If you have had dengue and are then infected by the Zika virus (ZIKV), it appears you will not develop a more severe form of the disease than someone who has not had prior contact with dengue—contrary to what was previously thought. Your case of Zika may even be milder and fleeting. The notion that prior dengue infection may have the effect of moderating Zika emerged from two recent studies, one published June 20, 2017, in the journal Clinical Infectious Diseases and the other June 23, 2017, in Nature Communications.
Both studies—the former conducted in Brazil on humans and the latter on monkeys in Puerto Rico—present the first evidence that dengue infection followed by Zika triggers an immune response in primates unlike the response observed in experiments with mice or cells cultured in the laboratory. Prior to the studies published in June, experimental models that used cells in vitro or mice with weakened immune systems had indicated that after a dengue infection, ZIKV could more easily evade the body’s defenses and proliferate more, resulting in a more severe case of Zika. Some research groups have used this hypothesis in an attempt to explain why so many more cases of microcephaly have been linked to Zika in Brazil, where dengue is endemic, than elsewhere in the world.
“Our findings indicate that no such exacerbation occurs or, if it does, it’s quite rare and can’t be detected in a study like the one we did,” says virologist Maurício Lacerda Nogueira, a professor at the São José do Rio Preto School of Medicine (FAMERP). Nogueira led the study published in Clinical Infectious Diseases, the first to signal that prior dengue infection in humans does not necessarily lead to a more severe case of Zika. Both viruses are transmitted by the Aedes aegypti mosquito.
Nogueira’s group collected blood from 65 residents of São José do Rio Preto who sought medical treatment between January and July 2016—the height of the Zika epidemic—and who presented symptoms resembling those of dengue or Zika, that is, fever, muscle pain, headache, and body rash. Located in northern São Paulo State, 450 kilometers from the capital, São José do Rio Preto lies in a region of endemic dengue that was swept by Zika in 2016.
Analyses of participants’ blood showed that 45 of them had ZIKV infection at the time, while 20 had dengue. Tests also revealed that 78% of those with Zika (35 individuals) and 70% of those with dengue (14) had been previously infected by the dengue virus.
In this study, conducted in partnership with researchers from two U.S. institutions and three institutions in São Paulo—the University of São Paulo (USP), São Paulo State University (Unesp), and the Butantan Institute—Nogueira and his team also examined the number of copies of ZIKV in the blood of individuals previously infected with dengue and compared the figure with the quantity found in the blood of those never exposed to the virus. If prior dengue infection facilitated replication of ZIKV, the quantity of the latter should be much higher in the first group of patients. That is not what researchers observed. Instead, the viral load was similar in both cases.
“Our study was powerful enough statistically to detect a very small difference—of only 10 times—in the concentration of the virus,” says Nogueira, who is a member of the FAPESP-funded Zika Virus Research Network in São Paulo (Rede Zika). It would be expected to find tens of thousands more copies of ZIKV in the blood of someone with prior exposure to dengue if the phenomenon observed in mice and cells in vitro also occurred in humans.
Shortly after Zika began spreading through Brazil—the Ministry of Health recorded nearly 310,000 cases in 2015 and 2016, according to a study published in June 2017 in the journal The Lancet—the suspicion grew that prior dengue infection could produce more severe cases of Zika, much as what happens with dengue hemorrhagic fever (DHF). Characterized by bleeding and, in more severe cases, by a sharp drop in blood pressure, DHF usually strikes people who have already had the disease and are then infected by a different virus subtype, four of which exist in Brazil. The problem is that the antibodies produced by the immune system to fight one infection do not always efficiently neutralize the other, resulting in partial immunity.
According to the antibody-dependent enhancement (ADE) hypothesis, incomplete immunity may facilitate the virus’s entry into cells of the defense system where it manages to reproduce, increasing the number of its copies in the body and also the severity of the infection. Since the dengue and Zika viruses are quite similar evolutionally—both belong to the flavivirus family—it was previously thought that partial immunity, which enhances dengue disease, might also result in more severe Zika disease.
This suspicion gained strength in mid-2016 when the first research came out showing that the antibodies that protect against dengue also act against ZIKV, but do not neutralize it completely. In March 2017, researchers in the United States found that this partial immunity enhanced replication of ZIKV in mice with weakened immune systems. The findings recently presented in Clinical Infectious Diseases indicate that what happens with cells in vitro and with mice does not necessarily happen with humans.
“These findings do not completely exclude the possibility that ADE occurs, but they are an important indication that first having dengue doesn’t lead to more severe Zika infection,” says immunologist Jorge Kalil, USP professor and co-author of the study. “In fact, there are unpublished reports that people who already had dengue presented a milder form of infection when they contracted Zika.”
The hypothesis that prior dengue infection can result in a milder form of Zika recently received a significant boost. In the article published in Nature Communications on June 23, 2017, the group led by virologist Carlos Sariol of the University of Puerto Rico presented indications that developing immunity to the dengue virus might moderate ZIKV infection in monkeys, an animal whose defense system is more similar to that of the human’s. Researchers at the Caribbean Primate Research Center infected eight rhesus monkeys with Zika and then followed their immune response for 60 days. Half of the monkeys had been infected with dengue about three years earlier, while the other half had never had contact with the virus.
In tests of animal blood in vitro, dengue antibodies had provided only partial immunity against ZIKV, facilitating replication and corroborating the findings of research with mice. But it was different with the monkeys. Instead of worsening the cases, the dengue antibodies helped reduce the concentration of ZIKV in the blood faster, shortening the infection. “We urge caution in using immune deficient mouse models to understand the pathogenesis of ZIKV in people,” the researchers wrote in the article in Nature Communications.
Based on these findings, the group led by Sariol raised the hypothesis that pregnant women previously exposed to ZIKV might display a lower probability of transmitting the virus to their fetus, reducing the risk of central nervous system damage in the child. Transmission of ZIKV from mother-to-be to baby seems to require a longer-lasting infection and the presence of greater quantities of the virus.
“If enhancement caused by dengue antibodies led to microcephaly, we should have identified hundreds of cases in Rio Preto and Ribeirão Preto,” Nogueira explains. “We didn’t find any.” The virologist’s team also followed 55 women in Rio Preto who had Zika during pregnancy. All of them gave birth to children with no microcephaly. While some of the children did suffer neurological damage, it was much milder than what has been reported in the Northeast.
“Most certainly, this article [in Clinical Infectious Diseases] has broad implications, both epidemiologically and in terms of vaccine development,” says researcher and study co-author Nikos Vasilakis, of the University of Texas. “These data suggest that other factors may be responsible for Zika congenital syndrome.”
The evidence that dengue infection might lead to more severe Zika disease has raised concerns regarding vaccine development, especially the dengue vaccine, now being tested in Brazil. “There was a fear that vaccinating the population against dengue might lead to more severe cases of Zika,” says Kalil. “These findings indicate that this shouldn’t be a problem.”
Epidemiological study of dengue (serotypes 1-4) in a cohort of São José do Rio Preto, São Paulo, Brazil, during 2014-2018 (No. 13/21719-3); Grant Mechanism Thematic project; Principal Investigator Maurício Lacerda Nogueira (FAMERP); Investment R$2,306,387.68
TERZIAN, A. C. B. et al. Viral load and cytokine response profile does not support antibody-dependent enhancement in dengue-primed Zika-infected patients. Clinical Infectious Diseases. June 20, 2017.
PANTOJA, P. et al. Zika virus pathogenesis in rhesus macaques is unaffected by pre-existing immunity to dengue virus. Nature Communications. June 23, 2017.