Yellow fever vaccination in healthy Gambian children of different ages to establish safety and immunogenicity of a booster dose: a open-label, non-randomised, single-site, phase 3 vaccine trial.

Abstract

Yellow fever is a vaccine-preventable viral haemorrhagic fever. Vaccine-induced neutralising antibody in children can wane faster than previously thought. This clinical trial investigated the safety and immunogenicity of a yellow fever booster in children of different ages. This open-label, non-randomised, single-site, phase 3 vaccine trial conducted at a health centre in The Gambia enrolled healthy children into three cohorts defined by age. The oldest cohort was aged 6-9 years, the middle cohort was aged 4-5 years, and the youngest cohort was aged 1-3 years. Children were eligible if they had received a primary yellow fever vaccine at age 9-12 months and had no history of a serious adverse event to the yellow fever vaccine or immunodeficiency. All children received a yellow fever 17D booster dose. The primary outcome of neutralising antibody responses to the booster was analysed after 28 days using a linear mixed model in children with complete immunology data and who received their primary vaccine in the 9-12-month period. Safety was a coprimary outcome in all participants. There were no missing data. This trial was registered with ClinicalTrials.gov (NCT05332197) and it is complete and closed to new participants. The trial enrolled 610 children (175 in the oldest cohort, 198 in the middle cohort, and 237 in the youngest cohort) between Sept 6, 2022, and Sept 20, 2023. Median age at booster vaccination was 7·2 years (IQR 6·4-9·7) for the oldest cohort, 4·0 years (3·9-5·2) for the middle cohort, and 2·3 years (1·9-3·4) for the youngest cohort. There was a roughly equal sex split in all three cohorts. Immunology analysis was based on 589 children. Baseline PRNT₉₀ seropositivity occurred in 106 (65% [95% CI 65-72]) of 164 children in the oldest cohort, 130 (67% [60-73]) of 195 children in the middle cohort, and 189 (82% [77-87]) of 230 children in the youngest cohort. 581 (99% [97-99]) of 589 total children were seropositive post-booster. The oldest and middle cohorts had a greater fold change in neutralising antibody on PRNT₉₀ (7·72 [95% CI 6·27-9·16], p=0·0001 for the oldest cohort; and 6·13 [5·08-7·19], p=0·044 for the middle cohort) compared with the youngest cohort (4·62 [3·89-5·35]). There were two severe adverse events; neither were related to the study vaccine. Yellow fever booster vaccination was safe and immunogenic in healthy Gambian children. Protective neutralising antibody waned following primary vaccination and boosting had a more pronounced effect in the oldest and middle cohorts (aged 4-9 years) than in the youngest cohort (aged 1-3 years). These data could be of value to policy makers to inform need and optimal timing of yellow fever booster vaccination in children in endemic areas. Wellcome Trust.