Characterization of cross-reactive immunity following coronavirus vaccination or natural infection

Abstract

Abstract SARS-CoV-2 has infected more than 100 million people worldwide. Several vaccine candidates have been deployed under emergency use authorization, but it is unclear whether a coronavirus (CoV) vaccine can protect against other CoV. To investigate this proof-of-concept, we evaluated cross-reactive immunity following vaccination with a modified vaccinia Ankara expressing SARS-CoV-1 spike protein. We first vaccinated C57BL/6 mice intramuscularly and then measured heterologous antibodies (SARS-CoV-2, OC43 and mouse hepatitis virus, MHV) by ELISA. Interestingly, the SARS-CoV-1 vaccine elicited cross-reactive antibodies that recognize these other CoV. Sera from mice immunized with the SARS-CoV-1 vaccine neutralized SARS-CoV-2 pseudovirus in vitro (5-fold greater than control naïve sera; p=0.007), and transfer of these immune sera into naïve mice provided partial protection after heterologous challenges. Similar cross-reactivity was observed following immunization with a SARS-CoV-2 vaccine, and we mapped a conserved CD8 T cell epitope in both SARS-CoV-1 and CoV-2 spike protein, allowing us to develop an MHC tetramer to track this cross-reactive response. Finally, we interrogated whether a CoV infection could elicit cross-reactive immunity. We show that an OC43 infection generated cross-reactive antibodies against SARS-CoV-2, OC43 and MHV, and conferred partial protection against MHV challenge. In summary, our findings demonstrate that cross-reactive immunity can be elicited by vaccination, providing a framework for the rational design of universal CoV vaccines. Moreover, these data suggest that prior infection with endemic CoV may provide partial protection against other CoVs.