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

Introduction Vaccinating 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 Findings This 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. Conclusions These 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 registration ClinicalTrials.gov NCT00289224


Overview
 Title of the study: Controlling cholera using a ring vaccination strategy  Original protocol from which the data will be obtained:

Summary
Objectives To explore the potential of a ring vaccination strategy in controlling cholera by leveraging the data of the large clinical trial conducted in Kolkata. We will first explore the magnitude of risk around cholera cases at different spatio-temporal scales. Based on this exploration, we will identify the suitable scale for the ring vaccination in that setting, and will estimate overall and indirect protective effectiveness (PE) of the oral cholera vaccine using a ring vaccination strategy.

Demographic Surveillance System (DSS)
Starting October 2007, a demographic surveillance system (DSS) was initiated to better define the corresponding dynamics in rates of birth, deaths, and migration in the population over time.
Demographic events were recorded on a monthly basis during community health worker (CHW) visits.

Demographic Events
Out-migrations: Individuals who were present at the time of dose 1 but migrated out of the study area any time after dose 1 and during the period of follow-up under analysis.
Internal migrations: Individuals who were present at time of dose 1 but migrated from one place to another place within the study area after dose 1 and during the period of follow-up under analysis.
Deaths: Individuals who were present at time of dose 1 but died after dose 1 and during the period of follow-up under analysis.

Births:
The births took place during the period of follow-up under the analysis.

Disease Surveillance
Nine clinics were established in the community to conduct the diarrheal disease surveillance. Private medical practitioners were encouraged to refer patients with diarrhea to these clinics. Additionally, surveillance was established in the two hospitals serving the study population. Patients from the study area were identified by use of household identification cards and a computerized database. Study physicians recorded pertinent clinical details on a structured clinical data form. Rectal swabs were obtained from all participants presenting with history of loose stools and transported in Cary-Blair media to a laboratory at NICED within 8 h of specimen collection. At the laboratory, rectal swabs were analyzed for Vibrio cholerae by serogroup, biotype, and serotype, by use of conventional methods. All patients whose swabs yielded V cholerae O1 or O139 were visited by a study team at their residence 7 days after the positive culture to verify that the individual whose identity had been given at the treatment center had visited on the recorded date of presentation.

Follow-up Period
The last day of vaccination was 10 September 2006. This study will include cases reported in the project clinic/hospital from 1 October 2006 to until 5 years of post-dosing.

Definition of Principal Outcome Events
Diarrheal visit: A diarrheal visit is defined as an inpatient or outpatient visit for care of diarrhea in which the patient described:  3 or more loose or liquid stools; or  At least 1 loose bloody stool; or  1-2 or an indeterminate number of loose or liquid stools and exhibited at least some dehydration Diarrhea episode: A diarrheal episode is defined as follows:  All diarrheal visit(s) for which the date of onset of symptoms for a diarrheal visit was less than or equal to 7 days from the date of discharge for the previous visit, constitute a single "diarrheal episode".
 The onset of a diarrheal episode was defined as the day on which it was reported to have begun for the first visit of the episode. Cluster: The original protocol was a cluster randomized trial. The unit of randomization was the premise, which is a household or group of households that usually share the same latrine(s) and water supply.
The premise address is pre-assigned by the Kolkata Municipal Corporation. It may be one building with several flats or may be a group of huts.
Age eligible population: Persons from the study population aged 12.0 months and older at time of dose 1.

Randomized population:
The randomized population includes individuals who were age-eligible and randomized to receive either the cholera vaccine or placebo. Incomplete dose: Individuals who did not ingest full amount of the administered dose. These individuals will be considered as non-participant in the analysis. Wrong dose given: Individuals who were given the agent that is not assigned to him/her. These individuals will be considered as non-participants in the analysis.

Pre-dosing period:
The pre-dosing period is the period on or before receipt of the first dose. Events whose onsets occur in this period will not be considered in the analysis.
Post dose 1 Interval: Post dose 1 interval begins on the date of the 1 st dose and ends on the date of the 2 nd dose. The interval range is 14 -44 days. Events whose onsets occur in this period will not be considered in the analysis.
Post dose 2 Interval: Post dose 2 interval begins on the date of the 2 nd dose and ends 30 September 2006. Events whose onsets occur in this period will not be considered in the analysis.

Post-follow up period:
The time after the completion of the follow up period is defined as post-follow up period. Events whose onsets occur in this period will not be considered for analysis.
Vaccinees: Individuals who received two doses the oral cholera vaccine.

Non-vaccinees:
Individuals who received at least one dose of placebo or the non-participants in the vaccination program.

Index case: A cholera case occurred anytime during the follow-up period in the study area
Index control: An index control will be randomly selected for each index case from the same study population matching by age-group (<5 years, 5-<15 years, and 15 years and above) at date of admission of its index case. The index controls are those who did not have cholera from 7 days prior to the onset date of its index case until the end of the surveillance period. Considering the size of study area, we will limit the orders of neighbor up to 50 meters.

Ring:
We call the spatial as scale as ring, because we will include all people within the specified distance centering the index case/control.

