Modified Vaccinia Ankara Vector-Based Vaccine Protects Macaques from SARS-CoV-2 Infection, Immune Pathology and Dysfunction in the Lung

Routhu, Nanda Kishore; Cheedarla, Narayanaiah; Gangadhara, Sailaja; Bollimpelli, Venkata Satish; Boddapati, Arun Kumar; Shiferaw, Ayalnesh; Rahman, Sheikh Abdul; Sahoo, Anusmita; Edara, Venkata; Lai, Lilin; Floyd, Katharine; Wang, Shelly; Fischinger, Stephanie; Atyeo, Caroline; Shin, Sally A.; Gumber, Sanjeev; Kirejczyk, Shannon; Cohen, Joyce; Jean, Sherrie M.; Wood, Jennifer S.; Connor-Stroud, Fawn; Stammen, Rachelle L.; Upadhyay, Amit A.; Pellegrini, Kathryn; Montefiori, David; Shi, Pei-Yong; Menachery, Vineet D.; Alter, Galit; Vanderford, Thomas H.; Bosinger, Steven E.; Suthar, Mehul S.; Amara, Rama Rao

A combination of vaccination approaches will likely be necessary to fully control the SARS-CoV-2 pandemic. Here, we show that modified vaccinia Ankara (MVA) vectors expressing membrane anchored pre-fusion stabilized spike (MVA/S), but not secreted S1, induced strong neutralizing antibody responses against SARS-CoV-2 in mice. In macaques, the MVA/S vaccination induced strong neutralizing antibodies and CD8+ T cell responses, and showed protection from SARS-CoV-2 infection and virus replication in the lung as early as day 2 following intranasal or intratracheal challenge. Single-cell RNA sequencing analysis of lung cells at day 4 post-infection revealed that MVA/S vaccination also protected macaques from infection-induced inflammation and B cell abnormalities, and lowered induction of interferon stimulated genes. These results demonstrate that MVA/S vaccination induces both neutralizing antibodies and CD8+ T cells in the blood and lung and serves as a potential vaccine candidate against SARS-CoV-2.