Development of a pan-betacoronavirus vaccine

The SARS-CoV-2 pandemic represents an exceptional public health crisis highlighting the need for better understanding of the mechanisms controlling broadly protective immune responses and generating vaccine candidates able to elicit such responses. The program project entitled "Programming Long-lasting Immunity to Coronaviruses (PLUTO)" proposes a comprehensive research plan towards designing pan-sarbecovirus and pan-betacoronavirus vaccines with broad protection by applying in-depth B cell characterization in the context of coronavirus immune histories imprinted by successive vaccinations and/or infections. Two complementary research projects will establish correlates of robust, durable and protective coronavirus humoral immunity (Project 1) as well as design and test efficacy of viral variant-proof pan-sarbecovirus and pan-betacoronavirus vaccines (Project 2). The Cores will synergize with the two research projects to support successful completion of research aims and the long-term goal of the project. The Administrative Core will manage the consortium, coordinate cross-project activities, and create the structure and environment needed to accomplish PLUTO's goals. The Antibody Core will develop a large panel of recombinant monoclonal antibodies against coronavirus spike proteins to aid in defining specificity of immune responses elicited by coronavirus infection and/or vaccination in humans and animal models. The Animal Model Core will provide a central resource with approvals, facilities, and expertise to assess efficacy of broadly cross-reactive coronavirus antibodies and vaccines in robust pre- The Research Projects will collaborate with each other with the support of the services provided by Antibody and Animal Model Cores and overall coordination by the Administrative Core. Project 2 will focus on the development and design of variant-proof pan- sarbecovirus vaccines as well as pan-betacoronavirus vaccines clinical models against a spectrum of coronaviruses, including Select Agents. A multidisciplinary team of scientists from five institutions who have an outstanding track record of working collaboratively will conduct the proposed studies. The integrated and synergistic activities across Projects and Cores will drive successful completion of the program project's ambitious research agenda, enabling achievement of the long-term PLUTO goal of developing viral variant- proof pan-sarbecovirus and pan-betacoronavirus vaccines. These findings will contribute to curbing the current SARS-CoV-2 pandemic and help to mitigate the risk of future pandemics with coronaviruses.