ABSTRACT The current COVID-19 pandemic is a global health emergency, causing severe respiratory disease requiring hospitalization and even death in a significant proportion of the human population. Although therapeutic intervention including novel pharmaceuticals or the passive transfer of immune serum from recovered patients could provide short-term relief in mortality and morbidity, the development of a successful vaccine will ultimately be required to prevent the continued spread and seasonal recurrence of this disease within the human population. However, very little is known about either the quality of adaptive immune response or the viral antigen targets that are necessary to prevent the infection. Here we propose to evaluate a novel vaccination approach recently developed in my laboratory that we will now apply to SARS-CoV-2. Specifically, we will generate Vaccinia virus (VacV) vectors expressing the SARS-CoV-2 Spike (S) protein that have been engineered to targeted the S protein for MHC-II presentation. Overall, this study will evaluate whether VacV expressing SARS-CoV-2 S protein could be a potential vaccine candidate and whether the “immunogenicity” of the S protein can be enhanced by targeting the protein for MHC-II presentation.