As Zika virus raced through the Americas and the Caribbean in 2015 and 2016, it infected an estimated 800,000 people and left nearly 4000 newborns with serious brain damage. But by mid-2017, the virus had all but disappeared from the region—or so it seemed. A new analysis of Zika-infected travelers who returned to the United States or Europe in 2017 or 2018 has found that 98% had visited Cuba, which did not report any cases to world health officials at the time the country’s outbreak apparently peaked.
“It was startling,” says Kristian Andersen, a genomic epidemiologist at Scripps Research in San Diego, California, who led the work conducted by 38 researchers from five countries. The group estimates that Cuba had 5707 unreported Zika cases, with most occurring in 2017. Those numbers are similar to counts in other Caribbean islands with comparable populations 1 year earlier.
In February 2016, the Zika outbreak was so severe in South America and the Caribbean that the World Health Organization (WHO) took the rare step of declaring it a Public Health Emergency of International Concern. But by November 2016, cases in the region had fallen steeply and WHO lifted the emergency.
To better understand the outbreaks that continued to linger, Andersen and colleagues looked at cases of Zika in travelers recorded by the Florida Department of Health and the European Centre for Disease Prevention and Control. Between June 2017 and October 2018, there were 155 cases—confirmed by antibody or viral tests—and all but one person had traveled to Cuba.
To further probe the timing and origin of the Cuban outbreak, the researchers sequenced Zika virus from nine infected people who returned to Florida and compared their viruses to ones from other countries in the region. Because viral mutations occur at predictable rates, the group could construct a molecular clock which revealed that the virus emerged in Cuba about 1 year later than elsewhere in the Caribbean. In their study in Cell today, the researchers also concluded that Zika had come to Cuba several times from several different Caribbean islands.
Jennifer Gardy, a genomic epidemiologist in the global health program at the Bill & Melinda Gates Foundation in Seattle, Washington, says analyzing viral sequences from travelers can help clarify the contours of epidemics that might otherwise have remained under the surveillance radar. “Surveillance is one of our best defenses again infectious disease, but the systems are rarely perfect—cases can be missed for many reasons,” Gardy says.
Andersen suggests a combination of factors likely explains why Cuba’s outbreak was “hidden” from the rest of world. Following the emergence of Zika in Brazil in May 2015, Cuba launched an aggressive pesticide-spraying program to control the Aedes aegypti mosquito that transmits the virus. (In lockstep with that program, cases of dengue, another disease spread by A. aegypti, plummeted in early 2016.) Zika cases also dropped steadily throughout Latin America and the Caribbean that year, presumably because the virus quickly infects large portions of populations, creating widespread immunity. When WHO lifted its emergency declaration, it relaxed requirements for member countries to report Zika cases. By the end of 2016, Cuba had confirmed only 187 cases of Zika, and it stopped reporting numbers altogether in 2017. It reported no cases of Zika-related brain damage to babies.
Contributing to the difficulty in reporting, the virus is “exceptionally difficult” to diagnose in infected people, Andersen notes. Antibodies to Zika and dengue viruses are similar, and tests can confuse the two. Zika-infected patients rarely have symptoms, and levels of the virus in their blood quickly drop, further complicating infection confirmation.
Andersen hopes his team’s approach will be applied to a wide array of diseases in returning travelers. “This [work] sets up a framework for investigating infectious diseases more closely,” he says. “It’s a really important new tool to monitor infectious diseases around the world.”
Michael Worobey, an evolutionary biologist who has analyzed viral histories in his lab at the University of Arizona in Tucson, says the new study reminds him of when he worked as a forest fighter. People posted on towers throughout the forest tracked lightning strikes. The next day, they would fly over the spots in the forest where lightning had hit. “If you saw smoke, you’d send crews out there before there was a conflagration,” Worobey says. “This new work is a demonstration of something we missed. If we improve our surveillance next time, we’ll catch it earlier, and certainly knowing there’s an outbreak of something like Zika spreading around could impact controlling it.”