Immunogenicity, reactogenicity, and safety of a reduced-interval 4CMenB primary immunisation schedule in UK infants: a multicentre, open-label, assessor-blinded, phase 4 randomised controlled trial

BACKGROUND: Until July, 2025, infants in the UK received the four-component meningococcal B vaccine (4CMenB) at ages 8 weeks and 16 weeks, boosted at 1 year. 4CMenB introduction was associated with large reductions in serogroup B (MenB) invasive meningococcal disease in childhood (cases now peak at age 3 months vs age 5-6 months before routine immunisation). A shorter interval between 4CMenB priming doses could reduce cases further. This study aimed to compare the immunogenicity, reactogenicity, and safety of 4CMenB priming schedules. METHODS: This multicentre, open-label, assessor-blinded, phase 4, randomised controlled trial compared reduced-interval 4CMenB (Group 1) priming at ages 8 and 12 weeks and 13-valent pneumococcal conjugate vaccine (PCV13) at 16 weeks with the standard-schedule 4CMenB (Group 2) at ages 8 and 16 weeks and PCV13 at 12 weeks, via computer-generated block randomisation (1:1). 4CMenB and PCV13 boosters were given at 1 year. Six hospitals in England enrolled full-term, unvaccinated, immunocompetent infants without previous invasive meningococcal disease. Participants received 4CMenB and PCV13 doses of 0·5 mL, intramuscularly. Blood samples obtained at post-primary, pre-booster, and post-booster timepoints were tested by masked staff for human serum bactericidal antibody (hSBA) against three MenB reference strains (44/76-SL: fHbp, 5/99: NadA, and NZ98/254: PorA), and serotype-specific pneumococcal antibodies against 12 PCV13 serotypes. The primary outcome compared immune responses after 4CMenB priming at 4 weeks post-primary vaccinations using hSBA geometric mean titres (GMTs) and ratios (GMRs), and the proportion of infants achieving protective thresholds (titre of ≥4). Secondary outcomes compared immunogenicity to 4CMenB and PCV13 pre-booster and post-booster, and reactogenicity via diaries, including combined 12-week and 16-week data, analysed in all vaccinated infants with antibody results available, according to their randomised group, which included blood samples taken outside the recommended timing. Safety was assessed in all enrolled participants via adverse event monitoring. This study is registered with the International Standard Randomised Controlled Trial Number registry, ISRCTN52318758, and is completed. FINDINGS: The study was conducted between Aug 25, 2021, and Oct 3, 2024. During the recruitment period between Aug 25, 2021, and Nov 22, 2022, 221 infants were randomly assigned (113 to Group 1 and 108 to Group 2; 110 [50%] of 221 were male and 111 [50%] were female). 219 completed the study (111 in Group 1; 108 in Group 2). 4 weeks after primary 4CMenB immunisation, the proportion of infants with protective hSBA titres did not significantly differ between groups for all strains (fHbp strain: 91 [93%] of 98 participants in Group 1 achieved protective titres vs 97 [97%] of 100 in Group 2; risk difference [RD] -0·04 [95% CI -0·10 to 0·02], p=0·21; NadA strain: 97 [100%] of 97 vs 98 [100%] of 98; PorA strain: 60 [64%] of 94 vs 69 [75%] of 92; RD -0·11 [-0·24 to 0·02], p=0·11). However, 4 weeks post-primary hSBA GMTs were significantly lower in Group 1 versus Group 2 (geometric mean ratios were 0·65 [95% CI 0·47-0·90] for fHbp, 0·61 [0·46-0·79] for NadA, and 0·73 [0·53-1·00] for PorA), pre-booster hSBA GMTs were not significantly different between groups (GMRs fHbp: 0·95 [0·76-1·20], NadA: 0·79 [0·49-1·27], PorA: 0·95 [0·82-1·10]), and post-booster hSBA GMTs were higher in Group 1 than Group 2, although only significantly so for PorA (GMRs fHbp: 1·09 [0·79-1·51], NadA: 1·33 [0·93-1·92], PorA 1·55 (1·09-2·22]). For serotype-specific pneumococcal responses, pre-booster IgG geometric mean concentrations were significantly higher for 10 of 12 serotypes in infants receiving PCV13 at age 16 weeks versus 12 weeks, while proportions achieving protective antibody thresholds (≥0·35 μg/mL) were significantly higher for four serotypes. Post-booster, 11 of 12 pneumococcal serotypes had similar geometric mean concentrations, with no difference in proportions achieving protective thresholds for all 12 serotypes. The most frequently reported reactions, at any given timepoint, were irritability (69% [69 of 100] in Group 1 vs 97% [99 of 102] in Group 2), persistent crying (42% [42 of 100] vs 87% [89 of 102]), and inactivity (32% [32 of 100] vs 69% [70 of 102]). Combined reactogenicity data for ages 12 weeks and 16 weeks showed significantly less frequent irritability (RD -0·10 [95% CI -0·17 to -0·03]; p=0·0091) and crying (-0·19 [-0·30 to -0·08]; p=0·0012) with the reduced-interval schedule than the standard schedule. INTERPRETATION: A reduced-interval 4CMenB schedule could provide earlier protection against MenB disease in infants and was less reactogenic than the previous standard schedule. Based on these findings, the UK childhood immunisation programme adopted these changes in July, 2025. Ongoing national surveillance will evaluate the real-world impact. FUNDING: GSK.