Prior dengue infection does not increase Zika disease severity

July 17, 2017
A TEM micrograph showing Dengue virus virions (the cluster of dark dots near the center). Image: CDC

Individuals infected with Zika virus after having dengue fever do not appear to become more severely ill than people with Zika who have never had dengue. This is the conclusion of a study published on June 20 in the journal Clinical Infectious Diseases.

The study involved 65 people who live in and around São José do Rio Preto (São Paulo State, Brazil), where dengue is endemic and there was a particularly rapid outbreak of Zika during the 2016 epidemic.

The study is the first to show that prior dengue infection in human beings infected by Zika does not necessarily lead to a worse illness. Previous research using only cells and rodents suggested prior dengue infection would intensify Zika disease by facilitating replication of the virus.

Some physicians and virologists suspected this possible viral amplification could explain the concentration of Zika-associated microcephaly cases in the Northeast of Brazil, where dengue is more prevalent than in other regions of the country.

"Our results show this aggravation doesn't occur, or occurs only very rarely and can't be detected by a study such as this," said virologist Maurício Lacerda Nogueira, a professor at the São José do Rio Preto Medical School (FAMERP) and principal investigator for the study.

The study was performed in partnership with researchers at US institutions and three others in São Paulo State: São Paulo State University (UNESP), the University of São Paulo (USP), and Butantan Institute.

During the period when the Zika epidemic was at its most intense, between January and July 2016, Nogueira's team collected blood samples from 65 people who presented with fever and symptoms of dengue or Zika (similar and easily confused) at the emergency unit of the reference hospital in São José do Rio Preto, a healthcare hub for northern and northwestern São Paulo.

Analysis of the viral genetic material found in these blood samples showed 45 patients had been infected by Zika and 20 by dengue. The tests also showed 78 percent of those with Zika (35 people) and 70 percent of those with dengue had been infected previously by .

Shortly after the Zika epidemic emerged, it began to be suspected that prior infection by dengue could lead to more severe clinical manifestations of Zika, similar to those of dengue hemorrhagic fever, such as bleeding under the skin, a large decrease in blood pressure and even shock in particularly severe cases. About 90 percent of patients with have previously had dengue and are infected by a different subtype (there are four subtypes of dengue virus).

The problem is that the antibodies produced by the immune system against one subtype do not always effectively neutralize the other subtypes, leading to only partial immunity.

According to a hypothesis called antibody-dependent enhancement (ADE), incomplete immunization appears to help the virus enter defense system cells, where it reproduces, increasing the number of copies of itself in the organism and intensifying the severity of the infection. Because dengue and Zika are both flaviviruses and genetically similar, it was believed that the partial immunization observed after dengue infection might also occur in Zika-infected individuals with prior dengue infection.

This suspicion was strengthened in mid-2016, when research first showed that antibodies against dengue virus also protect individuals against Zika virus but do not neutralize it completely. In March 2017, U.S. researchers found partial immunization to be the explanation for multiplication of Zika in a study using mice with weakened immune systems.

The study just published in Clinical Infectious Diseases now suggests what is true of cells cultured in vitro and laboratory mice does not necessarily apply to humans.

With the help of immunologist Jorge Kalil Filho, a professor at the University of São Paulo's Medical School (FM-USP), Nogueira and his team measured the numbers of Zika virus copies in the blood of patients previously infected by dengue and compared them with the numbers found in the blood of patients who had never been exposed to dengue. If prior dengue infection facilitated the multiplication of Zika, the number should be much higher in the former group, but the researchers found both groups had similar viral loads.

"Our study had sufficient statistical power to detect a very small difference in viral load—a difference of only 10 times, in fact," Nogueira said. If ADE had occurred in this situation, viral load should have been tens of thousands of times greater.

"These findings don't entirely rule out the possibility that ADE occurs, but they constitute importance evidence that having had dengue doesn't increase the severity of Zika disease," said Kalil, a co-author of the study. "In fact, some people who have had dengue present with a milder form of infection when they contract Zika according to unpublished reports."

"If ADE caused by dengue led to microcephaly, we would have identified hundreds of cases in São José do Rio Preto and Ribeirão Preto, but we found none at all," Nogueira said.

