Fighting Cholera

Haiti study shows lasting protection from two-dose vaccine  

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People who received the recommended two doses of an oral cholera vaccine during the height of the 2010-2017 cholera outbreak in Haiti were, on average, 76 percent less likely to become sick with the life-threatening bacterial infection than people who were not vaccinated, and this protection appeared to last for at least four years, according to a new study.

People who received only a single dose of the vaccine also gained some protection from the disease, but it appeared to be limited to the first two years following vaccination.

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The study was led by researchers in the Harvard Medical School Department of Global Health and Social Medicine and Massachusetts General Hospital, with colleagues at Zanmi Lasante (Partners In Health) in Haiti.

Published in the September issue of Lancet Global Health, the study provides robust evidence of the vaccine’s effectiveness, the authors said, and should assuage any lingering concerns about its effectiveness amid an ongoing outbreak.

“Our findings yield crucial insight for understanding the optimal use of oral vaccines in the context of comprehensive cholera control and prevention,” said lead author Molly Franke, assistant professor of global health and social medicine at HMS.

“In the challenging conditions present in Haiti in the wake of the earthquake and in the midst of an active cholera outbreak, the consistent, long-term protection provided by the vaccine makes these vaccines well worth the investment,” she said. 

The bacterium Vibrio cholerae kills by causing an infection that produces acute diarrhea, which in turn causes massive dehydration and the rapid loss of vital electrolytes such as potassium, calcium and chloride.

Since cholera was introduced to Haiti by infected Nepalese UN peacekeepers in the wake of the catastrophic 2010 earthquake, more than 800,000 cases of cholera have been recorded and 10,000 people have died of the disease.

Left untreated, cholera can swiftly turn devastating, even deadly, but prompt fluid replacement can avert the most serious complications and save lives. HMS researchers have been at the forefront of the battle to find the best way to stop the disease.

A comprehensive approach

The current study lends support for the long-term effectiveness of vaccination as part of a comprehensive anti-cholera program that also includes treatment centers and efforts to improve access to clean water. This program is carried out as part of a longstanding global health collaboration between researchers and clinicians at Zanmi Lasante, HMS and affiliated hospitals, including Mass General.

Understanding the effectiveness and duration of protection afforded by cholera vaccines is a key part of those efforts.

The study is the first report of the field effectiveness of two doses of killed, bivalent, whole-cell oral cholera vaccines up to four years after vaccination. The research found consistent protection with two doses of the vaccine, which remained unchanged throughout the follow-up. To analyze the effects of the vaccine, the researchers studied two groups of people, one of 178 people with laboratory-confirmed cholera, the other of 706 of the infected patients’ neighborhood contacts who had not been sick with cholera.

The researchers then compared vaccination rates in the two groups. Some people had not returned for a second dose of vaccine during the campaign. Both the single-dose and the two-dose recipients developed immunity; however, those treated with a single-dose lost their protection, on average, within two years. Those who received both doses maintained immunity for the entire duration of the study.

The study also provides evidence of long-term protection for this type of cholera vaccine outside of south Asia, where cholera is historically endemic, Franke said. Ongoing exposure to the bacterium produces some immunity, so the dynamics of the disease and the protection afforded by the vaccine, may be different in south Asia than in places like Haiti, where cholera is newly endemic. For this reason, it remained unclear whether the earlier vaccine effectiveness estimates from south Asia would apply in Haiti.

In addition, the research offers the first estimates of the long-term duration of protection with a single dose of this type of vaccine. Among those who did not take a second dose, the researchers found high levels of protection during the first year after vaccination, which declined to zero by the end of the second year.

Researchers say this study can offer invaluable insight into the ongoing debate over the optimal vaccination approach in resource-limited settings, where cholera is most likely to occur. A vexing question has been whether, given the current oral cholera vaccine shortage, it makes more sense to immunize fewer people with two doses of the vaccine or give twice as many people a single dose of the vaccine. The findings of the current study underscore the benefits of receiving two doses in the context of Haiti, the researchers said.

Making the case

In the early days of the outbreak, HMS global health faculty working in Haiti were among the first to make the case for vaccination. The plan to provide the vaccine was surprisingly controversial. Skeptics cited several reasons: the vaccine had been proven effective solely in areas with smoldering cholera, not in a full-blown outbreak; the impoverished landscape and absence of a functioning health system in much of rural Haiti would present logistical challenges to delivering a complex, two-dose vaccination program. Opponents have also argued that a more prudent approach might be to focus on water and sanitation interventions in order to save scarce funds.

In the face of these doubts, the researchers said, it is crucial to provide scientific evidence about the effectiveness of the vaccine.

The government of Haiti, with the support of HMS faculty and Zanmi Lasante, carried out two waves of vaccination in 2012 and 2014, training field workers, fighting rainy season mud and ensuring that tens of thousands of patients swallowed two doses of the vaccine two weeks apart.

The same challenges that make it difficult to deliver care or administer a two-dose vaccination make it difficult to conduct research in settings like these.

In this case, the researchers built their study on a scaffolding of existing relationships that began when senior author Louise Ivers, associate professor of medicine, associate professor of global health and social medicine at HMS, executive director of global health at MGH, and a senior advisor at PIH, began working with Zanmi Lasante clinicians in 2003. Franke and Ivers integrated the work into the binational clinical and research team that was already trusted by the community. This powerful combination of partners is necessary for performing global health research that provides meaningful results, Ivers said.

“When we launched the vaccination campaign, many doubted it would work. Now we know that the vaccine can save lives, even in these extremely challenging conditions,” Franke says. “Hopefully, these results will help change the way the world responds to cholera not just in Haiti, but around the world.”

Co-authors included Jason Harris, HMS associate professor of pediatrics at Mass General; Gregory Jerome and Ralph Ternier of Zanmi Lasante (PIH in Haiti); and Wilfredo Matias, clinical fellow in medicine at Brigham and Women’s Hospital.

This research was supported by grants from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and by the Bill & Melinda Gates Foundation.