Research Article: Potential for Controlling Cholera Using a Ring Vaccination Strategy: Re-analysis of Data from a Cluster-Randomized Clinical Trial

Date Published: September 13, 2016

Publisher: Public Library of Science

Author(s): Mohammad Ali, Amanda K. Debes, Francisco J. Luquero, Deok Ryun Kim, Je Yeon Park, Laura Digilio, Byomkesh Manna, Suman Kanungo, Shanta Dutta, Dipika Sur, Sujit K. Bhattacharya, David A. Sack, Mathuram Santosham

Abstract: IntroductionVaccinating a buffer of individuals around a case (ring vaccination) has the potential to target those who are at highest risk of infection, reducing the number of doses needed to control a disease. We explored the potential vaccine effectiveness (VE) of oral cholera vaccines (OCVs) for such a strategy.Methods and FindingsThis analysis uses existing data from a cluster-randomized clinical trial in which OCV or placebo was given to 71,900 participants in Kolkata, India, from 27 July to 10 September 2006. Cholera surveillance was then conducted on 144,106 individuals living in the study area, including trial participants, for 5 y following vaccination. First, we explored the risk of cholera among contacts of cholera patients, and, second, we measured VE among individuals living within 25 m of cholera cases between 8 and 28 d after onset of the index case. For the first analysis, individuals living around each index case identified during the 5-y period were assembled using a ring to define cohorts of individuals exposed to cholera index cases. An index control without cholera was randomly selected for each index case from the same population, matched by age group, and individuals living around each index control were assembled using a ring to define cohorts not exposed to cholera cases. Cholera attack rates among the exposed and non-exposed cohorts were compared using different distances from the index case/control to define the rings and different time frames to define the period at risk. For the VE analysis, the exposed cohorts were further stratified according to the level of vaccine coverage into high and low coverage strata. Overall VE was assessed by comparing the attack rates between high and low vaccine coverage strata irrespective of individuals’ vaccination status, and indirect VE was assessed by comparing the attack rates among unvaccinated members between high and low vaccine coverage strata.Cholera risk among the cohort exposed to cholera cases was 5–11 times higher than that among the cohort not exposed to cholera cases. The risk gradually diminished with an increase in distance and time. The overall and indirect VE measured between 8 and 28 d after exposure to a cholera index case during the first 2 y was 91% (95% CI 62%–98%) and 93% (95% CI 44%–99%), respectively. VE persisted for 5 y after vaccination and was similar whether the index case was a young child (<5 y) or was older. Of note, this study was a reanalysis of a cholera vaccine trial that used two doses; thus, a limitation of the study relates to the assumption that a single dose, if administered quickly, will induce a similar level of total and indirect protection over the short term as did two doses.ConclusionsThese findings suggest that high-level protection can be achieved if individuals living close to cholera cases are living in a high coverage ring. Since this was an observational study including participants who had received two doses of vaccine (or placebo) in the clinical trial, further studies are needed to determine whether a ring vaccination strategy, in which vaccine is given quickly to those living close to a case, is feasible and effective.Trial NCT00289224

Partial Text: Cholera is estimated to infect about 2.8 million individuals and cause 91,000 deaths per year worldwide [1]. The current prequalified oral cholera vaccines (OCVs) provide over 80% (direct) protection in the first 6 mo after vaccination [2–4], with protection of up to 65% for 5 y estimated in an endemic setting [5]. However, this estimate does not include herd protection. When herd protection is taken into account, with coverage of 50%, the disease might be eliminated in endemic areas [6]. Despite this information, there is need to identify potentially effective strategies for reducing transmission and saving lives from cholera. A major limitation for implementation of OCV vaccination stems from the limited number of doses available in the global stockpile [7] as well as limited resources to deliver vaccine to those living in cholera-prone areas.

This study used existing data from a clinical trial approved by the ethics committee of the National Institute of Cholera and Enteric Diseases, the Health Ministry Screening Committee of India, and the International Vaccine Institute Institutional Review Board. Participants aged >17 y and parents or guardians of participants aged 1–17 y provided written informed consent. Written assent was also obtained from adolescents aged 12–17 y. Thumbprints were obtained and witnessed if the participant, or their guardian, was illiterate. Any patient coming from our study area irrespective of his/her participation in the initial trial gave written informed consent at the time they came to a project clinic/hospital for treatment of diarrhea. We obtained verbal individual household consents as well as community consents to carry out census and demographic surveillance in the study area.

This retrospective analysis of cholera vaccine trial data from an endemic setting provides an opportunity to evaluate the dynamics of cholera transmission and OCV effectiveness among contacts of cases, as a surrogate for a ring vaccination strategy. The results demonstrate that the risk for cholera among individuals living within 10 m of a cholera case and within 2 wk from the onset of cholera for the index case is extremely high (9- to 11-fold) compared to the risk among individuals living within the same distance of a control (non-cholera case) within same time frame. Such an elevated risk in this defined distance and time frame around a case strongly suggests transmission of cholera among persons living in the same household or close by [15,16]. The higher risk for cholera among individuals living as far as 25 m from a cholera case in this highly populated urban slum setting illustrates that transmission extends beyond the immediate household and supports the need for interventions targeted to individuals living outside the immediate household.



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