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Principal Investigator: Amy L Hartman
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $5,220,489
Funding agency: National Institute of Allergy and Infectious Diseases
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.
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