Pre-exposure to Dengue Virus May Predict Reaction to Zika Virus

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Antibodies to dengue may either confer protective immunity to the Zika virus or enhance disease severity in secondary, related infections such as Zika.

Two recently published studies suggest that pre-exposure to the dengue virus (DENV) could predict a person’s reaction to the Zika virus (ZIKV) because of of the antigenic similarity between the viruses. One study was published on June 23, 2016 in Nature Immunology and the other on June 27, 2016 in Proceedings of the National Academy of Sciences of the United States of America (PNAS). Dengue and Zika are both mosquito-borne flaviviruses that are cross-reactive.

In the PNASreport, researchers tested the sera and monoclonal antibodies (mAbs) of nine subjects that had previously been exposed to dengue. They showed the dengue sera binds or neutralizes Zika, demonstrating cross-reactivity. For some of the subjects who were immune to the dengue virus, this may mean they had protective immunity from the Zika virus and would not likely experience a negative reaction. However, for some, the prior exposure to dengue may enhance infection with Zika as a result of antibody-dependent enhancement (ADE), as the dengue viral envelope is more than 50% homologous to the Zika envelope protein. The researchers found that although a large number of dengue patient mAbs were able to bind viral epitopes to Zika, only a few were able to cross-neutralize the virus. As a result, they wrote, “Identifying potential targets for broadly cross-neutralizing antibody responses could inform the design of vaccines or antibody-based therapies in the future.”

Although the findings could have important implications in the future design of a Zika vaccine, the researchers also discovered that pre-existing dengue-induced antibodies could make Zika infection worse. The researchers hypothesized that ADE could occur, and cross-reactive antibodies could join up to form virus-antibody complexes to actually facilitate the infection of cells, causing higher disease loads and higher disease severity. After further investigation, the researchers concluded, “The data presented suggest that ZIKV infection may have the potential to reactivate cross-reactive dengue-induced memory responses in patients with prior DENV exposures.” However, Jens Wrammert, PhD, assistant professor of pediatrics (infectious diseases) at Emory University School of Medicine and Emory Vaccine Center, also warned in an Emory press release, “We find antibody-mediated enhancement of infection with cells in the laboratory, but we have yet to clarify what effects these antibodies have on the outcome of infection in humans.” The researchers also suggested that the appearance of microcephaly or Guillain Barré syndrome might be related to the the reactivation of pre-existing cross-reactive antibodies acquired through previous infection from dengue.

The second study in Nature Immunology also found that antibodies to certain epitopes from dengue that were unable to neutralize Zika instead promoted ADE. They explained that there are four prominent serotypes of dengue, and infection with one of the serotypes increases the severity of disease if another serotype is encountered, largely due to ADE. In other words, infection with one strain does not protect against infection against the other three strains, and antibodies that are present to the first strain may actually make secondary infection more severe. Thus, the Nature authors wrote of the possibility that "pre-existing immunity to DENV might increase ZIKV replication.”


In vaccine trials for Dengvaxia by Sanofi Pasteur, hospitalization from DENV infection for patients under 9 years of age was more common for vaccinated children than non-vaccinated children, which the authors hypothesized was because the vaccine “primed” the children for secondary infection instead of providing protective immunity. In this context, the authors wrote, a vaccine against ZIKV must account for the potential cross-reactivity between DENV and ZIKV. They also noted that pre-existing immunity might drive greater ZIKV replication and it is possible that “vaccination of DENV-naïve subjects against ZIKV might promote ADE of DENV infection and, conversely, that vaccination against DENV might promote ADE of ZIKV.” Lastly, they suggested ADE from prior infection of DENV might aid in the transplacental transfer of ZIKV.

On June 27, 2016, Emergent BioSolutions announced it received a task order from the Biomedical Advanced Research and Development Authority (BARDA) valued at nearly $22 million to develop and manufacture three cGMP lots of a Zika vaccine for use in a Phase I clinical trial. An Emergent spokesperson told this publication that the vaccine is not based on yellow fever, and that "Emergent is only working on developing a manufacturing process-BARDA will be handling any animal or clinical studies."

Sources: Nature Immunity, PNAS, Emory University, Emergent BioSolutions