proportion of immunized students with titers ≥1:4 was 86% (95% CI, 71%–95%) against the isolate from the campus outbreak and 57% (95% CI, 41%–72%), 38% (95% CI, 24%–54%), and 31% (95% CI, 18%–47%), respectively, for the other 3 outbreak strains. Conclusions. MenB-4C elicited short-term protective titers against 4 strains responsible for recent university campus outbreaks. By 7 months the prevalence of protective titers was <40% for 2 of the 4 outbreak strains. A booster dose of MenB-4C may be needed to maintain protective titers.
Highlights • Epidemic serogroup A meningococcal disease in Sub-Sahara Africa is currently controlled by a monovalent serogroup A conjugate vaccine. • Epidemics caused by serogroup C, W and X strains ...continue to occur in the region. • Novel protein antigens such as Factor H binding protein (FHbp) used in licensed serogroup B vaccines are shared across capsular groups. • We prepared a native OMV with genetically attenuated endotoxin and over-expressed FHbp. • The vaccine elicited broader serum bactericidal antibody responses than MenB-4C.
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