The overall goal of this proposal is to develop effective prophylactic vaccines against the novel SARS Coronavirus-2 (SARS-CoV-2) infection that has recently emerged as a pandemic across the world. The SARS-CoV-2 has already infected more than 120,000 people and over 4000 people died due to COVID-19, a disease caused by SARS-CoV-2. Thus, there is an urgent need for the development of a vaccine that can rapidly induce anti-viral immunity and prevent infection. Previous data from other related coronavirus infections such as SARS-CoV and MERS-CoV demonstrate that a strong neutralizing antibody response against the spike protein can effectively prevent infection. Thus, a primary goal of this proposal is to develop a modified vaccinia Ankara (MVA) based vaccine that expresses SARS-CoV-2 spike protein to generate a rapid and strong neutralizing antibody response both in systemic and mucosal compartments. There are several advantages to MVA based vaccines that include their excellent safety and a single dose of MVA vaccination can provide protection against multiple virus infections including SARS-CoV, MERS, Zika and Ebola viruse. A novel aspect of this proposal is that we will compare the immunogenicity and protective ability of different forms of the spike protein with a goal of inducing neutralizing antibodies against both SARS-CoV-2 and SARS-CoV. This proposal has two specific aims. The goal of Aim 1 is to generate MVA vaccines and characterizing the anti-spike antibody response in mice. We will also compare parenteral (i.m.) vs mucosal (intranasal) vaccinations to determine the best route for inducing mucosal antibody response. The goal of Aim 2 is to evaluate the protective efficacy of the MVA-based SARS-CoV-2 vaccines. There is an urgent and unmet need to develop and characterize small animal models for evaluating vaccine efficacy against SARS-CoV2. Mice have served as an excellent model system to not only understand immunity to the related SARS virus but also for evaluating vaccines and antiviral therapeutics. In this Aim, we will develop and characterize a mouse model of SARS-CoV2 infection and use this model to test the protective efficacy of our MVA-based vaccine candidates. The completion of these studies will not only provide a mouse model for SARS-CoV2 infection but also develop vaccine candidates against SARS-CoV2.