Gopal Sapparapu, Estefania Fernandez, Nurgun Kose, Bin Cao, Julie M. Fox, Robin G. Bombardi, Haiyan Zhao, Christopher A. Nelson, Aubrey L. Bryan, Trevor Barnes, Edgar Davidson, Indira U. Mysorekar, Daved H. Fremont, Benjamin J. Doranz, Michael S. Diamond, James E. Crowe, Sapparapu, Gopal, Fernandez, Estefania, Kose, Nurgun, Cao, Bin, Fox, Julie M, Bombardi, Robin G, Zhao, Haiyan, Nelson, Christopher A, Bryan, Aubrey L, Barnes, Trevor, Davidson, Edgar, Mysorekar, Indira U, Fremont, Daved H, Doranz, Benjamin J, Diamond, Michael S, Crowe, James E

Zika virus (ZIKV) is an emerging mosquito-transmitted flavivirus that can cause severe disease, including congenital birth defects during pregnancy(1). 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.

Shahzada Khan, Erik M. Woodruff, Martin Trapecar, Krystal A. Fontaine, Ashley Ezaki, Timothy C. Borbet, Melanie Ott, Shomyseh Sanjabi

Understanding the host immune response to vaginal exposure to RNA viruses is required to combat sexual transmission of this class of pathogens. In this study, using lymphocytic choriomeningitis virus (LCMV) and Zika virus (ZIKV) in wild-type mice, we show that these viruses replicate in the vaginal mucosa with minimal induction of antiviral interferon and inflammatory response, causing dampened innate-mediated control of viral replication and a failure to mature local antigen-presenting cells (APCs). Enhancement of innate-mediated inflammation in the vaginal mucosa rescues this phenotype and completely inhibits ZIKV replication. To gain a better understanding of how this dampened innate immune activation in the lower female reproductive tract may also affect adaptive immunity, we modeled CD8 T cell responses using vaginal LCMV infection. We show that the lack of APC maturation in the vaginal mucosa leads to a delay in CD8 T cell activation in the draining lymph node and hinders the timely appearance of effector CD8 T cells in vaginal mucosa, thus further delaying viral control in this tissue. Our study demonstrates that vaginal tissue is exceptionally vulnerable to infection by RNA viruses and provides a conceptual framework for the male to female sexual transmission observed during ZIKV infection.