Lancet Infectious Diseases: Cholera control: one dose at a time :: Efficacy of a single-dose regimen of inactivated whole-cell oral cholera vaccine: results from 2 years of follow-up of a randomised trial

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Lancet Infectious Diseases
http://www.thelancet.com/journals/laninf/issue/current
Available online 14 March 2018
In Press, Corrected ProofNote to users
Comment

Cholera control: one dose at a time
Louise C Iversa, b,
https://doi.org/10.1016/S1473-3099(18)30170-1
Open Access
Cholera continues to harm the most vulnerable people worldwide.1 As an indicator of human progress, the sustained or new presence of the disease in any region is a stark reminder of how far we, as a society, have to go to reach Sustainable Development Goal 6: ensuring availability and sustainable management of water and sanitation for all.2 Diarrhoeal diseases are a major source of preventable morbidity and mortality, and in 2015 claimed the lives of more than 1·3 million people, of whom 499,000 were children younger than 5 years.3

As a contributor to the global burden of diarrhoeal disease, Vibrio cholerae is a particularly harsh pathogen, causing rapid onset of severe nausea, vomiting, and profuse watery diarrhoea that can lead to death within hours—even of the healthiest young adults. Whole communities can be rapidly affected in epidemics, causing both physical harm and psychological distress. The pervasive social determinant of the problem—poor or no access to safe water, sanitation, and hygiene—means that displaced people, refugee populations, and those in conflict zones are at risk of major outbreaks of the illness. Cholera also continues to occur routinely, regularly, and with great impact (although often with less media attention) in endemic countries, such as Bangladesh and now Haiti, where children and the poorest people are the most at risk of being harmed. In both epidemic and endemic circumstances, the public health role of cholera vaccination has been re-emerging with interest from policy makers over the past 8 years.

In The Lancet Infectious Diseases, Firdausi Qadri and colleagues 4 describe results of 2 years of follow-up of a large, randomised, double-blind, placebo-controlled efficacy trial of a single dose of an inactivated whole-cell oral cholera vaccine (OCV) in Bangladesh. They found that a single dose provided protection for at least 2 years when given to adults (vaccine protective efficacy against all cholera episodes 59%, 95% CI 42–71) and to children aged 5 years or older (52%, 8–75). The findings make an important contribution to cholera control around the world, and could help to take us one step closer to WHO’s ambitious goal of reducing deaths from the disease by 90% by 2030.5

Increasing practical experiences with large-scale public health use of OCV—initially including reactive vaccination campaigns in Guinea and Haiti in 2012,6 ;  7 revitalised WHO’s support of cholera-affected countries,8 and investment by GAVI, the vaccine alliance, in a global stockpile of vaccine—have resulted in millions of doses of OCV being used each year since 2014. The vaccine has most often been given in two doses, 14 days apart, as recommended by the manufacturers.9 Yet giving a second dose of OCV on schedule can be challenging during crisis situations. Furthermore, multiple competing demands on the global stockpile mean that, at times, officials might have to decide if they should vaccinate a population without guarantee of the availability of the second tranche of doses.

Qadri and colleagues’ trial complements findings from other important studies on the use of a single-dose OCV, which were largely secondary analyses and shorter-term prospective observational studies.10 ;  11 Together, the evidence shows that single-dose OCV campaigns can be effective both in the short term in outbreaks and for up to 2 years in endemic settings. With these data to further support decision making on who to vaccinate against cholera and when to vaccinate them, government agencies, multilateral organisations, and non-governmental organisations should continue to invest in cholera vaccines as a part of the toolkit to control and prevent the disease.

However, a single dose of OCV did not protect children younger than 5 years compared with placebo (vaccine protective efficacy against all cholera episodes −13%, 95% CI −68 to 25),4 consistent with the 6-month results of the same study.12 Other studies show some, but reduced, protection of two doses of OCV in this age group as well, which has implications for strategies on the use of OCV in highly endemic regions where young children are an important risk group.13 Further studies are needed to determine how best to protect the youngest individuals, and to identify the ideal dosing schedule of the vaccine.

