Identifying the optimal schedule for a multi-pathogen combination vaccine for diarrheal disease

INTRODUCTION: Diarrheal disease causes 1·7 billion cases and 340,000 childhood deaths annually, with rotavirus still bearing the highest death burden despite vaccine availability. A combination vaccine targeting multiple enteropathogens could expand protection while reducing injections, visits, and costs. However, optimizing administration schedules is complex due to differences in pathogen transmissibility, immunity, and age-specific burden. METHODS: We developed an age-structured, compartmental model with pathogen-specific parameters from eight LMIC sites. Two-dose viral (rotavirus, norovirus, adenovirus 40/41) and bacterial (Shigella, ETEC) vaccines were modeled across five age schedules and variable vaccine coverage. We examined two scenarios where (a) VE was the same at all ages of administration (age-uniform) and (b) VE was lower in early childhood (age-attenuated). Outcomes included annual cases and deaths in children under five. RESULTS: With age-uniform VE, the earliest schedules produced the greatest reductions in burden, with birth/6 weeks yielding the largest mean reduction in deaths (56%, 95% UI: 41-74%) and 6/10 weeks producing similar reductions (55%, 95% UI: 39-74%). Case reductions were also comparable between schedules, with birth/6 weeks reducing cases by 34% (95% UI: 15-69%) and 6/10 weeks by 35% (95% UI: 15-70%). With age-attenuated VE, 6/10 weeks was optimal, reducing cases by 21% (95% UI: 7-49%) and deaths by 42% (95% UI: 29-58%). CONCLUSION: All schedules reduced diarrheal disease burden. Under age-uniform VE, birth/6 weeks conferred the greatest reduction in deaths, although impacts were similar to 6/10 weeks. Under age-attenuated VE, the 6/10 weeks schedule performed best.