We conducted 4 years of epidemiologic and genomic surveillance of single-dose effectiveness of a killed whole-cell oral cholera vaccine (kOCV) and Vibrio cholerae transmission in the Democratic Republic of the Congo. We enrolled 1,154 patients with diarrhea
342 of those had culture-confirmed cholera. We performed whole-genome sequencing on clinical and water V. cholerae isolates from 200 patient households, which showed annual bimodal peaks of V. cholerae clade AFR10e infections. A large clonal cholera outbreak occurred 14 months after a kOCV campaign of >
1 million doses, likely because of low (9%) vaccine coverage in informal settlements. Clinical and water isolates collected in the same household were closely related, suggesting person-to-person and water-to-person transmission. Single-dose kOCV vaccine effectiveness 24 months after vaccination was 59.8% (95% CI 19.7%-79.9%), suggesting modest single-dose kOCV protection. kOCV campaigns combined with water, sanitation, and hygiene programs should be used to reduce cholera in disease-endemic settings worldwide.