Vaccine coverage:
We will computed level of vaccine coverage within the ring, taking into account the two-dose recipients and all individuals presented in the ring at the onset of the illness of its index case.
High and low vaccine coverage rings will be defined post hoc; rings with vaccine coverage (two doses) at 20 th percentile of the population will be defined as low vaccine coverage ring and rings with vaccine coverage at 80 th percentile of the population were defined as high vaccine coverage ring.

Data Analysis
We generated the following cohorts for the analysis in order to measure the risk for cholera around cholera cases as well as to measure vaccine effectiveness:

Evaluation of magnitude of risk around a cholera case
The first step of this analysis is to evaluate magnitude of risk around a cholera case. This will be achieved by evaluating the risk of cholera among contacts of index cases (cohort 1) relative to the contacts of index controls (cohort 2) at different space and time scale omitting index cases and index controls in the analysis. The cumulative incidence rate will be calculated in each cohort was follows: Numerator: Cumulative total number of cholera cases in a given cohort.
Denominator: Cumulative total number of individuals in a given cohort.
In a second step we will compare these two risks using risk ratios. We will calculate the risk ratio of being a case occurring within a specified timeframe, t1 to t2, and within a specified distance range, d1 to d2, among contacts of index cases versus among contacts of index controls.
Statistical model: Both crude and multivariable logistic regression models will be used to calculate relative risk (RR) and 95% confidence intervals for the relative risk between contacts of index cases versus contacts of index controls.

Assessment of vaccine protective effectiveness (PE)
We will assess overall and indirect vaccine protective effectiveness Overall Vaccine Protective Effectiveness (PE): The overall vaccine PE will be calculated by comparing the cumulative incidence rate among all contacts (irrespective of their vaccination status) of the index cases living in the high vaccine coverage ring versus the attack rate (cohort 3) among all contacts of the index cases living in the low vaccine coverage ring (cohort 4). The cumulative incidence rate in cohorts 3 and 4 will be calculated as described above for cohorts 1 and 2.
Statistical model for overall vaccine PE: Both crude and multivariable logistic regression models will be used to calculate relative risk (RR) and 95% confidence intervals for the relative risk between contacts living in high vaccine coverage rings versus contacts living in low vaccine coverage rings. The adjusted relative risk will be transformed into vaccine PE as (1-RR) x 100%.

Indirect Vaccine Protective Effectiveness (PE)
The indirect PE will be calculated by evaluating the cumulative incidence rate among non-vaccinee (placebo or no dose recipient) contacts of the index cases living in high vaccine coverage rings (cohort 5) versus the attack rate among non-vaccinee contacts of the index cases living in low vaccine coverage rings (cohort 6). The cumulative incidence rate in cohorts 5 and 6 will be calculated as described above for cohorts 1 and 2.
Statistical model for indirect vaccine PE: Both crude and multivariable logistic regression models will be used to calculate relative risk (RR) and 95% confidence intervals for the relative risk between contacts living in high vaccine coverage rings versus contacts living in low vaccine coverage rings. The adjusted relative risk will be transformed into vaccine PE as (1-RR) x 100%.

This bias-indicator study
Since the high and low vaccine coverage rings will be defined post hoc, we will also evaluate PE against non-cholera diarrhea, defined as watery diarrhea (no blood in stools) and a faecal culture negative for V cholerae 01 in a bias indicator study. This bias-indicator study is designed to assess whether the results with respect to PE against cholera could be attributed to bias. An absence of PE in the bias-indicator study will be interpreted as suggesting an absence of bias in the PE against cholera. In bias indicator study, we will also calculate both overall and indirect vaccine protective efficacy. the bias-indicator study will be calculated as described above for cohorts 1 and 2, but with the outcome being non-cholera diarrhea.
Statistical model for overall vaccine PE: Both crude and multivariable logistic regression models will be used to calculate relative risk (RR) and 95% confidence intervals for the relative risk between contacts living in high vaccine coverage rings versus contacts living in low vaccine coverage rings. The relative risk will be transformed into vaccine PE as (1-RR) x 100%.

Indirect Vaccine Protective Effectiveness (PE)
The indirect PE will be calculated by evaluating the attack rate among non-vaccinee (placebo or no dose recipient) contacts of the index cases living in high vaccine coverage rings (cohort 5) versus the attack rate among non-vaccinee contacts of the index cases living in low vaccine coverage rings (cohort 6). The cumulative incidence rate in cohorts 5 and 6 for the bias-indicator study will be calculated as described above for cohorts 1 and 2, but with the outcome being non-cholera diarrhea.
Statistical model for indirect vaccine PE: Both crude and multivariable logistic regression models will be used to calculate relative risk (RR) and 95% confidence intervals for the relative risk between contacts living in high vaccine coverage rings versus contacts living in low vaccine coverage rings. The adjusted relative risk will be transformed into vaccine PE as (1-RR) x 100%.

Candidate variables for inclusion as covariates in the model
The factors known to be risk for cholera in the earlier study will be considered for the regression model.
These are:

Age
In years (continuous) Sex 0=female, 1=male Vaccination status 0=non-participants/placebo recipient, 1= vaccine recipient Individuals living in a household owning at least one luxury item 0=No, 1=Yes; items: Refrigerator, motorbike, television or washing machine