Optimising DTwP-containing vaccine infant immunisation schedules in Uganda and Nepal (OptImms): two open-label, non-inferiority, randomised controlled trials.

BACKGROUND: Few data are available comparing the WHO diphtheria-tetanus-pertussis (DTP)-containing vaccine schedule with reduced-dose or delayed three-dose schedules in infants. We aimed to identify an alternative schedule that is non-inferior or superior to the WHO schedule in maintaining early pertussis antibody levels before booster, while creating space for integration of new vaccines. METHODS: In two parallel, open-label, randomised, non-inferiority trials in Uganda and Nepal, healthy infants aged 42-50 days were randomised in a 4:4:4:3:3 ratio via an online system to five diphtheria-tetanus-whole-cell pertussis-Haemophilus influenzae type b-hepatitis B (DTwP-Hib-HepB) vaccination schedules (WHO schedule [ages 6, 10, and 14 weeks]; reduced two-dose schedules at ages 6 and 14 weeks or ages 2 and 4 months; or delayed three-dose schedules at ages 2, 3, and 4 months or ages 2, 4, and 6 months), using site-stratified block randomisation with a block size of 18. The primary outcome was the pre-booster IgG antibody response against pertussis antigens (pertussis toxin; filamentous haemagglutinin [FHA]; pertactin; fimbriae 2 and 3 [Fim 2 and 3]). Antibody responses during and 1 month after the primary series were assessed as secondary endpoints. The two-dose schedules were compared with the WHO schedule as primary analyses, and the exploratory analyses were to compare delayed three-dose schedules with the WHO schedule. All these analyses were conducted in the per-protocol population. For the primary endpoint, non-inferiority margins for geometric mean ratios (GMRs) between two-dose and WHO schedules were calculated for each pertussis antigen separately as 35% of the standard deviation of the geometric mean concentrations of the WHO group, and non-inferiority was concluded if the lower bound of the 95% CI of the GMR exceeded the non-inferiority margin. A non-inferiority margin of 0·67 was used for all other non-inferiority comparisons. The trials were registered with ISRCTN (Uganda [ISRCTN60356654] and Nepal [ISRCTN12240140]) and are complete. FINDINGS: Between Oct 1, 2021, and July 12, 2022 (Uganda) and Dec 5, 2021, and Feb 26, 2023 (Nepal), 956 infants were recruited per country and randomly allocated across the five study groups; pre-booster analyses were conducted in 876 participants in Uganda and 851 participants in Nepal. Two-dose schedules at ages 6 and 14 weeks and ages 2 and 4 months did not meet non-inferiority criteria for pertussis antibodies pre-booster, except FHA (non-inferiority margin 0·59) in Nepal (6 and 14 weeks GMR 0·83 [95% CI 0·61-1·13]; 2 and 4 months 1·20 [0·88-1·64]). Delayed three-dose schedules at ages 2, 3, and 4 months and ages 2, 4, and 6 months produced similar or higher post-primary series and pre-booster responses compared with the WHO schedule, but the WHO schedule achieved higher antibody responses against all pertussis antigens, except FHA in Nepal, at age 3 months. INTERPRETATION: The WHO DTP schedule is the preferred schedule in high-pertussis-burden settings, as it elicits the greatest antibody responses in the first 3 months of life when infants are particularly vulnerable. Although delayed three-dose schedules may be considered in low-risk contexts and in settings with maternal immunisation programmes, early infant protection should guide policy decisions. FUNDING: Gates Foundation.