Replication-Competent Vesicular Stomatitis Virus Vaccine Vector Protects against SARS-CoV-2-Mediated Pathogenesis in Mice

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of human infections, and an effective vaccine is critical to mitigate coronavirus-induced disease 2019 (COVID-19). Previously, we developed a replication-competent vesicular stomatitis virus (VSV) expressing a modified form of the SARS-CoV-2 spike gene in place of the native glycoprotein gene (VSV-eGFP-SARS-CoV-2). Here, we show that vaccination with VSV-eGFP-SARS-CoV-2 generates neutralizing immune responses and protects mice from SARS-CoV-2. Immunization of mice with VSV-eGFP-SARS-CoV-2 elicits high antibody titers that neutralize SARS-CoV-2 and target the receptor binding domain that engages human angiotensin-converting enzyme-2 (ACE2). Upon challenge with a human isolate of SARS-CoV-2, mice that expressed human ACE2 and were immunized with VSV-eGFP-SARS-CoV-2 show profoundly reduced viral infection and inflammation in the lung, indicating protection against pneumonia. Passive transfer of sera from VSV-eGFP-SARS-CoV-2-immunized animals also protects naive mice from SARS-CoV-2 challenge. These data support development of VSV-SARS-CoV-2 as an attenuated, replication-competent vaccine against SARS-CoV-2. Graphical Abstract Highlights • A replicating VSV-SARS-CoV-2 vaccine induces high-titer neutralizing antibodies • Infectious SARS-CoV-2 is undetectable in the lung of vaccinated mice post-challenge • SARS-CoV-2-induced lung inflammation and pathology is decreased in vaccinated mice • Transfer of vaccine-derived immune sera to naive mice protects against SARS-CoV-2 Case, Rothlauf et al. report the efficacy of a replicating VSV-based SARS-CoV-2 vaccine. Immunized hACE2-expressing mice challenged with SARS-CoV-2 are protected against lung infection, inflammation, and pneumonia. Neutralizing antibodies are a correlate of this protection, as passive transfer of vaccine-derived immune sera protects naive mice from subsequent SARS-CoV-2 challenge.