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Getting sick with the mosquito-borne Zika virus makes people more vulnerable to developing dengue disease and suffering more severe symptoms when they become ill with dengue, according to researchers at the University of California at Berkeley.
This new Berkley study published in the journal Sciences On August 28, 2020, he discovered that the double whammy of dengue and Zika have been hitting each other around the world for the past few years. These mosquito-borne viruses are closely related, with approximately 40 percent homology within the envelope protein.
The study, which was based on data from two cohorts of Nicaraguan children who experienced a Zika epidemic in 2016 and a dengue epidemic in 2019, is the first to investigate the impacts of immunity to Zika on dengue disease in humans.
Their findings confirm previous suspicions that some Zika virus antibodies, which generally serve to protect the body from infection, may interact with dengue viruses in ways that can worsen dengue infection. This interaction, known as antibody-dependent enhancement, could make it difficult for researchers to design a safe and effective vaccine that protects against Zika without also increasing the risk of dengue.
“The key our study establishes is that a previous Zika infection significantly increases the risk of symptomatic and more severe forms of dengue disease,” said study first author Leah Katzelnick, who conducted the research as a postdoctoral fellow at the University of California. , Berkeley School of Public Health, in a press release.
“That finding raises the questions: Could a vaccine targeting Zika alone put people at higher risk for more serious dengue disease? And how can you design a Zika vaccine that only induces good antibodies to protect it? against Zika, but not induced by other potentially potentiating antibodies that are harmful to diseases? “
When the Zika virus first appeared in Latin America in late 2015, many speculated whether flavivirus, a close cousin of dengue viruses, could interact with dengue viruses in similar ways.
Dengue disease is caused by not one but 4 closely related types of flaviviruses, each of which can present a slightly different set of symptoms and severity. Getting sick with one type of dengue virus can increase the chance that a person will develop a second, more serious illness when infected with a different type of dengue virus.
However, after a person has been infected with 2 types of dengue virus, they generally gain some degree of immune protection against the future severity of dengue.
“The first question was, ‘How will a previous dengue virus infection affect Zika?’ because everyone in Latin America, to some degree or another, is eventually immune to dengue and has antibodies against dengue, “added study lead author Eva Harris, a professor of infectious diseases and vaccination at UC Berkeley.
Since 2004, Harris and his colleagues in Nicaragua have monitored a cohort of roughly 3,800 children living in Managua, the country’s capital, tracking any signs of dengue disease and collecting annual blood samples to detect the virus and its antibodies.
When chikungunya, another mosquito-borne virus, and Zika appeared in Nicaragua in 2014 and 2016, the cohort expanded to capture these emerging pathogens.
Using data from the cohort, Harris published a 2019 study showing that a previous infection with the dengue virus can confer a small amount of protection against Zika, and other studies now support this conclusion. But the reverse question, whether Zika antibodies protect against dengue disease in the future, or potentially potentiate it, remains a mystery.
In July 2019, Harris landed in Managua with Katzelnick, who would be stationed in the Nicaraguan capital for the remainder of the year as a Fogarty Global Health Fellow. The two arrived at the beginning of what would become a massive epidemic of dengue virus type 2, one of the most serious of the four serotypes and the first major outbreak of dengue since the Zika epidemic in 2016.
“We saw the epidemic spread in real time and we started thinking, you know what, there are a lot of cases. I wonder if a previous infection with Zika is pushing people into symptomatic illness,” Harris said.
The team collected data from their pediatric cohort and from another study of children treated at a nearby pediatric hospital. By mid-fall, researchers had enough evidence to show that having a previous Zika infection increased a person’s chances of having a symptomatic dengue infection.
And as cases increased, they found that a previous Zika infection can also increase the severity of dengue disease.
The team relied on the pediatric cohort blood sample bank dating back to 2004 to investigate other disease patterns. It found that people who had a dengue infection, followed by a Zika infection, were still at high risk of developing a second, more serious dengue infection.
Furthermore, when a person had two consecutive dengue infections, the type of dengue virus that caused the second infection influenced whether the person was protected or experienced an enhanced dengue disease.
“I think this can help us understand the epidemics that are coming,” Harris said. “So, for example, if you have a type 2 dengue epidemic after a large Zika outbreak, you need to prepare your hospitals to treat people who may be more likely to develop a more serious illness.”
When we get sick, our bodies make large proteins called antibodies to help our immune systems fight infection. These antibodies have specific chemical forms that allow them to adhere to the pathogen in question, indicating that the invader is being degraded by immune cells.
For viruses like Zika and dengue, they can also cover the virus and prevent it from entering the cells of the body, effectively neutralizing it.
Antibody-dependent enhancement can occur when an antibody designed to bind to one virus, such as Zika, tries to bind to a slightly different virus, such as dengue. Zika virus antibodies can adhere to dengue viruses, but not well enough to neutralize them.
As a result, when a passing immune cell detects the antibody “flag” and tries to break down the dengue virus, it can become infected with the virus.
“This mechanism not only allows the virus to enter more cells to infect, but it also suppresses the immune response of those cells, allowing the virus to produce even more virus,” Katzelnick said.
“And because they are immune cells, they move through the body. Therefore, they can start a larger infection.”
In a 2017 study, Katzelnick, Harris, and the Nicaraguan team showed that infection with one dengue virus could lead to more severe illness with a second dengue virus through antibody-dependent enhancement.
Although this mechanism has complicated the search for effective vaccines for both Zika and dengue, Katzelnick and Harris say that it is still possible to design vaccines that stimulate the body to create antibodies that only stick to the target virus and not another.
“Zika remains a horrible problem that has many complicated ethical considerations, partly due to the way it affects pregnant women and potentially their children as well,” Katzelnick said.
“I hope that people continue to work hard to find ways to develop a safe vaccine, even if it is more challenging than we originally thought.”
The co-authors of this study are listed in the study. And this research was funded by several organizations, including grant P01AI106695 from the National Institutes of Health (NIH). No industry conflicts of interest were disclosed.
ZikaNews publishes research-based news about Zika disease.
