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Unreported Zika Outbreak in Cuba Uncovered With Genomics, Travel Surveillance

NEW YORK – Cuba experienced a spike in unreported Zika cases in 2017, as the Zika virus (ZIKV) epidemic was subsiding in Brazil and other parts of the Americas, according to a new viral genome sequencing and travel surveillance study.

"Our study highlights how Zika virus may still be 'silently' spreading and provides a framework for understanding outbreak dynamics," co-senior and co-corresponding authors Kristian Andersen, an immunology and microbiology researcher at the Scripps Research Institute, and Scott Michael, a biological sciences researcher at Florida Gulf Coast University, and their colleagues wrote in a paper detailing the findings and published in Cell today.

The international research team sequenced more than a dozen new ZIKVs collected through surveillance programs that track travelers returning to Florida or sites in Europe. Along with additional travel surveillance data, local case reports, and phylogenetic clues, the sequences pointed to a previously unappreciated and unreported ZIKV outbreak in Cuba in 2017, involving ZIKVs introduced multiple times from other Caribbean islands.

"[W]e show that the establishment of the virus was delayed by one year and that the ensuing outbreak was sparked by long-lived lineages of Zika virus from other Caribbean islands," the authors reported, adding that "although mosquito control in Cuba may initially have been effective at mitigating Zika virus transmission, such measures need to be maintained to be effective."

Epidemic ZIKV cases in the Americas and beyond reached a climax in 2016, more than a year after the virus and related congenital complications were reported in Brazil, the team explained. Infections with the RNA virus appeared to peter out internationally by mid-2017 — but not before reaching four dozen countries — and its potential transmission since then remains more difficult to discern.

"Due to widespread surveillance gaps and inconsistent reporting," the authors noted, "we therefore hypothesized that local Zika outbreaks could still be occurring in the Americas, despite not being captured by the international community."

For their analysis, the researchers searched for travel-associated ZIKV, dengue virus, and chikungunya virus cases in data accrued by Florida's Department of Health between 2014 and 2018, along with related disease and travel data collected by the Pan American Health Organization, the European Centre for Disease Prevention and Control's European Surveillance System, and the US Centers for Disease Control and Prevention GeoSentinal Global Surveillance Network.

"In contrast to local case reporting, travel surveillance relies on diagnosing patients that have acquired infections while traveling outside the country of diagnosis," the authors explained. "As many regions in the Americas affected by the Zika epidemic attract large volumes of international visitors from countries with stronger surveillance systems, we hypothesized that, by creating a framework integrating local case reporting and travel surveillance with genomic epidemiology, we would be able to uncover potentially still-ongoing Zika outbreaks."

Of 91 travel-associated ZIKV cases identified in Florida from June 2017 to October 2018, for example, the team found that all but one infected individual was returning from Cuba. Likewise, 63 of 64 travel-associated cases caught in Europe during that time frame involved travel to Cuba. Data from the CDC's GeoSentinal network, too, suggested that travelers were more likely to return from Cuba with ZIKV infections in 2017 than in the years before or after that.

Based on Cuba's population size and rates of ZIKV diagnoses reported for travelers returning from the country, the researchers used statistical modeling to estimate that there were roughly 5,700 unreported cases in that country, many occurring in 2017. 

Using a multiplex PCR method called PrimalSeq, the researchers generated nine new ZIKV genomes from travelers returning from Cuba in 2017 or 2018 and four ZIKV genome sequences from individuals infected in Florida, which were assessed phylogenetically in combination with available sequences from 283 ZIKV isolates collected in Cuba between 2013 and 2018 and 273 ZIKVs from other parts of the Americas or Pacific.

Although the Cuban ZIKV isolates broadly clustered with other ZIKVs from the Americas, for example, their results suggested that the proposed outbreak in Cuba resulted from viruses introduced on multiple occasions from other islands in the Caribbean, likely arriving roughly a year before the outbreak took hold.

"Considering that all known large Zika outbreaks in the Americas, including Cuba, may have involved prolonged virus maintenance," the authors noted, "a better understanding of how Zika virus is maintained during low mosquito abundance could lead to novel vector control and outbreak mitigation strategies."