Design and development of generalizable countermeasures against prototype Phenuiviruses

PROJECT SUMMARY/ABSTRACT Prototype pathogens are those that, if well-characterized, can be used to develop generalizable medical countermeasures (MCMs) against new or unknown but related viruses. In 2021, NIAID convened a panel of subject matter experts to delineate prototype pathogens across several viral families. Rift Valley fever virus (RVFV), Toscana virus (TOSV), and Severe fever with thrombocytopenia syndrome virus (SFTSV) were named key prototype pathogens for the Phenuiviridae family. Whether generalizable vaccine approaches will work for virus families such as Phenuiviridae is unknown. The goal of P4-Phenuiviridae is to study two prototype phenuiviruses in parallel - RVFV and TOSV - using similar systems and approaches, draw conclusions on what is and is unable to be generalized between the two viruses, and extend our observations into a more distantly related phenuivirus (SFTSV). A major gap in the field, which hampers generalizable vaccine development, is a lack of knowledge of commonalities in viral glycoprotein Gn/Gc structure and function across members of the family and the therapeutic potential of targeting common epitopes within the viral glycoproteins. As part of this U19, we assembled a unique team with extensive experience in RVFV, TOSV, structural biology, biochemistry, vaccine development, and mAb identification to significantly enhance NIAID's prototype portfolio. We will use parallel approaches to understand the basic biology of RVFV and TOSV Gn/Gc structure and function, and to identify commonalities and differences to inform immunogenicity, mAb identification, and vaccinology. Our Aims are: 1) Understand Gn/Gc structure and function to inform stabilized immunogen design; 2) Reverse design of Phenuivirus Gn/Gc antigens through mAb isolation and epitope mapping; and 3) Compare efficacy of mRNA, stabilized glycoprotein, and VSV-based vaccines across prototype Phenuiviruses. We will accomplish these aims by working in synergy with the Cores and other Projects within this Center. Our deliverables will be a generalizable approach for vaccine and therapeutic antibody development for Phenuiviruses. By studying both RVFV and TOSV in parallel, we have the unique ability to curate a more solidly generalizable platform and propel the field forward in ways previously not feasible.