Immunogenicity and safety of a pentavalent meningococcal MenABCWY vaccine in healthy adolescents and young adults: a phase 3, multicountry, randomised, observer-blinded, active-controlled non-inferiority trial.

Abstract

Neisseria meningitidis serogroups A, B, C, W, and Y (MenA, Men B, MenC, MenW, and MenY) cause nearly all invasive meningococcal disease globally, and clinical outcomes are often severe. We aimed to evaluate the safety and immunological non-inferiority of a MenABCWY vaccine, comprising MenB-fHbp and MenACWY-TT, compared with US-licensed vaccines MenB-fHbp and MenACWY-CRM, in healthy adolescents and young adults. In this phase 3, observer-blinded, active-controlled trial at 75 sites in the USA, the Czech Republic, Denmark, Hungary, and Poland, healthy individuals aged 10-25 years were randomly allocated (2:1), stratified by previous MenACWY vaccination status, to receive two doses of MenABCWY vaccine (at months 0 and 6) or two doses of MenB-fHbp vaccine (months 0 and 6) plus one dose of MenACWY-CRM vaccine (month 0). This study had two primary immunogenicity objectives: evaluating MenA, MenC, MenW, and MenY immune responses following two doses of MenABCWY versus one dose of MenACWY-CRM in ACWY-naive and ACWY-primed participants, and evaluating MenB immune responses following two doses of MenABCWY versus two doses of MenB-fHbp. Immune responses were evaluated by human serum bactericidal assay using human complement against MenA, MenC, MenW, and MenY strains and four diverse, vaccine-heterologous MenB strains. Non-inferiority was shown if the lower bounds of the 95% CIs for the differences in rates of seroresponse or composite response (all MenB strains combined) exceeded -10%. Safety objectives comprised evaluating frequencies of solicited local reactions and systemic events reported within 7 days after each vaccination and adverse events up to 1 month after the second vaccination. This study is registered with ClinicalTrials.gov, NCT04440163, and with EudraCT, 2019-004313-13, and is completed. Between June 17, 2020, and Aug 3, 2021, 2431 participants were recruited and randomly allocated. At baseline, the safety population (n=2412) had a median age of 16·0 years (IQR not calculated) and a mean age of 16·1 years (SD 4·55), with 1176 (49%) male and 1236 (51%) female participants. 1881 (78%) participants were White, and 621 (26%) were Hispanic or Latino in ethnicity. Among ACWY-naive participants, differences in MenA, MenC, MenW, and MenY seroresponse rates between vaccination groups receiving two MenABCWY doses versus one MenACWY-CRM dose ranged from 2·5% (95% CI -0·2 to 6·0) for MenA to 41·0% (95% CI 34·4 to 47·5) for MenC. Among ACWY-primed participants, differences in MenA, MenC, MenW, and MenY seroresponse rates between vaccination groups ranged from -3·2% (95% CI -6·5 to 0·5) for MenA to 0·7% (95% CI -2·2 to 4·3) for MenW. The differences in MenB seroresponse rates across test strains between vaccination groups receiving two MenABCWY doses versus two MenB-fHbp doses ranged from 1·4% (95% CI -1·0 to 4·3) for MenB test strains expressing fHbp variant A56 to 10·9% (95% CI 5·2 to 16·6) for MenB test strains expressing fHbp variant B24; the difference in composite response for all MenB test strains was 9·6% (95% CI 4·2 to 15·2). Reactogenicity events, mostly mild to moderate in severity, were reported at similar frequencies across groups; none led to study withdrawal. Similar proportions of each group reported one or more adverse events (368 [21%] of 1763 participants in the MenABCWY group vs 132 [20%] of 649 participants in the MenB-fHbp plus MenACWY-CRM group). The immunological non-inferiority and safety profile of a two-dose MenABCWY series (months 0 and 6) compared with three separate injections of MenB-fHbp (months 0 and 6) and MenACWY-CRM (month 0) for protection against MenA, MenB, MenC, MenW, and MenY indicate that MenABCWY could simplify the vaccination strategy against invasive meningococcal disease through fewer injections, potentially increasing vaccination rates among adolescents and young adults. Pfizer.