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

Abstract

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+ TEM, TCM, and TRM 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.

A Broad-Spectrum Multi-Antigen mRNA/LNP-Based Pan-Coronavirus Vaccine Induced Potent Cross-Protective Immunity Against Infection and Disease Caused by Highly Pathogenic and Heavily Spike-Mutated SARS-CoV-2 Variants of Concern in the Syrian Hamster Model

“…A detailed comparison of the early innate immunity events that occur after administration of the combined mRNA/LNP vaccine vs. the Spikealone mRNA/LNP vaccine would help elucidate the underlying mechanism behind the strong protective immunity induced by the combined mRNA/LNP vaccine.The antiviral B and T cell immune mechanisms reported in this study, are expected to inform the design of next-generation broad-spectrum pan-Coronavirus vaccines1,4,5,6,19 . The present results from the hamster model confirm our and others recent reports in mouse models that increased frequencies of lung-resident IFN-γ + TNF-α + CD4 + and IFN-γ + TNF-α + CD8 + T EFF cells specific to common antigens protected against multiple SARS-CoV-2 VOCs1,3,27 . Interferons restrict SARS-CoV-2 infection in human airway epithelial cells2,62 .…”

“…The Coronavirus disease 2019 (COVID-19) pandemic has created one of the largest global health crises in nearly a century 1,2,3,4,5,6 . As of January 2024, the number of confirmed SARS-CoV-2 cases has reached over 770 million, and COVID-19 disease caused nearly 7 million deaths 1,5,6 .…”

“…Recently, our group and others have: (i) Identified specific sets of highly conserved SARS-CoV-2 non-Spike antigens targeted by frequent cross-reactive functional CD4 + and CD8 + T cells from asymptomatic COVID-19 patients (i.e., unvaccinated individuals who never develop any COVID-19 symptoms despite being infected with SARS-CoV-2) 3,5,20,21,22,23,24,25,26 ; (ii) Discovered that increased frequencies of lung-resident CD4 + and CD8 + T cells specific to common antigens protected against multiple SARS-CoV-2 VOCs in mouse models 1,3,27 ; and (iii) Demonstrated that enriched cross-reactive lung-resident memory CD4 + and CD8 + T cells that selectively target earlytranscribed SARS-CoV-2 antigens, from the replication and transcription complex (RTC) region, are associated with a rapid clearance of infection in so-called "SARS-CoV-2 aborters" (i.e., unvaccinated SARS-CoV-2 exposed seronegative individuals who rapidly abort the virus replication) 28,29,30,31,32 .…”

Comparative antibody and cell-mediated immune responses, reactogenicity, and efficacy of homologous and heterologous boosting with CoronaVac and BNT162b2 (Cobovax): an open-label, randomised trial

“…This finding is biologically plausible—antibody alone might not explain the protection provided by inactivated vaccines, as T-cell responses and potentially non-neutralising antibodies to internal virus genes, such as the nucleocapsid, 15 might also play a role, especially against strains such as omicron, which have high escape rate from neutralising antibody elicited by the ancestral virus. For T-cell response, previous studies using vaccinated transgenic mice with humanised ACE2 receptor showed that CD4 + and CD8 + T cells protected against severe disease by ancestral strain 16 and CD4 + T cells conferred heterologous protection against the beta variant, 17 and experiments using human samples suggested T-cell cross-reactivity against omicron. 18 , 19 Our study provides a head-to-head comparison of T-cell response between homologous and heterologous vaccination, and shows that both homologous and heterologous third doses could boost T-cell responses in people with two previous doses of CoronaVac.…”