MVA-CoV2-S vaccine candidate confers full protection from SARS-CoV-2 brain infection and damage in susceptible transgenic mice

The protective efficacy of vaccines against SARS-CoV-2 infection in the brain is yet unclear. Here, in the susceptible transgenic K18-hACE2 mouse model of severe COVID-19 disease, we report a detailed spatiotemporal description of the SARS-CoV-2 infection and replication in different areas of the brain. Remarkably, SARS-CoV-2 brain replication occurs primarily in neurons, producing important neuropathological alterations such as neuronal loss, incipient signs of neuroinflammation, and vascular damage in SARS-CoV-2 infected mice. Notably, one or two doses of a modified vaccinia virus Ankara (MVA) vector expressing the SARS-CoV-2 spike (S) protein (MVA-CoV2-S) conferred full protection against SARS-CoV-2 cerebral infection, preventing virus replication in all areas of the brain and its associated damage. This protection was maintained even after SARS-CoV-2 reinfection. To our knowledge, this is the first study of a COVID-19 vaccine candidate showing 100% efficacy against SARS-CoV-2 brain infection and damage, reinforcing the use of MVA-CoV2-S as a promising vaccine candidate against SARS-CoV-2/COVID-19, worth to move forward into clinical trials.The authors thank the Centro de Investigación en Sanidad Animal (CISA)-Instituto Nacional de Investigaciones Agrarias (INIA-CSIC) (Valdeolmos, Madrid, Spain) for the BSL-3 facilities. SARS-CoV-2 MAD6 virus isolate was kindly provided by José M. Honrubia and Dr. Luis Enjuanes (CNB-CSIC, Madrid, Spain). We also thank to Dr. Konstantin L. Levitsky for excellent technical assistance with the confocal acquisition. We thank the Spanish Research Council (CSIC) and the Spanish Ministry of Science and Innovation (MICINN) for continuous support. This research was supported by MCIN/Spanish Research Agency (AEI)/ 10.13039/501100011033 grants: PID2019-105995RB-I00 (J.T.-A. and J.V.), PID2020- 114481RB-I00 (J.G.-A. and M.E.), and PID2019-106410RB-I00 (J.L.-B.). Moreover, this research work was also funded by Red TerCel ISCIII, RD16/0011/0025 (J.T.-A.); Consejería de Salud y Familias, Junta de Andalucía Grant, PECOVID-0078-2020 (R.R.-L. and J.V.); Fondo COVID-19 grant COV20/00151 [Spanish Health Ministry, Instituto de Salud Carlos III (ISCIII)], Fondo Supera COVID-19 (Crue Universidades-Banco Santander) grant and CSIC grant 202120E079 (J.G.-A.); and CSIC grant 2020E84, La CaixaImpulse grant CF01-00008, Ferrovial and MAPFRE donations (M.E.). Additionally, we have also funding from the European Commission-NextGenerationEU, through CSIC's Global Health Platform (PTI Salud Global) (J.G.-A. and M.E.) and the European Research Council (ERC Advanced Grant PRJ201502629) (J.L.-B.).N