Relative Efficacy of Oral Rotavirus Vaccination against Gastroenteritis-Associated Antibiotic Use and Antimicrobial Resistance Gene Carriage

Background: Rotavirus (RV) is the leading cause of severe gastroenteritis (GE) in low- and middle-income countries (LMICs), but the efficacy of oral RV vaccines (ORVs) remains suboptimal. ORVs have underappreciated potential to reduce inappropriate antibiotic use driven by viral diarrhoeal illness, but their impact on antibiotic exposure and antimicrobial resistance gene (ARG) carriage remains unquantified. We quantified the indirect efficacy of RV vaccination on antibiotic use and ARG carriage among infants in Zambia and Ghana.

Methods: Using a prospective cohort study nested within a phase III clinical trial in Zambia and Ghana, comparing a novel parenteral vaccine (NRRV) to a standard-of-care oral vaccine (Rotarix®, RV1), the ROTA-Biotic study examined the effects of vaccine type on antibiotic usage for severe RV GE (RVGE) and ARG carriage. We assessed antibiotic use between RV1 and NRRV using causal mediation analysis with severe RVGE as the mediator, and quantified ARG carriage by shotgun metagenomic sequencing.

Findings: We included 838 children (412 from Zambia, 426 from Ghana) and followed them up from 6- weeks to 18 and 24 months of age respectively. RV1 was associated with 0·68 times fewer antibiotic courses in Zambia (95% CrI: 0·47 - 0·97) compared to NRRV, corresponding to a RV1 relative vaccine efficacy against antibiotic use of 32% (95% CrI: 2·83% - 52·94%) in Zambia. Severe RVGE was infrequent in Ghana to permit robust estimation. Past RV infection was associated with significantly higher faecal ARG abundance at 18 months.

Interpretation: Efficacious RV vaccines reduce antibiotic use and ARG carriage in infants in settings with a high burden of enteric diseases and AMR. However, the modest absolute reductions against a high background of inappropriate use indicate that vaccination must be paired with antimicrobial stewardship to meaningfully reduce AMR selection pressure in these settings.