Invasive meningococcal disease is an uncommon but serious disease predominantly affecting children. This phase 2b study evaluated MenABCWY in 6-month-old infants followed by MenB-fHbp and MenABCWY in 2-month-old infants, the latter being the target age and intervention. Participants were randomized to MenABCWY, 60 µg or 120 µg MenB-fHbp+MenACWY-TT, or 4CMenB+MenACWY-TT, administered as 2 primary and 1 booster dose. The primary safety objective was to describe the safety profile of MenABCWY in participants enrolled at 2 months. Primary immunogenicity objectives were the percentage of participants achieving seroprotective serum bactericidal antibody using human complement titers. Overall, 314 and 12 participants were randomized to sentinel cohort and open-label expanded-enrollment stages, respectively. Based on 2 reports of fever requiring invasive investigations and accompanied by cerebrospinal fluid pleocytosis and 1 report arising from a previous study, the Sponsor terminated the study. Local reactions and systemic events after primary vaccination were generally mild to moderate, and tended to be higher with MenABCWY versus 4CMenB+MenACWY-TT. Immunogenicity data suggest that 1 month after vaccination 2, MenABCWY responses for MenA/C/W/Y were robust and comparable with 4CMenB+MenACWY-TT in 2-month-old participants. Immune responses for MenB test strains were higher with MenABCWY versus 4CMenB+MenACWY-TT and generally similar with 60 µg and 120 µg MenB-fHbp+MenACWY-TT or MenABCWY. Based on the limited results, the consistency of MenB immune responses with 60 µg and 120 µg MenB-fHbp suggests doses < 60 µg could be investigated to assess whether a more acceptable safety profile in conjunction with beneficial immune responses is possible in 2-month-old infants.

Introduction Infants and young children typically have the highest age-related risk of invasive meningococcal disease. The immunogenicity and safety of a single primary dose and a booster of a meningococcal A/C/W/Y tetanus toxoid conjugate vaccine (MenACWY-TT; Nimenrix^®) in infants were evaluated. Methods In this phase 3b, open-label, single-arm study, healthy 3-month-old infants received a single Nimenrix dose followed by a booster at age 12 months (1 + 1 series). Functional antibodies before and 1 month after each vaccination were evaluated with serum bactericidal antibody assays using rabbit (rSBA) or human (hSBA) complement for each A/C/W/Y serogroup. Primary endpoints were rSBA seroprotection (titers ≥ 1:8) rates and geometric mean titers (GMTs); supportive secondary endpoints included hSBA seroprotection (titers ≥ 1:4) rates and GMTs. Local reactions and systemic events occurring within 7 days, adverse events (AEs), serious AEs, and newly diagnosed chronic medical conditions following vaccination were assessed. Results Overall, 147 and 143 participants received the primary and booster Nimenrix doses, respectively. rSBA seroprotection rates across serogroups were 82.3–91.1% at 1 month after the primary dose and increased to 100% at 1 month after the booster. rSBA GMTs were considerably higher after the booster (1299.5‒2714.1) than after the primary dose (54.7‒202.4). In hSBA evaluations performed as supportive to rSBA evaluations, seroprotection rates increased from 38.8 to 95.5% after the primary dose to 100% after the booster, with corresponding GMT increases (8.8‒149.8 to 1208.4‒7299.6). Local reactions and most systemic events were mild to moderate in severity; no new safety concerns were identified. Conclusion Nimenrix given at ages 3 and 12 months had a favorable safety profile and elicited protective immune responses and robust anamnestic booster responses across A/C/W/Y serogroups. These results provide important support for this alternative Nimenrix 1 + 1 immunization schedule for infants < 6 months, allowing flexibility in infant meningococcal immunization. Trial Registration ClinicalTrials.gov, NCT04819113.

Invasive meningococcal disease (IMD) is an uncommon but rapidly progressive and life-threatening infection caused by Neisseria meningitidis , responsible for significant morbidity and mortality worldwide. The majority of cases arise from serogroups A, B, C, W, X and Y, with infants, adolescents, and young adults being disproportionately affected. Vaccination has played a critical role in mitigating the global impact of IMD by leveraging tailored vaccine formulations. Conjugate vaccines, such as those targeting meningococcal serogroups A, C, W, X and Y [MenACWY(X)], and protein-based vaccines for meningococcal serogroup B (MenB) illustrate the nuanced strategies required to address the distinct characteristics of these serogroups. This chapter delves into the complexities surrounding meningococcal vaccine clinical trials, emphasizing the multifaceted scientific and logistical challenges involved in their design and implementation. Key areas of focus include the evaluation of immunogenicity using the serum bactericidal assay (SBA) as a surrogate of protection, the integration of real-world evidence to supplement clinical trial outcomes, and the development of age-specific approaches to address diverse population needs. Additionally, the chapter explores the intricacies of clinical development program design, regulatory frameworks, and the challenges encountered in meningococcal vaccine clinical trials. The chapter concludes by offering a forward-looking perspective on the future of meningococcal vaccine research, underscoring its pivotal role in shaping public health strategies.

Background/Objectives: Meningococcal disease is primarily caused by serogroups A, B, C, W, and Y. Current US vaccination recommendations include routine serogroup A/C/W/Y (MenACWY) vaccination (ages 11–12 and 16 years) and a two-dose, 0-, 6-month MenB vaccination series (age 16–23 years) based on shared clinical decision-making. Administration of the first-in-class Pfizer pentavalent MenABCWY vaccine (Penbraya^TM), which received US licensure in 2023 as a two-dose, 0-, 6-month series, is endorsed when the MenACWY and MenB vaccines are recommended at the same visit. This study evaluated the immunogenicity and safety of two extended two-dose schedules of MenABCWY in healthy adolescents. Methods: In this observer-blinded, phase 2b study (ClinicalTrials.gov, NCT04440176; 19 June 2020), 309 healthy 11- to 14-year-olds were randomized 1:1 to receive a 0-, 36-month or 0-, 12-month Pfizer MenABCWY schedule, which more closely aligns with current US MenACWY vaccination recommendations. Endpoints included serum bactericidal assay using human complement seroprotection rates (titers ≥ 1:8 or ≥1:16, depending on strain), seroresponse rates (≥4-fold increase from baseline titer), and geometric mean titers (GMTs). Safety was also assessed. Results: One month after the second Pfizer MenABCWY dose, serogroup A/B/C/W/Y seroprotection rates were 100% for the 0-, 36-month schedule and 96.6–100% for the 0-, 12-month schedule; seroresponse rates were 100% and 92.9–100%, respectively. GMTs generally trended higher with the 0-, 36-month schedule. Seroprotection rates through 24 months after the second dose of the 0-, 12-month schedule were 44.0–75.0% for serogroup B and 88.9–100% for serogroup A/C/W/Y). No safety issues were identified. Conclusions: These data support Pfizer MenABCWY dosing flexibility and utility within the current or possible future US meningococcal vaccination framework.