Vaccines and therapeutic antibodies to respiro, rubula, peribunya and phenuiviridae (R2P2)-revampp

The federal Cooperative Agreement award U19AI181984, totaling $44,108,652.00, was granted by the National Institute of Allergy and Infectious Diseases (NIAID) under the Allergy and Infectious Diseases Research program (CFDA 93.855). The purpose of this 3-year award is to develop vaccines and antibody-based treatments for viruses in the Paramyxoviridae, Peribunyaviridae, and Phleboviridae families, with a focus on prototype viruses such as human parainfluenza virus 3 (HPIV3), Oropouche virus (OROV), and Rift Valley fever virus (RVFV).

The R2P2-REVAMPP Center established under this award involves a collaborative team of researchers from institutions including The Washington University, Charité - Universitätsmedizin Berlin, Fondazione Biotecnopolo DI Siena, University of Pittsburgh, Columbia University, and others. Through parallel projects, the center aims to define structure-function relationships of viral glycoproteins, identify monoclonal antibodies with high barriers to resistance, and evaluate the comparative efficacy of different vaccine platforms against the prototype viruses. The sub-awardees are contributing expertise in areas like viral entry mechanisms, antibody isolation, immunogenicity assessments, and animal model studies to support the development of these medical countermeasures.

Abstract

The vaccines and therapeutic antibodies to respirovirus, rubulavirus, peribunyavirus and phenuivirus (R2P2) revampp center will utilize both well-defined and novel approaches to develop prototype vaccines and human monoclonal antibody (MAB)-based treatments for rapid response to viruses from the paramyxoviridae, peribunyaviridae and phleboviridae families. R2P2 is composed of four primary research projects: two that collectively focus on prototype viruses of the paramyxoviridae family including human parainfluenza viruses 3 and 1 (HPIV3, HPIV1), and human and BAT mumps virus (MUV, batmuv); and two that focus on prototype viruses of the bunyavirales order including the peribunyaviridae oropouche (orov) and LA crosse (lacv) and the phenuiviridae rift valley fever virus (rvfv) and toscana virus (tosv). Each project in R2P2 follows a parallel structure and makes use of the principles of reverse vaccinology, where insights from the structural and function studies will provide a framework to understand the molecular correlates of immunity and antigenicity and provide a roadmap for designing optimized immunogens. The foundational studies carried out in this revampp center will fill gaps in basic understanding of viral entry and will also inform how to extend the stabilization approaches successfully used to advance vaccines against agents with class i fusogens (e.g., RSV), to those with class II. A key R2P2 feature is that all four projects compare the same three vaccine platforms: protein subunit, mrna, and chimeric VSV, allowing for cross comparisons that will rapidly yield information about platform performance in translating to related pathogens. The questions of which antigen stabilization paradigms, and which vaccine platforms are most amenable to generalizing from the prototype pathogens will be answered in depth and breadth by these comparisons across virus families. We assembled a collaborative team of world-renowned experts on viral envelope protein structure and function, leading immunologists, vaccinologists with extensive experience in industry and regulatory issues, and industry partners (e.g., modena, GSK). The inclusion of junior investigators with exceptional promise is designed to ensure the engagement of the next generation of leaders in viral glycoprotein biology, viral immunology and vaccinology in pandemic preparedness. These projects are served by an administrative core (core a), a data management core (core b), and three scientific cores that perform structural biology, biophysics and protein engineering (core c), antibody isolation and assessment (core d), and correlates of immune protection (core e) experiments in collaboration with multiple projects. The knowledge accumulated in this project and the robustness of the approaches implemented to develop prototype vaccines will be expanded to different viruses of the same families to evaluate their potential and broad applicability against emerging viruses of the bunyavirales order and paramyxoviridae family.