A Surprising Link Between Zika and Dengue

New research finds some dengue fever antibodies can help neutralize Zika—but they can also make Zika infections worse.

Before Zika spurred a global health emergency, the mosquito best known for transmitting the virus was most notorious for spreading several other dangerous diseases—including dengue fever, chikungunya, and yellow fever.

But there’s more to how these viruses are related to one another than just the bug that carries them. New research shows that certain dengue antibodies can either neutralize Zika—or help it replicate. The findings, published in two separate papers on Thursday, may be a crucial step toward developing a vaccine for Zika.

Although Zika can be dangerous to anyone who contracts it, the virus is of particular concern to pregnant women. In recent months, scientists have confirmed that Zika can cross the placenta, stunt fetal growth, and infect a developing baby’s brain. In Brazil, Zika has been linked to thousands of cases of microcephaly, a birth defect in which improper brain development leads to babies born with abnormally small heads. (The risk of this kind of neurological damage among pregnant women infected with Zika isn’t known. One early study suggested that women who get Zika in their first trimester have a 1 percent risk of  their fetus developing microcephaly; another study put the risk at 22 percent.)

It makes sense that scientists would focus on dengue as a way to better understand Zika. Both are in the same family of viruses, and understanding cross-reactivity among related viruses is a cornerstone of vaccination. This kind of research “was the immunological basis for the first human vaccine against smallpox introduced more than 200 years ago,” according to a 2012 paper in the Expert Review of Vaccines, “and continues to underpin modern vaccine development.”

Now, researchers have identified two antibodies, generated by people who have been infected with dengue, that can bind to the Zika virus and prevent an infection. In their paper, published in Nature on Thursday, they describe the importance of studying the structures of those antibodies as a way to design a vaccine that protects against Zika. And although researchers knew going-in that Zika and dengue are both flaviviruses, the antibody response was a surprise.

“We did not indeed expect that neutralizing antibodies generated after dengue infection could be even more potent in neutralizing Zika virus,” Giovanna Barba Spaeth, one of the paper’s authors, told me. The finding has major implications for protection against both Zika and dengue, since the antibodies target the same region on both viruses. “It suggests that a vaccine including this region would generate protection against both viruses,” she said.

But the path to developing a vaccine isn’t exactly straightforward.

In a related paper, published in Nature Immunology, researchers found that antibodies generated by someone who has previously had dengue aren’t always protective. These antibodies can actually enhance Zika’s ability to replicate and thrive. In other words, a previous dengue infection may put someone at higher risk of contracting Zika—even though certain dengue-prompted antibodies could help lead to a Zika vaccine. But in areas where there have been both Zika and dengue outbreaks, it’s difficult to compare the severity of post-dengue Zika with cases in which people have only contracted Zika. “Most of the people who have had Zika have been previously infected with dengue,” said Gavin Screaton, one of the authors of the Nature Immunology paper.  “After people have had Zika, it is difficult to distinguish those who have had Zika only from those who have had Zika and dengue.”

The mechanism in which the antibodies from one virus enhance the infection of another virus is known as antibody-dependent enhancement, and it’s a feature that has already complicated attempts at developing a vaccine for dengue alone. (Antibody-dependent enhancement also helps explain why secondary dengue infections are often more dangerous to a person than the first time that person comes down with the virus.)

“Given that the prevalence of dengue exceeds 90 percent in some regions affected by Zika,” Nature wrote in a statement about the new research, “these findings could have important implications” for understanding the mechanics of Zika’s spread—understanding which is critical for vaccine development.

But these findings also present a spate of new challenges for such efforts. Because a Zika vaccine, if developed, would need to be used in areas where dengue infections are common, researchers must now consider the antibodies produced in someone who contracts either virus. “The outcome of Zika infection on a dengue-immune population will depend by the type of antibodies the individuals have developed—protecting or enhancing,” Barba Spaeth told me.

There is a possibility, researchers wrote in Nature Immunology, that vaccination against Zika could make people more susceptible to dengue—and, conversely, that vaccination against dengue could put them at higher risk of a robust Zika infection.

“The precise reason for the explosion of [Zika] infection and its complications in Brazil will need to be fully determined,” they wrote, but it is possible that preexisting immunity to dengue is one of the main things driving the Zika outbreak, which might in turn create a greater risk of complications for those who are infected.