Background Shigella is a leading cause of diarrhea and dysentery in children in low resource settings, which is frequently treated with antibiotics. The primary goal of a Shigella vaccine would be to reduce mortality and morbidity associated with Shigella diarrhea. However, ancillary benefits could include reducing antibiotic use and antibiotic exposures for bystander pathogens carried at the time of treatment, specifically for fluoroquinolones and macrolides (F/M), which are the recommended drug classes to treat dysentery. Methods We used data from the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study to estimate the impact of two one-dose (6 or 9 months) and three two-dose (6 & 9 months, 9 & 12 months, and 12 & 15 months) Shigella vaccines on diarrheal episodes, overall antibiotic use, and F/M use. Further, we considered additional protection through indirect and boosting effects. To estimate the absolute and relative reductions in the incidence of diarrhea and antibiotic use under each vaccination scenario, Monte Carlo simulations with random sampling were performed. Findings We analyzed 9392 diarrhea episodes and 15697 antibiotic courses among 1715 children in the MAL-ED birth cohort study. There were 273.8 diarrhea episodes, 30.6 shigellosis episodes, and 457.6 antibiotic courses per 100-child years. A Shigella vaccine given at 9 & 12 months prevented 1.7 (95% CI: 1.3, 2.1) severe Shigella diarrhea episodes (46.5% reduction),11.0 (95% CI: 10.0, 11.9) Shigella diarrhea episodes of any severity (35.9% reduction), 3.1 (95% CI: 2.6, 3.7) F/M courses (2.9% reduction overall), 5.8 (95% CI: 5.2, 6.6) antibiotic courses (1.0% reduction overall), and 6.3 (95% CI: 5.2, 7.5) F/M (3.2% reduction) and 11.2 (95% CI: 9.7, 12.9) antibiotic (1.2% reduction) exposures to bystander pathogens, respectively, per 100 child years. Interpretation A Shigella vaccine could make substantial reductions in Shigella diarrhea, antibiotic use to treat shigellosis, and bystander exposures due to shigellosis treatment. However, the reductions in overall diarrhea episodes and antibiotic use would be modest.

The authors have declared no competing interest.

This work was supported by Wellcome (219741/Z/19/Z to ETRM wellcome.org). The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) was a collaborative project supported by the Bill & Melinda Gates Foundation (OPP1131125 gatesfoundation.org), the Foundation for the NIH, the National Institutes of Health, and the Fogarty International Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study involves human participants. For the parent study, ethical approval was obtained from the Institutional Review Boards at the University of Virginia School of Medicine (Charlottesville, USA) (14595) and at each of the participating research sites: Ethical Review Committee, ICDDR,B (Bangladesh) Committee for Ethics in Research, Universidade Federal do Ceara National Ethical Research Committee, Health Ministry, Council of National Health (Brazil) Institutional Review Board, Christian Medical College, Vellore Health Ministry Screening Committee, Indian Council of Medical Research (India) Institutional Review Board, Institute of Medicine, Tribhuvan University Ethical Review Board, Nepal Health Research Council Institutional Review Board, Walter Reed Army Institute of Research (Nepal) Institutional Review Board, Johns Hopkins University PRISMA Ethics Committee Health Ministry, Loreto (Peru) Ethical Review Committee, Aga Khan University (Pakistan) Health, Safety and Research Ethics Committee, University of Venda Department of Health and Social Development, Limpopo Provincial Government (South Africa) Medical Research Coordinating Committee, National Institute for Medical Research Chief Medical Officer, Ministry of Health and Social Welfare (Tanzania). For the current study, we obtained ethical approval at the University of Virginia School of Medicine (Charlottesville, USA) (22398) and Emory University (Atlanta, USA) (STUDY00003285).

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The statistical analysis plan is available at osf.io/3asxh. Deidentified participant data from the MAL-ED study is publicly available at ClinEpiDB.org.