A Multi-Epitope/CXCL11 Prime/Pull Coronavirus Mucosal Vaccine Boosts the Frequency and the Function of Lung-Resident CD4 ⁺ and CD8 ⁺ Memory T Cells and Protects Against COVID-19-like Symptoms and Death Caused by SARS-CoV-2 infection

The pandemic of the coronavirus disease 2019 (COVID-19) has created the largest global health crisis in almost a century. Following exposure to SARS-CoV-2, the virus particles replicate in the lungs, induce a “cytokine storm” and potentially cause life-threatening inflammatory disease. Low frequencies of function SARS-CoV-2-specific CD4 ⁺ and CD8 ⁺ T cells in the lungs of COVID-19 patients were associated with severe cases of COVID-19. The apparent low level of T cell-attracting CXCL9, CXCL10, and CXCL11 chemokines in infected lungs may not be sufficient enough to assure the sequestration and/or homing of CD4 ⁺ and CD8 ⁺ T cells from the circulation into infected lungs. We hypothesize that a Coronavirus vaccine strategy that boosts the frequencies of functional SARS-CoV-2-specific CD4 ⁺ and CD8 ⁺ T cells in the lungs would lead to better protection against SARS-CoV-2 infection, COVID19-like symptoms, and death. In the present study, we designed and pre-clinically tested the safety, immunogenicity, and protective efficacy of a novel multi-epitope//CXCL11 prime/pull mucosal Coronavirus vaccine. This prime/pull vaccine strategy consists of intranasal delivery of a lung-tropic adeno-associated virus type 9 (AAV-9) vector that incorporates highly conserved human B, CD4 ⁺ CD8 ⁺ cell epitopes of SARS-CoV-2 ( prime ) and pulling the primed B and T cells into the lungs using the T cell attracting chemokine, CXCL-11 ( pull ). We demonstrated that immunization of HLA-DR*0101/HLA-A*0201/hACE2 triple transgenic mice with this multi-epitope//CXCL11 prime/pull Coronavirus mucosal vaccine: ( i ) Increased the frequencies of CD4 ⁺ and CD8 ⁺ T _EM , T _CM , and T _RM cells in the lungs; and ( ii ) reduced COVID19-like symptoms, lowered virus replication, and prevented deaths following challenge with SARS-CoV-2. These findings discuss the importance of bolstering the number and function of lung-resident memory CD4 ⁺ and CD8 ⁺ T cells for better protection against SARS-CoV-2 infection, COVID-19-like symptoms, and death.