Feb. 8, 2019: EPI Researcher discovers that people who have developed immunity against dengue virus have built-in protection against infection from the Zika virus.
In the epicenter of the Zika epidemic in northeast Brazil, 73 percent of people living in an urban slum in Salvador were infected in 2015, but a new study finds that those with immunity to dengue, a genetically similar virus, had a reduced risk of infection with Zika.
“This study is the first to demonstrate that immunity to dengue can protect against Zika infection in human populations,” said Derek Cummings, a University of Florida Emerging Pathogens Institute researcher and biology professor. Cummings worked with a team led by the Brazilian Ministry of Health that included scientists from the University of California San Francisco, the Federal University of Bahia, the University of Pittsburgh and the Yale School of Public Health.
For the study, published yesterday in the journal Science, the team examined a cohort of 1,453 individuals participating in a long-term health survey in Pau da Lima, Salvador, Brazil, who may have been exposed to Zika during the 2015 outbreak. Using multiple immune assays, the team characterized this cohort’s immunity to dengue before and after the Zika outbreak and identified Zika infections.
To do this, the team developed a novel assay that measured immunoglobulin G3 responses to Zika, a specific antibody that recognizes Zika.
“One of the challenges in studying dengue and Zika is distinguishing immunity to one virus from the other. We used multiple methods to disentangle immune responses to each virus,” said Federico Costa, an associate professor at the Federal University of Bahia and an associate adjunct professor at the Yale School of Public Health.
A majority of individuals in the cohort had been infected with dengue before the Zika outbreak. For those with prior immunity to dengue, each doubling of antibody titers was associated with a 9 percent reduction in risk of Zika infection.
“Even though there was protective immunity in the population, this community was heavily infected,” said Albert Ko, a professor and chair of epidemiology at Yale School of Public Health and co-corresponding author with Cummings. “Dengue immunity reduced individuals’ risk, but still 73 percent of the population was infected by Zika.”
The results provide evidence that acquired immunity to the Zika virus has driven Zika transmission to low levels.
“The Zika pandemic has created overall high rates of immunity to this virus in the Americas, which will be a barrier for outbreaks in coming years,” said Isabel Rodriguez-Barraquer, an assistant professor at University of California, San Francisco and one of the lead authors of the study.
The study was supported by the U.S. National Institutes of Health, Yale School of Public Health and the Brazilian Ministries of Health, Education and Science and Technology.
Why would immunity to dengue virus confer protection against Zika virus?
Several years ago, researchers hypothesized that people who had previously been infected with dengue virus were possibly more susceptible to Zika virus infection. Given the re-emergence of dengue in South America thirty years ago, this seemed a plausible explanation for the explosive Zika outbreak in Brazil in 2015.
The general thinking was that prior dengue virus infections could increase the pathogenicity or transmission of Zika via a mechanism known as antibody-dependent enhancement. People previously infected with dengue harbor antibodies that protect them from reinfection, but these same antibodies may actually cause an increase in: susceptibility to infection, the likelihood of developing a severe disease, and transmission of other very closely related flaviviruses. Test tube studies showed that the Zika virus increased its replication rate when in the presence of other flavivirus antibodies. Studies in people, however, were less clear.
Researchers agreed the only way to really test the idea would be to screen blood samples of people infected with both dengue and Zika viruses to better understand the body's immunological interactions. And when they did, they found an entirely different result: some people previously infected with dengue virus were conferred a little protection against Zika virus.
Zika virus is both genetically and antigenically similar to dengue. When phylogenetic relationships are examined, Zika and dengue nestle close to each other like neighboring tree branches. Cummings’ recent study showed that individuals with the middle to highest levels of dengue antibodies present in their blood had a 38 to 44 percent reduction in their chances of being Zika positive after the 2015 outbreak. This is consistent with the idea that the body’s immune system, having recognized and cleared dengue virus, was able to more efficiently clear the evolutionarily-similar Zika virus.
There is still much to understand in these interactions. Immunity to dengue has both protective and deleterious impacts on future dengue infection. It is still possible that dengue immunity may protect some individuals at some times from Zika as Cummings found here, but it may possibly also play a role in pre-disposing individuals to more severe disease with Zika at other times. Fuller characterization of how this immunity affects Zika over time is still needed.
Originally written for UF News by Rachel Wayne and published here on February 7, 2019; reposted to EPI’s website on Feb. 8, 2019 with light edits and addition of EPI Explainer by DeLene Beeland; photos of Pau da Lima neighborhood by Albert Ko.
Derek Cummings EPI Profile