Consortium for Immunotherapeutics against Emerging Viral Threats

Abstract SARS-CoV-2 rapidly emerged and spread throughout the globe to infect millions of people. The SARS-CoV-2 spike protein is the primary target of the immune response and thus most vaccine development efforts used the spike protein as an immunogen to elicit protective antibodies. However, as SARS-CoV-2 infections surged in multiple waves, viruses bearing mutations in spike protein emerged, which rendered vaccines that were developed based on initial sequences of the spike protein less effective. The persistence of these variants and the likely inevitable development of new variants requires continued efforts to develop novel immunogens based on SARS-CoV-2 spike that can elicit durable protection that remains effective in the face of new mutations. The Coronavirus Immunotherapeutics Consortium (CoVIC) has gathered hundreds of monoclonal antibodies from researchers around the world and is undertaking a broad, deep and multidisciplinary analysis of the binding sites of these antibodies to understand which epitopes on spike are associated with protection. We will examine at an atomic level the binding footprint of protective antibodies and assess whether certain epitopes are more resistant to the effects of spike mutations. We will also test a novel mouse model of SARS-CoV-2 infection that involves mice with triple knockin of human ACE2, TMPRSS2, and FcRN. These mice may better recapitulate the mechanism of infection and pharmacokinetics of protective antibodies elicited in response to vaccination. We will use these mice to examine the protective capacity of antibodies in longitudinal samples from individuals who received currently available vaccines. Given the critical role of data sharing and dissemination for rapid responses to emerging mutations and to maximize use of the information generated in this proposal by the broader scientific community, we are building the CoVIC database, termed CoVIC-DB, which allows real-time dissemination and analysis of information on this array of protective antibodies. CoVIC-DB is an open, web-accessible database that will serve as a long-term resource to understand key properties of antibodies against SARS-CoV-2 spike protein.