Canonical and alternative frame ORF were considered in the present CoV-2-consensus sequence design to ensure an as broad as possible screening for all potentially expressed protein sequences. Whether all these putative ORF are indeed expressed remains to be confirmed. If shown that not all these sequences are indeed expressed, the OLP set could be reduced by some 65 peptides, focusing exclusively on the canonical ORF. Consensus sequence design is highly dependent on the sequences included in the alignments used to construct them. We used publicly available sequences in the growing SARS-CoV-2 NCBI repository as a representative set of worldwide sequences. As noted, coverage of sequence diversity for in-vitro antigen test sets is critical as responses to autologous viral variants may be missed if these variant sequences are not matched [27]. This may be most critical for highly variable pathogens, such as HCV and HIV, where it has been shown that sequence entropy was directly related to the frequency of OLP reactivity in vitro and essential to identify the potential emergence of immune escape variants [59,60]. However, even genetically more stable pathogens such DNA viruses (for instance Epstein Barr Virus, EBV) have been reported to exist as a swarm of quasi-species and to lose specific T cell epitopes over time [61,62]. This is also supported by recent data showing some degree of adaptation to host immunity and sequence variability for SARS-CoV-2 as it moves through the global human population [63]. To cover these variant sites, variant OLP can be synthesized. An alternative approach to the synthesis of individual variant peptide sequences is the use of “toggled peptides”, where the sequence variation is directly incorporated into the peptide synthesis. To achieve this, peptide synthesis uses mixes of amino acids at variable positions, so that the resulting OLP resembles a mini-peptide library that can achieve an a-priori set coverage of circulating viral variants [64]. This would readily allow to cover more sequence diversity beyond the 25% frequency cut-off that was applied in the present study.