Yemeni children suspected of having cholera at a makeshift hospital in Sanaa earlier this month.


Cholera vaccine faces major test in war-torn Yemen

Imagine a poor, war-ravaged country the size of Spain where more than 20 million people are threatened by a deadly disease that’s spreading fast from city to city. You have 1 million doses of a vaccine at your disposal. Who would you try to protect?

That’s the question facing public health experts and international groups fighting an explosive cholera outbreak in Yemen. On 15 June, a group managing the modest global reserve of cholera vaccine decided to dispatch 1 million doses to the country, about half of what it had in stock; vaccina­tion is set to begin in early July. It will be one of the biggest tests yet for the vaccine. But where to deploy it is still under debate, says Dominique Legros, a cholera expert at the World Health Organization (WHO) in Geneva, Switzerland.

Health workers have limited experience with the vaccine—which consists of killed bacteria and is given orally—in large emer­gency situations. The global stockpile was created only 4 years ago and has been used mostly for smaller campaigns. “How do we use the vaccine to stop an outbreak from spreading? We’re still learning,” says Melissa Ko of GAVI, the Vaccine Alliance in Geneva, which funds the stockpile. Experts have de­cided to stretch the supply by giving just one rather than the recommended two doses but are still debating where to target their efforts. And some caution that, because of the vaccine’s limited efficacy, even a plentiful supply might have only a modest impact on the massive epidemic.

Cholera is only the latest tragedy to be­fall Yemen. Since 2015, forces loyal to Presi­dent Abdrabbuh Mansour Hadi have been fighting against Houthi rebels, a Shiite in­surgency aligned with former President Ali Abdullah Saleh, ousted in 2012. The rebels control the capital, Sanaa, and northern parts of the country whereas Hadi controls the south, including the port city of Aden. The conflict has killed thousands, destroyed much of the country’s infrastructure, and paralyzed the health system. WHO esti­mates that 14.5 million people have lost reg­ular access to clean water, creating an ideal environment for Vibrio cholerae.

Cholera cases began rising sharply in April and have already reached an esti­mated 200,000, causing 1300 deaths, most of them in the west of the country. There are now 5000 new cases every day, on both sides of the front lines. “The disease does not discriminate based on political alle­giances,” Legros says. V. cholerae produces a toxin that rapidly floods the gut with water, leading to massive diarrhea. Dehydration can kill victims within 6 hours, but replac­ing liquid and electrolytes with an oral re­hydration solution or intravenous fluids can save most people.

The vaccine is a relatively new weapon, and until recently it was hardly used in emergencies. Many worried that immuniza­tion might distract aid workers from treat­ing patients and providing clean drinking water. Production capacity for the vaccine was limited as well, and the need to give two doses 2 weeks apart for optimal protec­tion created extra logistical problems. The speed at which cholera spreads made tar­geting the vaccine tricky: “We have seen on several occasions that we were too late or not in the right place,” Legros says.

But acceptance began to build after the vaccine was successfully deployed during Haiti’s massive cholera outbreak in 2012. Production capacity has also increased; last year, a new vaccine facility opened in Korea, and an existing plant in India has increased its output. The International Coordinating Group (ICG) on Vaccine Provision, which manages the stockpile, hopes to buy 17 mil­lion doses at less than $2 each this year, up from just 2 million in 2013. In recent months the vaccine has gone to South Su­dan, Somalia, Malawi, and Mozambique.

Yemen’s government has asked for 3.5 mil­lion doses, more than ICG had in its stock and more than three times the number it granted. “Many countries are currently suf­fering from cholera and vaccine allocation needs to be fair and equitable,” Ko says. Legros thinks vaccination efforts should fo­cus on areas that are at high risk and not yet badly affected; those appear to be primarily in the southeast. But surveillance data are unreliable. Some of the 200,000 reported cholera cases may be other types of diar­rhea, whereas some places reporting fewer cases may just be missing many of them. Other factors figure in the decision as well, says Legros, such as access and whether lo­cal partners can help. “We are in dialogue with parties to the conflict to stress the neu­trality of health care and our need to access people no matter where they are,” he says.

To stretch supplies, the campaign will use only one dose per person. A two-dose regimen can yield up to 80% protection, but mounting evidence suggests that a single dose does a reasonable short-term job, says Louise Ivers of Partners in Health in Bos­ton, a charity that helped carry out the 2012 vaccination campaign in Haiti. A random­ized clinical trial in slums in Dhaka, where cholera is endemic, suggested that one dose protected about 40% of participants in the first 6 months. In a study conducted in Su­dan in 2015, a single dose offered 80% pro­tection during the first 2 months—although some participants may have been exposed to cholera the year before, essentially mak­ing the vaccine a booster and increasing its efficacy.

Even if the single-dose strategy yields lower protection, modeling studies suggest it might sometimes save more lives than giving two doses to half as many people. In April, WHO’s Strategic Advisory Group of Experts on Immunization deliberated the issue; its report is not out yet but, says Legros, “they are very open to the use of single dose in outbreak response.” Ongoing research may result in vaccines that offer stronger and long-lasting immunity, but Legros cautions that they’re not going to be the final answer. “You still have 2 billion people in the world with no access to safe water,” he says. “If you solve that, you solve the problem of cholera.”

For Yemen, it may simply be too little, too late, warns Renaud Piarroux, an infec­tious disease specialist at the University of Aix-Marseille in Marseille, France. By the time the vaccines are distributed, cholera may be everywhere, Piarroux says. “I will not say ‘Don’t do it,’ but I will not hope that it changes the course of the epidemic either.”