@ARTICLE{10.3389/fimmu.2022.859905, AUTHOR={Patarroyo, Manuel A. and Patarroyo, Manuel E. and Pabón, Laura and Alba, Martha P. and Bermudez, Adriana and Rugeles, María Teresa and Díaz-Arevalo, Diana and Zapata-Builes, Wildeman and Zapata, María Isabel and Reyes, César and Suarez, Carlos F. and Agudelo, William and López, Carolina and Aza-Conde, Jorge and Melo, Miguel and Escamilla, Luis and Oviedo, Jairo and Guzmán, Fanny and Silva, Yolanda and Forero, Martha and Flórez-Álvarez, Lizdany and Aguilar-Jimenez, Wbeimar and Moreno-Vranich, Armando and Garry, Jason and Avendaño, Catalina}, TITLE={SM-COLSARSPROT: Highly Immunogenic Supramutational Synthetic Peptides Covering the World’s Population}, JOURNAL={Frontiers in Immunology}, VOLUME={13}, YEAR={2022}, URL={https://www.frontiersin.org/articles/10.3389/fimmu.2022.859905}, DOI={10.3389/fimmu.2022.859905}, ISSN={1664-3224}, ABSTRACT={Fifty ~20–amino acid (aa)–long peptides were selected from functionally relevant SARS-CoV-2 S, M, and E proteins for trial B-21 and another 53 common ones, plus some new ones derived from the virus’ main genetic variants for complementary trial C-21. Peptide selection was based on tremendous SARS-CoV-2 genetic variability for analysing them concerning vast human immunogenetic polymorphism for developing the first supramutational, Colombian SARS-protection (SM-COLSARSPROT), peptide mixture. Specific physicochemical rules were followed, i.e., aa predilection for polyproline type II left-handed (PPIIL) formation, replacing β-branched, aromatic aa, short-chain backbone H-bond-forming residues, π-π interactions (n→π* and π-CH), aa interaction with π systems, and molecular fragments able to interact with them, disrupting PPIIL propensity formation. All these modified structures had PPIIL formation propensity to enable target peptide interaction with human leukocyte antigen-DRβ1* (HLA-DRβ1*) molecules to mediate antigen presentation and induce an appropriate immune response. Such modified peptides were designed for human use; however, they induced high antibody titres against S, M, and E parental mutant peptides and neutralising antibodies when suitably modified and chemically synthesised for immunising 61 major histocompatibility complex class II (MHCII) DNA genotyped Aotus monkeys (matched with their corresponding HLA-DRβ1* molecules), predicted to cover 77.5% to 83.1% of the world’s population. Such chemically synthesised peptide mixture represents an extremely pure, stable, reliable, and cheap vaccine for COVID-19 pandemic control, providing a new approach for a logical, rational, and soundly established methodology for other vaccine development.} }