UC Berkeley researchers find support for antibody-dependent enhancement in dengue disease

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A study led by UC Berkeley researchers in Nicaragua found support for the decades-old hypothesis of antibody-dependent enhancement, or ADE, in dengue disease.

Dengue fever, also known as breakbone fever, is a mosquito-borne tropical disease. Dengue fever is fairly common and has relatively mild and treatable symptoms, but a small proportion of patients with dengue develop a hemorrhagic fever or shock syndrome, both of which are potentially fatal.

The dengue virus that causes infection comes in four distinct serotypes, or viral strains, and each serotype has its own unique antibody.

ADE, an idea presented more than 40 years ago, is the hypothesis that forming antibodies for one serotype of dengue can actually increase the severity of a subsequent dengue infection, rather than neutralizing the virus like antibodies are expected to do. While evidence of ADE occurring has been found in animal and in vitro studies, the effect of ADE in humans has not yet been thoroughly investigated.

The new study allowed researchers to determine if pre-existing antibodies led to a greater chance of the dengue virus becoming deadly.

“The point is that we’ve been able to prove this in human populations with a long-term cohort study,” said Eva Harris, campus immunology professor and co-first author of the paper.

Researchers from Nicaragua health institutions, UC Berkeley, University of Washington and University of Michigan worked together on the study, which was published in Science magazine Thursday. More than 8,000 children were enrolled in the study and had regular blood tests for dengue antibodies over 12 years.

“Children who had dengue antibodies and became infected a second time were far more likely to be in the small group of children that developed the most severe disease,” Science magazine staff writer Jon Cohen said.

While the mechanism of ADE is widely debated, the idea rests on the possibility that some antibodies bind to certain viruses without neutralizing them. Instead, some antibodies may increase a virus’s ability to spread.

“Basically the antibody from one dengue serotype attaches to the second serotype and helps that virus get inside of cells,” Cohen said. “It’s the complex of antibodies attached to the virus that speeds the ability of a virus to get into a cell and then make more copies of itself.”

According to Cohen, skeptics of the theory refute the idea that a defensive mechanism like antibody production can hurt the body and that the nature of ADE potentially involves other immunological defense systems as well, not just antibodies.

Still, understanding the nature of ADE can lead to improvements with dengue vaccines, both in terms of cost effectiveness and maximizing success rates.

Increasing standardization in creating and conducting validation studies for ADE are the researchers’ top priorities for future clinical application, Harris said.

“We’re very interested in how this same phenomenon works with Zika. … What are the patterns with antibody responses and disease severity?” Harris said.

Contact Phil Zhang at [email protected] and follow him on Twitter at @philzhangDC.