{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:28:43Z","timestamp":1781108923743,"version":"3.54.1"},"reference-count":49,"publisher":"National Academy of Sciences","issue":"18","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,5,5]]},"abstract":"<jats:p>Human leukocyte antigen (HLA) class I molecules are highly polymorphic, restricting peptide binding to narrow sequence subsets. Designing peptides that bind multiple HLA supertypes\u2014termed superbinders\u2014offers a promising strategy for broad-spectrum T cell vaccines and immunotherapies. Here, we present superHLA, a computational framework that combines Markov Chain Monte Carlo optimization with state-of-the-art major histocompatibility complex binding predictors to design synthetic 9-mer peptides with broad HLA-binding profiles. Using superHLA, we generated over 190,000 candidate superbinders predicted to bind 8 to 12 HLA class I alleles across distinct supertypes. A multitier filtering pipeline\u2014incorporating sequence clustering, synthesis feasibility, cross-predictor validation, and self-peptidome exclusion\u2014yielded a final panel of 100 peptides for experimental testing. Of these, 21 bound 4 to 9 supertypes in vitro. Superbinders displayed distinct anchor residue preferences and showed minimal similarity to human peptides. These results suggest that HLA superbinders are more abundant than previously recognized and can be rationally designed at scale. This approach supports development of pan-HLA immunogens with broad population coverage and may inform applications in vaccine research, neoantigen discovery, and immunotherapy.<\/jats:p>","DOI":"10.1073\/pnas.2518820123","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T17:59:57Z","timestamp":1777399197000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":2,"title":["Computational design of HLA class I superbinders for broad T cell immunogenicity"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-2604-382X","authenticated-orcid":false,"given":"Elinor","family":"Peer","sequence":"first","affiliation":[{"name":"Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev","place":["Beer-Sheva, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6909-4779","authenticated-orcid":false,"given":"Liel","family":"Cohen-Lavi","sequence":"additional","affiliation":[{"name":"Department of Industrial Engineering and Management, Faculty of Engineering, Ben-Gurion University of the Negev","place":["Beer-Sheva, Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Sette","sequence":"additional","affiliation":[{"name":"Center for Vaccine Innovation, La Jolla Institute for Immunology","place":["San Diego"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0987-405X","authenticated-orcid":false,"given":"John","family":"Sidney","sequence":"additional","affiliation":[{"name":"Center for Vaccine Innovation, La Jolla Institute for Immunology","place":["San Diego"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0561-1578","authenticated-orcid":false,"given":"Tomer","family":"Hertz","sequence":"additional","affiliation":[{"name":"Department of Microbiology Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev","place":["Beer-Sheva, Israel"]},{"name":"Vaccine and Infectious Disease Division, Fred Hutch Cancer Research Center","place":["Seattle"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri3084"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.11.040193.001241"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2010.03300.x"},{"key":"e_1_3_4_4_2","first-page":"D948","article-title":"IPD-IMGT\/HLA database","volume":"48","author":"Robinson J.","year":"2020","unstructured":"J. Robinson , IPD-IMGT\/HLA database. Nucleic Acids Res. 48, D948\u2013D955 (2020).","journal-title":"Nucleic Acids Res."},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01966-10"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.143"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.17.1.51"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-294X.2009.04243.x"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2172-9-1"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1093\/Bioinformatics\/btl324"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.172.7.4314"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00292"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1323878"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2012.01.015"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2006.09.005"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003404"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1089\/aid.2005.21.165"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1237874"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky1006"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2224"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btl255"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0000796"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btm611"},{"key":"e_1_3_4_24_2","doi-asserted-by":"crossref","unstructured":"S. Raychaudhuri \u201cIntroduction to Monte Carlo simulation\u201d in IEEE 2008 Winter Simulation Conference (IEEE 2008) pp. 91\u2013100.","DOI":"10.1109\/WSC.2008.4736059"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2008.05.001"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkaa379"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts565"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btl158"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2018.05.014"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2020.06.010"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1700893"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msy096"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/0161-5890(94)90019-1"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471142735.im1803s100"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471142735.im1812s61"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1050"},{"key":"e_1_3_4_37_2","doi-asserted-by":"crossref","unstructured":"E. M. Lafuente P. A. Reche Prediction of MHC-peptide binding: A systematic and comprehensive overview\u2013E-Prints Complutense. 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Peer super-HLA. GitHub. https:\/\/github.com\/elinor5938\/super-HLA. Deposited 18 March 2026."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2518820123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T18:01:01Z","timestamp":1777399261000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2518820123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,28]]},"references-count":49,"journal-issue":{"issue":"18","published-print":{"date-parts":[[2026,5,5]]}},"alternative-id":["10.1073\/pnas.2518820123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2518820123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,28]]},"assertion":[{"value":"2025-07-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2518820123"}}