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September 25, 2017

Human Dengue Virus Antibodies Protect Mice and Unborn Pups from Zika Virus

An antibody administered soon after infection with Zika virus protected the fetuses of pregnant mice (left), while the fetuses in infected mice that did not receive the antibody withered away (right). Researchers have identified an antibody that protects against both dengue and Zika disease, a first step toward an antibody-based preventive drug to protect fetuses from brain damage caused by Zika, while also protecting their mothers from Zika and dengue. [Estefania Fernandez]

  • Scientists in the U.K. and U.S. have shown that antibodies from patients infected with Dengue virus (DENV) can also protect non-pregnant and pregnant mice and their fetuses from early infection with Zika virus (ZIKV). The studies, by researchers at Imperial College London, and the University of Washington in St. Louis, MO, suggest it may be feasible to develop an antibody therapy that protects people against both of the mosquito-borne flaviviruses, and when given to pregnant women could prevent the potentially devastating effects of Zika virus infection on their unborn children.

    The antibodies, and specifically the monoclonal antibody (mAb) designated EDE1-B10, recognize the Dengue virus E-dimer epitope (EDE). “Thus, in addition to their established inhibitory effects against DENV, these EDE antibodies have therapeutic potential against ZIKV…it may be possible to develop therapies that control diseases caused by both viruses,” commented Michael Diamond, M.D., Ph.D., the Herbert S. Gasser Professor of Medicine at Washington University School of Medicine, speaking to GEN. Professor Gasser is co-senior author of the team’s published paper in Nature Immunology, which is entitled, “Human antibodies to the dengue virus E-dimer epitope have therapeutic activity against Zika virus infection.”

    The reported work builds on prior studies at the laboratory of Professor Gavin Screaton, M.D., dean of the faculty of medicine at Imperial College. “These [prior studies] were mostly related to Dengue and all in cell culture or for structural analysis,” Dr. Diamond added. "The most recent studies…were performed with Zika but only in cell culture. However, the EDE1-B10 mAb had not been extensively characterized.”

    On the basis of prior in vitro neutralization studies, the researchers identified the EDE1-B10 antibody as a candidate immunotherapeutic for Zika virus infection, which had demonstrated “strong inhibitory activity against three virus strains that encompass the genetic diversity of ZIKV, as well as its neutralizing activity against DENV-1, DENV-2, and DENV-3,” they write in their published paper.

    To test the effects of the Dengue virus antibody against Zika virus, the team first infected non-pregnant adult mice with Zika virus, and treated them with the EDE1-B10 antibodies either 1, 3, or 5 days after infection. They found that whereas more than 80% of control animals died within three weeks of infection, all mice treated with the anti-Dengue antibody either 1 or 3 days after infection with Zika virus survived. Antibody therapy given 5 days after Zika virus infection wasn’t so effective, but still resulted in 40% of treated mice surviving.

    Importantly, the EDE1-B10 antibody therapy also led to significantly lower levels of viral RNA in immune-privileged tissues including the brain, testis, and eye, either 5 or 21 days after initial infection, as long as the antibodies were administered within 1 day of infection. The most dramatic effect was seen in the epididymis, where antibody therapy at day one reduced viral RNA levels 4,780-fold at day five. Delaying antibody therapy until day 3 after infection lessened the beneficial effects on viral burden in evaluated tissues, while administering therapy 5 days after infection “failed to decrease ZIKV RNA levels at day +21 in any of the sites tested,” the authors wrote.

    The team then tested whether the anti-Dengue antibodies could protect fetuses from infection with Zika virus. Female mice were infected with the virus on day six of their pregnancies, and then one day later were treated using either the anti-Dengue EDE1-B10 antibodies or placebo. Whereas 90% of fetuses in placebo-treated animals died within seven days, only 10% of fetuses in antibody-treated mothers died.

    To evaluate the effects of therapy on the extent of Zika virus RNA burden in maternal and fetal tissue, female mice were again infected with Zika virus on pregnancy day 6, and were treated with either antibody or placebo, on day one or day three after infection. By pregnancy day thirteen, mothers that had received antibody therapy 1 day after infection demonstrated 666,000-times lower levels of Zika virus RNA in their placentas than placebo-treated control mice, and the heads of their fetuses had 4,900-fold lower levels of Zika virus RNA than those of controls. In contrast, delaying antibody therapy to 3 days after infection was less effective at reducing viral load. Compared with control animals, Zika virus RNA levels in mothers given antibody therapy were reduced 23-fold in the placenta, and 19-fold in the fetal heads.

    Prior studies have indicated that antibodies generated in response to an initial Dengue virus infection can cause symptoms to be much worse following a second Dengue infection, and may also exacerbate subsequent infection by Zika virus. This effect of cross-reactivity is known as antibody-dependent enhancement (ADE). “As of now, ADE is only known for sure in the context of serial heterologous Dengue infections,” Dr. Diamond noted to GEN. “There is a theoretical concern, based on animal and in vitro studies, that Zika virus antibodies could cross-react and exacerbate Dengue infection, and reciprocally that Dengue virus antibodies could cross-react and worsen Zika virus infection—this has yet to be proven—ongoing human studies are investigating this.”

    With this potential in mind, however, the researchers generated leucine and alanine (LALA) antibody variants, which retained antibody efficacy but would not have the potential to case ADE. “We were surprised how effective the EDE1-B10 variants that lacked Fc effector functions (so called LALA variants) were at controlling Zika infection in the context of pregnancy,” Dr. Diamond stated to GEN. In effect, the new version of the antibody would be therapeutic against both viruses and safe for use in a dengue-endemic area, because it couldn’t worsen the effects of multiple infections. 

    The researchers suggest their studies provide “a first step toward developing a safe and effective therapeutic antibody against both ZIKV and DENV, without the possibility for pathogenic immune enhancement.” However, they acknowledge that we don’t yet know whether the findings in mice will translate to humans. Research in pregnant non-human primates will be needed before human studies could even be considered. “This group of antibodies is unique in being able to target Dengue and Zika,” Dr. Screaton stated. “The next step is to see whether they are effective in larger animal models, and potentially even humans."

    For potential future use in a clinical setting, the aim would be to engineer the antibodies further to increase half life, and administer early in pregnancy, Dr. Diamond explained to GEN. “Thus it may be possible to give one or two doses of this antibody and be protected for the duration of pregnancy, especially in high-risk areas. We are not sure yet of how this would be used in non-pregnant individuals; although it could be administered to males again in high-risk settings, to prevent acquisition of infection and potential sexual transmission.”

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