text: Degenerate CD8 Epitopes Mapping to Structurally Constrained Regions of the Spike Protein A T Cell Based Way Out From the SARS CoV 2 Variants Storm There is an urgent need for new generation anti SARS Cov 2 vaccines in order to increase the efficacy of immunization and its broadness of protection against viral variants that are continuously arising and spreading The effect of variants on protective immunity afforded by vaccination has been mostly analyzed with regard to B cell responses This analysis revealed variable levels of cross neutralization capacity for presently available SARS Cov 2 vaccines Despite the dampened immune responses documented for some SARS Cov 2 mutations available vaccines appear to maintain an overall satisfactory protective activity against most variants of concern VoC This may be attributed at least in part to cell mediated immunity Indeed the widely multi specific nature of CD8 T cell responses should allow to avoid VoC mediated viral escape because mutational inactivation of a given CD8 T cell epitope is expected to be compensated by the persistent responses directed against unchanged co existing CD8 epitopes This is particularly relevant because some immunodominant CD8 T cell epitopes are located within highly conserved SARS Cov 2 regions that cannot mutate without impairing SARS Cov 2 functionality Importantly some of these conserved epitopes are degenerate meaning that they are able to associate with different HLA class I molecules and to be simultaneously presented to CD8 T cell populations of different HLA restriction Based on these concepts vaccination strategies aimed at potentiating the stimulatory effect on SARS Cov 2 specific CD8 T cells should greatly enhance the efficacy of immunization against SARS Cov 2 variants Our review recollects discusses and puts into a translational perspective all available experimental data supporting these hot concepts with special emphasis on the structural constraints that limit SARS CoV 2 S protein evolution and on potentially invariant and degenerate CD8 epitopes that lend themselves as excellent candidates for the rational development of next generation CD8 T cell response reinforced COVID 19 vaccines 