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Antibody protects developing fetus from Zika virus

The most devastating consequence of Zika virus is the development of microcephaly, an abnormally small head, in babies infected in utero. Now, research has identified a human antibody preventing pregnant mice, from infecting the fetus with Zika and damaging the placenta. It also protects adult mice from the Zika disease.

The study is published Nov. 7 in Nature, as a fast-track advance online publication.

"This is the first antiviral that has been shown to work in pregnancy to protect developing fetuses from Zika virus. This is proof of principle that Zika virus during pregnancy is treatable, and we already have a human antibody that treats it, at least in mice."

Michael Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine Department of Pathology & Immunology, Department of Molecular Microbiology, Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St Louis, MO, USA and co-senior author of the study.

Diamond and co-senior author James Crowe Jr MD, of Vanderbilt University, along with colleagues screened 29 anti-Zika antibodies from people who had recovered from a Zika infection.

They found ZIKV-117, efficiently neutralized five Zika strains in the lab - representing the worldwide diversity of the virus to date.

To test whether the antibody also protects living animals, researchers gave the antibody to pregnant mice one day before or one day after they were infected with ZIKV-117. In either case, the antibody markedly reduced the levels of virus in pregnant females and their fetuses — as well as in their placentas — compared with pregnant mice that did not get the antibody.

"These naturally occurring antibodies isolated from humans represent the first medical intervention that prevents Zika infection and damage to fetuses."

James Crowe Jr MD, Department of Pediatrics, Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA and co-senior author of the study.

The placentas from the treated females appeared normal and healthy, unlike those from the untreated females, which showed destruction of the placental structure. Damage to the placenta can cause slow fetal growth and even can cause fetal death, both outcomes associated with Zika infection in humans.

"We did not see any damage to fetal blood vessels, thinning of the placenta, or growth restriction in the fetuses of antibody-treated mice. Anti-Zika antibodies are able to keep the fetus safe from harm by blocking the virus from crossing the placenta."

Indira Mysorekar PhD, Associate Professor, Obstetrics and Gynecology, Pathology and Immunology, Washington University, co-author and co-director, University Center for Reproductive Sciences.

The antibody also protected adult male mice against a lethal dose of Zika virus, even given five days after initial infection. Zika is rarely lethal in humans, so using a lethal dose allowed scientists to see how well the antibody behaved under the most stringent conditions. "We stacked the deck against ourselves by using a highly pathogenic strain of Zika, and even in that case, the antibody protected the mice," added Diamond.

The findings provide evidence that antibodies alone can protect adult and fetus from Zika. Furthermore, they suggest a vaccine can elicit protective antibodies in women, while also protecting her current and future pregnancies. Already in human trials, the vaccine was never tested in pregnant animals. But, this study presents strong evidence vaccine antibodies protect an adult and likely protect the fetus as well.

Although vaccine is likely the cheapest and simplest method for preventing Zika-related birth defects, an outside possibility exists such a vaccine could also worsen symptoms in people who get a second viral exposure. This occurs with dengue virus, a close relative of Zika. People who have antibodies against one strain of dengue get sicker when infected with a second strain — than people who do not have such antibodies. The phenomenon is known as antibody-dependent enhancement. Observed with Zika in a petri dish, it has never been introduced to living animals or in epidemiologic surveys of people in Zika-endemic regions.

So, researchers tested if they could eliminate the possibility of antibody-dependent enhancement in ZIKV-117 by modifying the antibody so it could not participate in the process. This revealed that a modified antibody was just as effective as the original in protecting the placenta and fetus.

Until a human vaccine is available, it may be possible to protect the fetus by administering antibodies to pregnant women to prevent transmission of the virus from mother to fetus. In this scenario, a woman living in a Zika-endemic area would receive ZIKV-117 antibodies throughout her pregnancy, starting when she first learns she is pregnant, regardless of whether she is diagnosed with Zika. Alternatively, pregnant women or their partners with acute infection could also be treated with antibodies.

Crowe is continuing the process of developing the ZIKV-117 antibody as a potential therapeutic, ramping up its production and laying the groundwork for human studies. Meanwhile, Diamond is focusing on determining whether ZIKV-117 antibodies could be used to clear persistent Zika infection. Together, they are working with others to gain a higher-resolution understanding of how ZIKV-117 binds the virus and inhibits infection.

Diamond adds: "We know that Zika can persist in certain parts of the body, such as the eyes and the testes, where it can cause long-term damage, at least in mice. We showed that the antibody can prevent disease, and now we want to know whether it can clear persistent infection from those parts of the body."

Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that can cause severe disease, including congenital birth defects during pregnancy1. To develop candidate therapeutic agents against ZIKV, we isolated a panel of human monoclonal antibodies (mAbs) from subjects with prior ZIKV infection. A subset of mAbs recognized diverse epitopes on the envelope (E) protein and exhibited potently neutralizing activity. One of the most inhibitory mAbs, ZIKV-117, broadly neutralized infection of ZIKV strains corresponding to African, Asian, and American lineages. Epitope mapping studies revealed that ZIKV-117 recognized a unique quaternary epitope on the E protein dimer–dimer interface. We evaluated the therapeutic efficacy of ZIKV-117 in pregnant and non-pregnant mice. mAb treatment markedly reduced tissue pathology, placental and fetal infection, and mortality in mice. Thus, neutralizing human mAbs can protect against maternal–fetal transmission, infection and disease, and reveal important determinants for structure-based rational vaccine design efforts.

Subject terms: virology; antibodies

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Nov 10, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Tray of Zika virus growing in animal cells. No treatment is available to block Zika virus in a pregnant
woman from infecting her fetus and potentially causing severe birth defects.  But researchers have
identified a human antibody that prevents pregnant mice, from infecting the fetus and keeps the placenta
from being damaged. The antibody also protects adult mice from Zika disease.

Image Credit:
Washington University School of Medicine in St. Louis


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