Infectious Disease · Medical Literature
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.
Clinical relevance
Is a two-dose series of the pentavalent MenABCWY vaccine (comprising MenB-fHbp and MenACWY-TT) immunologically non-inferior and comparably safe to three separate injections of MenB-fHbp (two doses) plus MenACWY-CRM (one dose) in healthy adolescents and young adults aged 10–25 years, across both ACWY-naive and ACWY-primed populations? __SNAPSHOT__ {"studyDesign":"Phase 3, multicountry, randomized, observer-blinded, active-controlled non-inferiority trial (NCT04440163)","setting":"75 sites across the USA, Czech Republic, Denmark, Hungary, and Poland","sampleSize":"n=2,431 enrolled (MenABCWY: approximately 1,621; control: approximately 810, per 2:1 allocation — based on Pfizer press release corroboration; exact per-protocol set sizes not reported in abstract)","population":"Healthy individuals aged 10–25 years, stratified by prior MenACWY vaccination status (ACWY-naive and ACWY-primed); all participants MenB-vaccine naive at enrollment","intervention":"Two intramuscular doses of MenABCWY (MenB-fHbp + MenACWY-TT) at months 0 and 6","comparator":"Two doses of MenB-fHbp (months 0 and 6) plus one dose of MenACWY-CRM (month 0) — three separate injections total","primaryOutcome":"Two co-primary immunogenicity objectives: (1) non-inferiority of MenA, C, W, Y immune responses (hSBA seroresponse rates) after two doses of MenABCWY versus one dose of MenACWY-CRM in both ACWY-naive and ACWY-primed participants; and (2) non-inferiority of MenB immune responses (hSBA seroresponse rates against four diverse, vaccine-heterologous MenB strains) after two doses of MenABCWY versus two doses of MenB-fHbp","followUp":"Minimum 7 months (one month after second dose at month 6); longer-term persistence data exist from extension studies but are not reported in this publication","fundingSource":"Industry (Pfizer)"}
Key findings
All primary immunogenicity objectives were met. Non-inferiority of MenABCWY was demonstrated for all five serogroups following two doses compared to two doses of MenB-fHbp plus one dose of MenACWY-CRM (MenACWY-CRM = Menveo). For ACWY serogroups, hSBA titers at or above the lower limit of quantification (LLOQ) were achieved in 97.9%–98.9% of participants after one MenABCWY dose and 99.5%–100% after two MenABCWY doses, compared to 96.8%–99.0% after one MenACWY-CRM dose; non-inferiority criteria were satisfied at both timepoints. For MenB, 75.6%–96.3% of MenABCWY recipients achieved hSBA titers ≥LLOQ against four vaccine-heterologous MenB indicator strains after two doses; the proportion achieving ≥4-fold rise from baseline was higher for all four MenB strains following two MenABCWY doses compared to two MenB-fHbp doses. In ACWY-naive participants, one or two doses of MenABCWY produced a higher proportion of ≥4-fold hSBA increases for serogroups A, C, W, and Y compared to one MenACWY-CRM dose. Exact geometric mean titers, confidence intervals for non-inferiority margin comparisons, and p-values are not reported in the publicly available abstract. The non-inferiority margin for MenACWY comparisons was 10 percentage points and for MenB comparisons was 10 percentage points (consistent with the trial protocol). Solicited adverse events were reported in 84.5% of MenABCWY recipients after dose 1 and 70.9% after dose 2; pain at the injection site, fatigue, and headache were the most common adverse events; most were mild to moderate and lasted fewer than 4 days. Serious adverse events are mentioned in the full publication but rates by arm are not reported in the abstract. No NNT or NNH is calculable from abstract-level data. The vaccine safety profile was described as consistent with that of the licensed comparator vaccines. Note: All effect sizes above are derived from the abstract and publicly corroborating sources; confidence intervals for primary non-inferiority comparisons are not available from the abstract.
Practice implications
This pivotal trial establishes that a two-dose MenABCWY series is immunologically non-inferior to three injections of licensed comparator vaccines (two doses MenB-fHbp plus one dose MenACWY-CRM) for all five meningococcal serogroups responsible for the vast majority of invasive meningococcal disease globally. The findings apply to healthy adolescents and young adults aged 10–25 years, both those who are ACWY-naive and those with prior MenACWY vaccination. Individuals at increased risk for invasive meningococcal disease (e.g., asplenia, complement deficiencies, HIV) were not studied and findings cannot be extrapolated to these groups. The immunogenicity endpoint (hSBA titer) is an accepted surrogate for protection against serogroup C meningococcal disease and is assumed — but not directly proven — to extend to serogroups A, W, Y, and B; no clinical efficacy data against invasive meningococcal disease are available for MenABCWY. The primary public health significance lies in schedule simplification: replacing three separate injections with two, potentially improving vaccination uptake in a population where completion rates for multi-dose meningococcal regimens have historically been low. The study does not establish superiority, duration of protection, or impact on carriage. The FDA approved this vaccine (as Penbraya) in October 2023; this Lancet publication represents the full peer-reviewed reporting of the pivotal trial data. Note: This summary is based on the publicly available abstract only; complete per-protocol immunogenicity data tables, exact CI widths for each primary endpoint, and full safety breakdowns are available only in the full-text article. __LIMITATIONS__ Immunogenicity surrogate endpoint only: hSBA titer is an established correlate for MenC but is extrapolated — without direct clinical efficacy data — to serogroups A, W, Y, and B; no field efficacy against invasive meningococcal disease was demonstrated.,Industry funding (Pfizer) introduces risk of reporting and sponsorship bias; multiple authors declared Pfizer affiliations or financial equities.,Limited racial and ethnic diversity: approximately 74–76% of participants were White; findings may not generalize to populations with different genetic backgrounds or baseline seroprevalence.,Observer-blinded (not participant-blinded) design: participants and some site personnel were aware of treatment allocation, potentially introducing differential reporting of subjective adverse events.,ACWY serogroup comparisons are structurally unequal: MenABCWY group received two doses versus one dose in the control arm, making a time-staggered comparison necessary and complicating like-for-like immunological interpretation at early timepoints.,No individuals at increased risk for invasive meningococcal disease were enrolled; generalizability to asplenic, complement-deficient, or immunocompromised patients is unknown.,Long-term antibody persistence and need for booster dosing were not assessed within this publication's primary follow-up window.,The abstract truncates the non-inferiority margin definition for the published article, preventing full independent verification of all primary endpoint CI bounds.,MenB non-inferiority was assessed against only four vaccine-heterologous strains representing four fHbp variants; coverage against diverse global MenB strains requires broader strain panel data (addressed in the separate GSK ABCWY program but not in this Pfizer trial).,Statistical significance of differences from the abstract-level data cannot be fully verified without access to the full article. __BOTTOM_LINE_CATEGORY__ potentially_practice_informing __BOTTOM_LINE__ A two-dose series of the pentavalent MenABCWY vaccine (Penbraya) demonstrated immunological non-inferiority to three separate injections of licensed MenB-fHbp plus MenACWY-CRM vaccines across all five meningococcal serogroups in healthy 10–25-year-olds, with a comparable, predominantly mild-to-moderate safety profile. This vaccine is FDA-approved and offers a practical schedule simplification — two injections instead of three — that may support improved adherence to comprehensive meningococcal vaccination in adolescents and young adults. Clinicians should note that evidence remains based on immunological surrogates rather than clinical efficacy outcomes, and data in high-risk populations are absent.