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# A modest proposal

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Amid heightened concerns about the Zika virus outbreak in parts of the Western Hemisphere, it is worth remembering that the most extreme countermeasures are not necessarily the only ones worth trying. We must engage in calculated and diverse responses that will ensure sustainable outcomes for this and other outbreaks.

On 1 February, after weeks of steadily escalating concern, the World Health Organization (WHO) declared a recent outbreak of Zika virus to be an international public-health emergency. As Nature Medicine went to press, the virus had been detected in at least 26 countries in the Western Hemisphere, with more than a million people infected in Brazil alone. The disease seems most seriously to afflict women who are exposed to the virus during pregnancy: the US Centers for Disease Control and Prevention (CDC), and researchers in Slovenia reported independently on 10 February that Zika virus was found in the brain tissue of three babies with microcephaly, or abnormally small heads, suggesting a link between infection in pregnant women and birth defects in babies born to them (N. Eng. J. Med. doi:10.1056/NEJMoa1600651, 2016).

Like the Ebola epidemic, the Zika outbreak came as a surprise to public-health officials, who are now struggling to provide swift and definitive counsel both to countries that are affected and to those who are at risk. The CDC is discouraging pregnant women from traveling to Zika-affected countries; by contrast, the WHO has not yet issued any travel advisories. At least 12 academic and pharmaceutical groups are working to develop a Zika vaccine, but they are all in the early stages. When Ebola made headlines in 2014, scientists had been working on candidate vaccines for nearly a decade, which enabled the deployment of a vaccine to West Africa within a year. Zika, however, doesn't have a stock of candidates that can be expedited to clinical trial. Some public-health agencies are calling for more extreme measures than the restriction of travel; the Colombian government, for instance, urged women to postpone pregnancy for the next six to eight months, and El Salvadorian health officials are asking women to wait even longer—until 2018.

And yet, between the extremes of delaying pregnancy and the extremely long wait for the development of a vaccine against the virus, the middle ground seems empty. Unlike Ebola, which spreads rapidly through direct human-to-human transmission, Zika relies mostly on Aedes mosquitoes for its dissemination. As such, a vital public-health measure is vector control. New technologies, such as the release of genetically modified mosquitoes to eliminate the wild population of Aedes aegypti—one of the species that transmits Zika—may offer a solution for curbing the spread of disease. But regulatory and financial hurdles are blocking these efforts.

Companies such as Oxitec, which has developed genetically modified mosquito technology, are plagued by regulatory obstacles that prevent them from testing their technology in the US (http://www.readcube.com/articles/10.1038%2Fnm0515-416). Oxitec formally filed an application with the US Food and Drug Administration (FDA) in 2011 for permission to begin a trial of modified A. aegypti mosquitoes, to be held in Key West, Florida. Nearly five years later, the trial has still not been approved, impeded to some extent by opposition from local residents. Oxitec CEO Hadyn Parry told Nature Medicine that the FDA has everything that it needs to make an assessment of whether to grant approval to the trial, including data from small trials—conducted in Panama, Brazil, and in the Cayman Islands—demonstrating that the company's technology reduced the wild A. aegypti mosquito population in the tested areas by more than 80%. Such a technology, if tested in Zika-endemic countries, could thus reduce the number of mosquitoes and rates of associated disease.

The drawn-out approval process probably stems from the fact that the regulation of genetically modified organisms is uncharted territory. The FDA has not indicated to Oxitec when a decision will be handed down, but the company told Nature Medicine that it is hoping the severity of the Zika outbreak will hasten the decision. And Oxitec is not the only player in this space: researchers are pursuing other modes of genetically modifying mosquitoes, including through the use of the popular gene-editing technology CRISPR-Cas9 to alter the mosquito genome with a method known as a gene drive, which renders the mosquito incapable of producing viable offspring. These technologies are nascent, but Oxitec's experience may serve as a cautionary tale of the regulatory challenges ahead.

Moreover, no new, mosquito-specific insecticide has been introduced to the market since the 1970s, which, according to Parry, is due in large part to a lack of funding for vector-control research. On 8 February, US President Barack Obama announced his request to Congress for $1.8 billion to help to combat the Zika outbreak. Vector control is listed as a beneficiary of these funds, but it is unclear how much of that total will be dedicated to this goal. By contrast, roughly$200 million has been allocated specifically for research into vaccines.

The development of a vaccine seems to offer a more surefire way of alleviating disease, and thus may be a more attractive option. But genetic modification of mosquitoes is appealing because it could enable us to combat multiple diseases, like dengue and chikungunya, for which these organisms serve as vectors, with the implementation of just one type of technology. Vaccines, on the contrary, are disease-specific, and in many cases, serotype specific.

On 9 February, the WHO tweeted, “Fogging followed by the controlled release of genetically modified mosquitoes may be worth considering for halting the spread of #Zika.” The takeaway from this isn't that resources into vaccine development should be limited—it is that funds should also be funneled into developing vector-control strategies, including, as the WHO says, fogging, or regular insecticide spraying. At a time when some are resorting to extreme calls such as delaying pregnancy, perhaps a trial to test genetically modified organisms is not so radical.

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A modest proposal. Nat Med 22, 219 (2016). https://doi.org/10.1038/nm.4065