Timing of Rotavirus Vaccine Doses and Severe Rotavirus Gastroenteritis among Vaccinated Infants in Low- and Middle-Income Countries.

Background: Altering rotavirus vaccine schedules may improve vaccine performance in low- and middle-income countries. We analyzed data from clinical trials of the monovalent (RV1) and pentavalent (RV5) rotavirus vaccines in low- and middle-income countries to understand the association between vaccine dose timing and severe rotavirus gastroenteritis incidence. Methods: We assessed the association between variations in rotavirus vaccine administration schedules and severe rotavirus gastroenteritis risk. We used the complement of the Kaplan-Meier survival estimator to estimate risk differences for different schedules. To adjust risk differences (RDs) for confounding, we calibrated estimates in the vaccinated arm using estimates from the placebo arm. Results: There were 3,114 and 7,341 children included from the RV1 and RV5 trials, respectively. The 18-month adjusted severe rotavirus gastroenteritis risk was 4.0% (95% confidence interval [CI] = 1.1, 7.1) higher for those receiving their first RV5 dose at <6 versus 6 weeks. For RV1, there was a 4.0% (95% CI = 0.0, 8.2) increase in 12-month adjusted risk for a 4- versus 6-week interval between doses. Further analysis revealed those receiving their first RV5 dose at 3-4 and 5-7 weeks had 2.9% (95% CI = 0.8, 5.3) and 1.3% (95% CI = -0.3, 3.0), respectively, higher risk compared with those at 9-12 weeks. Those receiving their first dose at 8 weeks had the lowest risk (RD: -2.6% [95% CI = -5.4, -0.1]) compared with those at 9-12 weeks. Conclusions: A modest delay in rotavirus vaccination start and increase in interval between doses may be associated with lower severe rotavirus gastroenteritis risk in low- and middle-income countries.