Still more evidence is needed on how to integrate vaccination strategies into evidence-based water, sanitation, and hygiene interventions to interrupt diarrhoeal disease—a subject in which evidence of impact is surprisingly scarce.14 What is notable about the discourse on OCV in 2018 are the burning questions not associated with whether vaccines should be used in endemic countries or whether they should be used during epidemics for cholera control, but rather how best to use them in a way that maximises effectiveness and efficiency in saving the lives of the most vulnerable people from this entirely preventable disease.

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Available online 14 March 2018
In Press, Corrected Proof — Note to users
Articles
Efficacy of a single-dose regimen of inactivated whole-cell oral cholera vaccine: results from 2 years of follow-up of a randomised trial
Firdausi Qadri, PhDa, Mohammad Ali, PhDb, Julia Lynch, MDc, Fahima Chowdhury, MPHa, Ashraful Islam Khan, PhDa, Thomas F Wierzba, PhDd, Jean-Louis Excler, MDc, Amit Saha, MMeda, Md Taufiqul Islam, MPHa, Yasmin A Begum, PhDa, Taufiqur R Bhuiyan, PhDa, Farhana Khanam, MSca, Mohiul I Chowdhury, MPHa, Iqbal Ansary Khan, MPHe, Alamgir Kabir, MSca, Prof Baizid Khoorshid Riaz, MPHf, Afroza Akter, MPHa, Arifuzzaman Khan, MBBSa,
Summary
Background
A single-dose regimen of inactivated whole-cell oral cholera vaccine (OCV) is attractive because it reduces logistical challenges for vaccination and could enable more people to be vaccinated. Previously, we reported the efficacy of a single dose of an OCV vaccine during the 6 months following dosing. Herein, we report the results of 2 years of follow-up.
Methods
In this placebo-controlled, double-blind trial done in Dhaka, Bangladesh, individuals aged 1 year or older with no history of receipt of OCV were randomly assigned to receive a single dose of inactivated OCV or oral placebo. The primary endpoint was a confirmed episode of non-bloody diarrhoea for which the onset was at least 7 days after dosing and a faecal culture was positive for Vibrio cholerae O1 or O139. Passive surveillance for diarrhoea was done in 13 hospitals or major clinics located in or near the study area for 2 years after the last administered dose. We assessed the protective efficacy of the OCV against culture-confirmed cholera occurring 7–730 days after dosing with both crude and multivariable per-protocol analyses. This trial is registered at ClinicalTrials.gov, number NCT02027207.
Findings
Between Jan 10, 2014, and Feb 4, 2014, 205,513 people were randomly assigned to receive either vaccine or placebo, of whom 204,700 (102,552 vaccine recipients and 102,148 placebo recipients) were included in the per-protocol analysis. 287 first episodes of cholera (109 among vaccine recipients and 178 among placebo recipients) were detected during the 2-year follow-up; 138 of these episodes (46 in vaccine recipients and 92 in placebo recipients) were associated with severe dehydration. The overall incidence rates of initial cholera episodes were 0·22 (95% CI 0·18 to 0·27) per 100,000 person-days in vaccine recipients versus 0·36 (0·31 to 0·42) per 100,000 person-days in placebo recipients (adjusted protective efficacy 39%, 95% CI 23 to 52). The overall incidence of severe cholera was 0·09 (0·07 to 0·12) per 100,000 person-days versus 0·19 (0·15 to 0·23; adjusted protective efficacy 50%, 29 to 65). Vaccine protective efficacy was 52% (8 to 75) against all cholera episodes and 71% (27 to 88) against severe cholera episodes in participants aged 5 years to younger than 15 years. For participants aged 15 years or older, vaccine protective efficacy was 59% (42 to 71) against all cholera episodes and 59% (35 to 74) against severe cholera. The protection in the older age groups was sustained throughout the 2-year follow-up. In participants younger than 5 years, the vaccine did not show protection against either all cholera episodes (protective efficacy −13%, −68 to 25) or severe cholera episodes (−44%, −220 to 35).
Interpretation
A single dose of the inactivated whole-cell OCV offered protection to older children and adults that was sustained for at least 2 years. The absence of protection of young children might reflect a lesser degree of pre-existing natural immunity in this age group.
Funding
Bill & Melinda Gates Foundation to the International Vaccine Institute.