Children who have previously been exposed to dengue virus appear to be protected from getting sick when infected with Zika virus, according to a study published January 22 in PLOS Medicine.

The study’s scientific team, led by Aubree Gordon of the University of Michigan and Eva Harris of the University of California, Berkeley, analyzed the large 2016 Zika epidemic in Nicaragua, while focusing on a pediatric cohort with a well-characterized history of exposure to the dengue virus. The cohort, established in 2004 to gather information about dengue in Nicaragua, follows approximately 3,700 children aged two to 14 years old. “What we saw was that having had a prior documented dengue infection in these kids protected them from symptomatic Zika,” Gordon says. “It didn't protect them from getting infected, but if they got infected, they were less likely to get sick.” Children with prior dengue infection had 38 percent less risk of showing symptoms when infected with Zika than those who were dengue-free. Zika symptoms included fever, rash, conjunctivitis, muscle, joint pain and headache.

The study was an epidemiological survey to determine if cross-protection was present, but it was not designed to uncover a mechanism for how that protection works, says one of the paper’s co-authors, Lionel Gresh, a molecular biologist currently working for the Pan American Health Organization. He suspects preexisting antibodies could be neutralizing the virus, and the immune system’s memory T cells that recognize the closely related dengue could be offering protection against Zika. “The idea is that somehow that previous infection with dengue has triggered some kind of immunity in your body that helps control the virus,” he says. “You still get infected with the virus, but to a level that it doesn’t cause sickness.”

The results support the hypothesis that an immunological interaction exists between dengue and Zika, which belong to the same Flavivirus genus. Both viruses are transmitted by the Aedes aegypti mosquito, which preys on the same populations. “This is an important paper that shows that dengue infection can reduce the risk of disease associated with the Zika infection,” says Albert Ko, a professor of epidemiology and medicine at Yale School of Public Health who conducts research on Zika in Brazil and was not involved in this research. “This is one of the first studies to really look at this in a nice rigorous prospective design.”

Before starting their study Gordon and her colleagues postulated two possible scenarios: Prior infection with dengue would either provide protection against Zika or enhance the latter’s infection. “There are four dengue virus types, and we know that infection with one dengue type provides short-term protection to infection against a different type,” Gresh says.” Because dengue and Zika viruses are very close to each other, we thought this [protection] might happen.”

A prior dengue infection, however, can sometimes also worsen a subsequent one—a mechanism known as antibody-dependent enhancement—which then produces severe dengue, a life-threatening illness. “With dengue, if you have two infections really close together, say within six months, you are going to be pretty much completely protected against the second infection,” Gordon notes. “But if you go further out, 10 or 15 years further out, you are not going to get any protection at all.”

But before the immune protection wanes there is a window of time between being fully protected and completely vulnerable, in which antibodies are present but diminished. If a person is infected in this interim period, the antibodies still bind to the virus but are unable to neutralize it, and the impact of the infection would be heightened. “We kind of went into it [the study] thinking that we would possibly see enhancement, but that’s actually not what we saw, we found protection,” Gordon says. “We can’t completely exclude that there is no enhancement—that remains to be seen. You may need more time between the infections.”

When Zika virus emerged in northeastern Brazil in 2015 and spread rapidly across the Americas, causing thousands of severe birth defects in the babies of women whom the virus infected during pregnancy, antibody-dependent enhancement due to preexisting dengue antibodies emerged as a hypothesis in the scientific community to explain the Zika congenital syndrome. The hypothesis still stands but “the jury is still out on that one,” Ko says, adding, this study lends credence to the argument the immune response for dengue affects the one for Zika—but a few open questions remain. He suspects the protection—or enhancement—a previous dengue infection may provide against Zika depends on the levels and types of antibodies in the body at the moment the Zika infection arises. Ko and his team are exploring that question in a large epidemiological study in urban areas of Brazil.

The science exploring the relationship between dengue and Zika may provide valuable data that can be used in the development of an effective vaccine, which would protect against infection with these viruses. Just as dengue infection may offer some protection against Zika, it remains to be seen if the inverse remains true: Does Zika infection protect against dengue? “If you immunize with Zika, does that potentially protect or could it potentially enhance a subsequent dengue infection?” Ko says.

The antibody-dependent enhancement in dengue has proved to be a hurdle in the development of a vaccine against the virus. In July 2018 The New England Journal of Medicine published an analysis of Sanofi’s dengue vaccine, given to more than 800,000 school children in the Philippines, confirming it increases the risk of hospitalization and severe complications in those who had never previously been infected. The current recommendation of the World Health Organization is to only vaccinate people known to have had a previous infection with the virus.

The enhancement effect worries researchers such as Gisela Herrera-Martínez, an immunologist at the Costa Rican Center of Medical Research, who runs a national trial of a Zika virus DNA vaccine. The U.S. National Institutes of Heath–funded research is testing the safety and efficacy of the vaccine in 2,400 volunteers in nine countries. In Costa Rica Herrera-Martínez’s team is just finishing the administration of vaccine—or placebos—to 240 participants. The findings of the new PLOS study worries Herrera Martínez because it raises the question of whether a previous dengue infection might diminish symptoms when a Zika infection occurs, making it harder to identify pregnant women at risk of having babies with congenital Zika syndrome.

And although Zika cases have waned in the Americas, the threat remains. “There are large numbers of women of childbearing age that have never experienced Zika and therefore are susceptible to having babies with Zika congenital syndrome,” Ko says. “There is probably a fair amount of silent transmission that isn’t being detected by the surveillance system. What’s more, Zika outbreaks are happening in Asia and south Asia. “It makes making a vaccine or vector control very important for an effective prevention strategy,” he says.

A high-quality vaccine would be an ideal solution. “But if we don’t get that,” Gresh notes, “an integrated strategy like the one we use to manage dengue, that combines efforts on vector control, surveillance and clinical management should be followed.”