His team also monitored 55 women who had Zika during pregnancy in São José do Rio Preto. They all gave birth to infants without microcephaly; some had neurological damage, but much milder than the cases reported in the Northeast.

"This article [in Clinical Infectious Diseases] undoubtedly has far-reaching implications, both in epidemiological terms and for the development of vaccines. These findings suggest other factors may be responsible for Zika congenital syndrome," said Nikos Vasilakis, a researcher at University of Texas Medical Branch and also a co-author of the study.

The early evidence that prior dengue infection might lead to more severe Zika disease raised concerns about the development of vaccines, especially against dengue. A is currently being tested in Brazil. "There were fears that vaccinating people against could lead to more severe cases of Zika," Kalil said. "The results we've obtained now suggest this problem may not exist."

Explore further: Pregnancy problems not necessarily tied to Zika viral load or Dengue fever

More information: Ana Carolina Bernardes Terzian et al. Viral load and cytokine response profile does not support antibody-dependent enhancement in dengue-primed Zika-infected patients, Clinical Infectious Diseases (2017). DOI: 10.1093/cid/cix558

Related Stories

Pregnancy problems not necessarily tied to Zika viral load or Dengue fever

June 13, 2017
UCLA-led researchers have found that Zika viral load and the degree of Zika symptoms during pregnancy were not necessarily associated with problems during pregnancy or fetal abnormalities at birth. They also found that the ...

Study shows prior viral infections can make Zika infection worse

March 31, 2017
(Medical Xpress)—A team of researchers with the Icahn School of Medicine at Mount Sinai in New York City has found that mice who have survived a dengue or West Nile viral infection fare worse when subsequently infected ...

Women's wellness: Learn more about Zika if you're traveling

July 10, 2017
The Zika infection in pregnant women can cause severe birth defects in their babies. So the U.S. Centers for Disease Control and Prevention (CDC) recommends that all pregnant women avoid traveling to areas where there is ...

Two Brazilian studies show new discoveries related to Zika virus

October 12, 2016
A Brazilian study shows that infection of a pregnant woman by Zika virus may represent a risk to the baby's neurological development even when it occurs only a few days before the mother gives birth.

Study suggests size of Zika epidemic may be underestimated

August 31, 2016
A study supported by FAPESP and coordinated by researchers at the São José do Rio Preto Medical School (FAMERP) in São Paulo State, Brazil, suggests official statistics may underestimate the size of the epidemic caused ...

Pre-existing immunity to dengue virus shapes Zika-specific T cell response

March 13, 2017
Although Zika and dengue are considered different virus "species," they are so closely related that the immune system treats Zika just like another version of dengue, report researchers at La Jolla Institute for Allergy and ...

Recommended for you

Two Group A Streptococcus genes linked to 'flesh-eating' bacterial infections

September 22, 2017
Group A Streptococcus bacteria cause a variety of illnesses that range from mild nuisances like strep throat to life-threatening conditions including pneumonia, toxic shock syndrome and the flesh-eating disease formally known ...

Ecosystem approach makes urinary tract infection more treatable

September 22, 2017
The biological term 'ecosystem' is not usually associated with urinary tract infections, but this should change according to Wageningen scientists.

Residents: Frontline defenders against antibiotic resistance?

September 22, 2017
Antibiotic resistance continues to grow around the world, with sometimes disastrous results. Some strains of bacteria no longer respond to any currently available antibiotic, making death by infections that were once easily ...

Superbug's spread to Vietnam threatens malaria control

September 21, 2017
A highly drug resistant malaria 'superbug' from western Cambodia is now present in southern Vietnam, leading to alarming failure rates for dihydroartemisinin (DHA)-piperaquine—Vietnam's national first-line malaria treatment, ...

Investigators may unlock mystery of how staph cells dodge the body's immune system

September 21, 2017
For years, medical investigators have tried and failed to develop vaccines for a type of staph bacteria associated with the deadly superbug MRSA. But a new study by Cedars-Sinai investigators shows how staph cells evade the ...

Individualized diets for irritable bowel syndrome better than placebo

September 21, 2017
Patients with irritable bowel syndrome who follow individualized diets based on food sensitivity testing experience fewer symptoms, say Yale researchers. Their study is among the first to provide scientific evidence for this ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.