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Mouse antibodies pinpoint Zika's weak spots

Cell Press

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IMAGE: This image shows the mapping of the three distinct Zika virus DIII epitopes onto the mature virion. view more

Credit: Daved Fremont/Cell 2016

Antibodies that specifically protect against Zika infection have been identified in mice, report Washington University School of Medicine in St. Louis researchers on July 27 in Cell. This is the second publication in recent weeks (another paper showing human Zika antibodies appeared in Science on July 14, DOI: 10.1126/science.aaf8505) that explores the surfaces that the antibodies target on the virus. The information will help inform the development of vaccines, diagnostics, and antibody-based prophylactic and therapeutic agents.

"Using biophysical methods, we characterized a panel of Zika-specific antibodies and developed a correlation between the precise epitopes that are recognized and protection against the virus," says immunologist Daved Fremont, co-senior author on the paper. "We found that our most protective antibodies bind the same region of the Zika virus that we and others have revealed for Dengue and West Nile, hinting that the humoral immune response targets genetically distinct, but structurally similar regions across this family of viruses."

"We now have two groups that have come out with papers showing that antibodies that specifically recognize Zika virus can protect against infection in vivo," says infectious disease researcher Michael Diamond, the other co-author on the paper. "This is the first step toward optimizing current vaccine strategies and potentially developing antibody-based therapeutics as well as augmenting efforts for generating diagnostics that would specifically differentiate Zika viruses from other related flaviviruses."

Antibody tests for Zika can be unreliable because some Zika antibodies can cross-react with other flaviviruses, such as Dengue virus and West Nile virus. Laboratories must use more expensive nucleic-acid-based tests, which look for the presence of viral particles, in order to confirm Zika infection.

Fremont and Diamond's laboratory identified antibodies by infecting mice engineered to be susceptible to Zika (DOI: 10.1016/j.chom.2016.03.010) with the virus and collecting their antibody-producing B cells. The researchers then screened the antibodies against Zika surface proteins. Six candidate antibodies were found, and from these, four were able to effectively prevent or treat Zika infection in cells and in mice. Haiyan Zhao, first author and a postdoctoral researcher in Fremont's laboratory, took the lead on using X-ray crystallography to visualize the viral epitopes as well as undertook binding assays to characterize the antibodies.

"The other two families of epitopes that we uncovered in this study, cryo-electron microscopy models of the mature virus would tell you are never exposed to antibodies, so we call these cryptic epitopes," says Fremont, who has been collaborating with Diamond on flavivirus research since 2003. "These results shed light on some of the gymnastics that Zika viral particles probably go through during infection." Dengue virus is also known to have these unexplained cryptic epitopes.

The researchers next want to identify at which stages of pregnancy the Zika antibodies have the most protective effects against the virus. Although the antibodies were identified in mice, they can be humanized without much difficulty, they say. In Science on July 14, Davide Corti of Humabs BioMed SA and Federica Sallusto of the Institute for Research in Biomedicine in Bellinzona, Switzerland reported producing fully human antibodies that could neutralize the Zika virus in mouse models, work Diamond says is quite complementary to findings in the Cell paper.

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This work was supported by grants from the National Institutes of Health and the Center for Structural Genomics of Infectious Diseases. Michael Diamond is a consultant for Inbios, Visterra, Sanofi, and Takeda Pharmaceuticals, is on the Scientific Advisory Boards of Moderna and OraGene, and is a recipient of research grants from Moderna, Sanofi, and Visterra.

Cell, Zhao and Fernandez et al.: "Structural basis of Zika virus specific antibody protection" http://www.cell.com/cell/fulltext/S0092-8674(16)30927-8

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