Effectiveness of One Dose of Killed Oral Cholera Vaccine in an Endemic Community in the Democratic Republic of the Congo: A Matched Case-Control Study

Background A global shortage of cholera vaccines has increased the use of single-dose regimens, rather than the standard two-dose regimen. There is limited evidence on single-dose protection, particularly in children. In 2020, a mass vaccination campaign resulting in largely single dose coverage, was conducted in Uvira, an endemic urban setting in eastern Democratic Republic of the Congo. We examined the effectiveness of a single-dose of the oral cholera vaccine Euvichol-Plus® in this high-burden setting. Methods We recruited medically attended confirmed cholera cases and age-, sex-, and neighborhood-matched community controls during two distinct periods after mass vaccination, October 2021 to March 2022 (12–17 months post-vaccination) and October 2022 to October 2023 (24–36 months post-vaccination). The odds of vaccination in cases and controls were contrasted in conditional logistic regression models to estimate unadjusted and adjusted vaccine effectiveness. Findings We enrolled 658 confirmed cases and 2,274 matched controls during the two study periods with 15·0% of cases being under five years old at the time of vaccination. The adjusted single-dose VE was 52·7% (95% CI: 31·4–67·4) 12–17 months post-vaccination and 45·5% (95% CI: 25·8– 60·0) 24–36 months post-vaccination. While protection in the first 12–17 months post-vaccination was similar for 1–4-year-olds and older individuals, over the third year post-vaccination the estimate of protection in 1–4 year-olds (adjusted VE 33·1%; 95% CI: -30·0–65·6) appeared to wane with confidence intervals spanning the null. Interpretation A single-dose of Euvichol-Plus® provided substantial protection against medically attended cholera for at least 36 months post-vaccination in this cholera endemic setting. While our evidence provides support for comparable levels of protection in young children and others in the short-term, protection among young children may wane significantly by the third year after vaccination. Funding Wellcome Trust and Gavi (GAVI-RFP-2019-062). Evidence before this study In late 2022, due to increasing demand for killed, whole-cell, oral cholera vaccines (kOCV) and limited production capacity, the International Coordinating Group (the organization managing emergency stocks of kOCVs) changed policy to deploy single-dose, rather than the standard two-dose regimen, for emergency vaccination campaigns. This decision was in line with WHO guidance on the use of a single dose in outbreaks, where short-term protection is key. However, this recommendation is based on a limited number of clinical studies with short-term follow-up. There is also limited evidence on the magnitude and duration of protection conferred by a single dose of kOCV, particularly in children under five years of age. We searched PubMed for randomized trials and observational studies published in English before November 1, 2023, that reported estimates of protection conferred by a single dose of kOCV, using the term “(effectiveness OR efficacy) AND cholera* AND vaccine”. We found no published studies estimating the effectiveness of a single dose of Euvichol-Plus®, and only one study reporting two-dose effectiveness. Despite this paucity of evidence, this is the only vaccine currently available in the global stockpile. To date, there has been one randomized trial conducted in Bangladesh between 2014 and 2016, and seven observational studies conducted between 2009 and 2016 in Guinea, Haiti, India, Malawi, Sudan, Zambia and Zanzibar, reporting effectiveness estimates of a single dose of the current generation of kOCV. Aside from the trial in Bangladesh, all estimates were based on secondary analyses that the studies were not powered to estimate. The Bangladesh trial is the only study to date that provides an age-stratified estimate of single-dose protection, and while it found an overall protective efficacy of 62% (95% CI: 43– 75) during the 2-year follow up for individuals aged five years or older, it found no significant protection conferred by the Shanchol kOCV (a bioequivalent of Euvichol-Plus®) for individuals under five years of age (protective efficacy: -44%, 95% CI -220 to 35). Four of the seven observational studies provide single-dose vaccine effectiveness (VE) estimates only during the first 12 months post-vaccination with estimates ranging from 43% (95% CI -84-82) in Guinea to 93% (95% CI 69-98) in Haiti. The three other observational studies providing a single dose VE estimate between 12-30 months post-vaccination were unable to demonstrate statistically significant protection conferred by kOCV, with estimates ranging between 32·5% (95% CI - 318·0-89·1) in India and 40% (95% CI -31-73) in Haiti. No vaccine protection estimates have been published from the two identified cholera endemic foci in Africa, the Democratic Republic of the Congo and Nigeria. Added value of this study In this vaccine effectiveness study, we show that a single dose of Euvichol-Plus® vaccine can provide significant protection against medically attended cholera for up to 36 months after vaccination in a cholera endemic setting in Africa, though protection in children under five years old remains unclear. These estimates help fill critical gaps in our understanding of the magnitude and duration of protection from a single dose of the most widely used kOCV, Euvichol-Plus® and is one of only a few studies to measure protection in an endemic setting in Africa. Implications of all the available evidence The corpus of available evidence suggests that use of a single dose of kOCV in emergency situations where cholera is endemic, like Uvira, is justified and that providing a second dose within the first 12-24 months post-vaccination may only provide marginal benefit to the general population. However, more evidence and analyses are needed to weigh the costs and benefits of tailored vaccination approaches for those under five years old, including possibility of providing a second dose at an earlier timepoint. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by the Wellcome Trust and Gavi (GAVI-RFP-2019-062). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approvals were obtained from Institutional Review Boards of the Johns Hopkins Bloomberg School of Public Health (IRB00015785), the London School of Hygiene & Tropical Medicine (25365) and the Ecole de Sante Publique at the University of Kinshasa (ESP/CE/65/2021). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors