An immunocompetent pregnant mouse model of Zika virus infection for development of vaccines that minimize antibody-dependent enhancement of pathogenesis 3179

Abstract Description Development of a Zika virus (ZIKV) vaccine that confers maternal and fetal protection without mediating antibody (Ab)-dependent enhancement of pathogenesis, a process promoted by cells bearing Fcγ receptors such as macrophages, is a global health priority. Yet, fundamental mechanisms of the immune response to ZIKV during pregnancy are still poorly understood, in part due to the lack of a robust immunocompetent small animal model. The ZIKV field remains reliant on C57BL/6 mice defective in their type I interferon (IFN-I) response to permit infection and induce gestational pathology, although the IFN-I system may mediate fetal demise during viral infections and alter both Ab and T cell responses. We thus developed an immunocompetent mouse model using a C3H/He x DBA/2 cross that permits increased fetal infection and damage over C57BL/6 syngeneic pregnancies. We validated the model’s relevance in vaccine research by showing that a ZIKV mRNA vaccine provides complete short-term fetal protection. Immunofluorescence staining has shown the contribution of border-associated macrophages and microglia to fetal brain infection in this model, and we expect ongoing spatial transcriptomics analysis of the maternal-fetal interface (MFI) to reveal key aspects of the macrophage response. This provides the field with an urgently needed immunocompetent mouse model and sets the stage for understanding vaccine-elicited immune mechanisms at the MFI that influence the outcome of ZIKV infection. Funding Sources Supported by NIH R01AI153500, R01AI163188, and R01AI180196, Conrad Prebys Foundation, LJI-Kyowa Kirin Interactive Fund, NUS Development Grant. Topic Categories Mucosal and Regional Immunology (MUC)