SARS-CoV-2, the virus that causes COVID-19, represents the third coronavirus to emerge as a global health threat in the past two decades, along with SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). With the expanding number of coronaviruses being discovered in reservoirs, emergence of novel coronaviruses into humans is imminent. Thus, coronaviruses that are closely related to MERS-CoV are still a pandemic threat. To that end, we are exploring the antigenic landscape of vaccine-induced immunity to MERS-CoV spike protein by defining mechanisms of action and protective capacity of B-cell and antibody responses that target non-classical areas of the spike protein. The goal is to understand which areas of the MERS-CoV spike protein are most optimal for eliciting robust, broad, and long-lasting immune responses. This research will lead to next-generation MERS-CoV vaccine designs that can be deployed shall a MERS-like outbreak occur.

There were four human coronaviruses, HKU1, 229E, NL63, and OC43, that circulate endemically causing relatively mild respiratory disease. During any given “flu season,” endemic human coronaviruses are responsible for up to 30% of common colds. The juxtaposition with SARS-CoV-2 as the fifth endemic coronavirus raises questions about endemic coronaviruses that were previously understudied. Pandemic preparedness led to the rapid development of highly effective COVID vaccines, and while we continue our pandemic preparedness work, we also explore the antigenic landscape of endemic coronaviruses towards “endemic preparedness.” We are dissecting the antigenic landscape of endemic coronaviruses by identifying and characterizing functional receptors, co-receptors, and attachment factors, deciphering the influence of immune responses on the clinical outcome following natural viral infection, isolating and characterizing monoclonal antibodies against endemic coronaviruses, and designing and evaluating vaccines that encompass endemic coronavirus antigens. 

Universal coronavirus vaccines must be developed to protect against multiple coronavirus types. We are taking two simultaneous vaccine approaches to elicit broader immune responses. Firstly, as we determine which areas of coronaviruses spike proteins are most cross-reactive, we design spike-based vaccine antigens to target those areas. Secondly, we engineer nanoparticles to display multiple vaccine antigens. Nanoparticles enhance immune responses, facilitate optimal spatial organization for B-cell engagement, and allow for the display of different antigens in one vaccine. Following in vitro antigenic characterization, we evaluate our vaccines in mouse models to assess immune responses. Beyond use as vaccines, we use our rationally designed antigens and nanoparticles as tools for dissecting coronavirus immune responses and isolating novel monoclonal antibodies. Together, this work fuels our understanding of coronavirus viral immunology in a cycle that continuously produces new and improved vaccine concepts.