3.2.1. T cell-mediated responses
Progressive evidences proposed that both antibody and cell-mediated arms of the adaptive immunity are the perquisites to defeat SARS-CoV2 infection (23). Meanwhile, the CD4+ T lymphocytes play determinant roles in affordable antibody response and effective CD8+ T cell cytotoxicity (24). Analysis of peripheral blood T cell populations of recovered individuals from COVID-19 infection showed that all the patients had specific CD4+ T helper (Th) cells for the SARS-CoV2 S protein, while only 70% of blood samples contained the S protein specific CD8+ cytotoxic T cells (16). Preclinical studies indicated that the magnitude of specific T lymphocytes especially in the lung is associated with better prophylaxis of COVID-19 patients (25). Histopathological evidences proposed that respiratory mucosal vaccination induced such lung resident memory T cell responses compare to injectable vaccines and accompanied by reinforced defense against SARS infection (26, 27). The phenotype of Th cells is also affected by the vaccination route, so that severe lung manifestations ensuing SARS-CoV infection were associated with Th2 phenotype dominance in parenterally vaccinated individuals (28, 29), while switching to Th1 responses by mucosal vaccination led to less severe SARS infection (30). So, inducing acceptable Th1 responses particularly in the tissue resident T cell populations should be considered in COVID-19 vaccination. Altogether, it seems that priming T cell-mediated antiviral responses is more reliable than induction of antibody secretion to achieve effective immunization in the elderly, forcefully protect the coverage of T cell response in designing the COVID-19 vaccine (23). On the other hand, some evidences showed that in 35% of healthy individuals with no history of SARS-CoV-2 infection, CD4+ T cells potentially recognized the SARS-CoV2 spike protein. In addition, CD4+ helper T cells are able to identify other SARS-CoV2 proteins in 40 to 60% of people not experience the COVID-19 infection [14, 15]. These findings suggest that there is a cross-activity between SARS-CoV2-specific CD4+ T cells and CD4+ T cells related to other members of human and animal beta coronaviruses [16]. Therefore, in a society, there are different degrees of pre-existing immunity that may explain the range of susceptibility of individuals to COVID-19 infection. Surprisingly, the cross-reactive CD4+ T cells primarily recognize the S2 subunit of the SARS-CoV2 spike protein. Also, CD4+ T cells-derived from COVID-19 patients make vigorous cross-reactivity with S2 domain of the human OC43 and 229E coronaviruses’ spike protein [15]. Since cross-reactive T cells realize both structural and non-structural viral epitopes [15, 17], it is likely that the vastness of induced responses of such cross-reactive T-cells by recombinant protein and viral vector-based vaccines compared to multivalent COVID-19 vaccines are dissimilar. So, the efficacy of killed or even live attenuated COVID-19 vaccine candidates possibly impaired due to the presence of pre-existing cross-reactive immunity. So, in terms of anti-coronavirus cross-reactive immunity, determining the status of participants in clinical trials is imperative.