{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T10:06:22Z","timestamp":1790071582644,"version":"4.0.1"},"reference-count":134,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Med. Sci.","Medical Sciences"],"abstract":"<jats:p>Since 2020, billions of doses of COVID-19 messenger RNA (mRNA) lipid nanoparticle vaccines have been administered worldwide, generating one of the largest pharmacovigilance databases for a modern therapeutic class. Intriguingly, their immunopharmacologic profile\u2014including the engagement of innate nucleic acid sensors, systemic type I interferon signaling, dendritic cell-mediated cross-priming of CD8+ T cells, and upregulation of programmed cell death ligand 1 (PD-L1)\u2014may extend beyond COVID-19 prophylaxis. Retrospective evidence from six independent cohorts, one of which is a multinational health-data network, indicated that vaccination within 100 days of immune checkpoint inhibitor (ICI) initiation may improve survival of patients with malignancies, including in immunologically cold tumors, although a substantial fraction of the original effect may be attributed to pandemic-era selection bias. Here, we examine the mechanistic basis and available evidence for the repurposing of licensed COVID-19 mRNA vaccines as antigen-agnostic immunomodulators. We identified five candidate contexts for prospective evaluation\u2014namely, (1) PD-L1-negative non-small cell lung cancer initiating ICI therapy, (2) perioperative immune dysfunction in major cardiac surgery, (3) chronic hepatitis B, (4) chronic HIV with persistent immune exhaustion, and (5) sepsis-induced immunoparalysis. Methodological foundations for confirmatory assessment\u2014comprising target trial emulation, Mendelian randomization, and pragmatic trial design\u2014are now sufficiently developed to enable implementation. Prospective evaluation of the antigen-agnostic repurposing hypothesis is operationally feasible, albeit constrained by residual confounding and uncertainty about the durability of vaccine-induced innate reprogramming.<\/jats:p>","DOI":"10.3390\/medsci14050572","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T18:23:53Z","timestamp":1789496633000},"page":"572","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["COVID-19 mRNA Vaccines as Antigen-Agnostic Immunomodulators: A Repurposing Perspective"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4435-586X","authenticated-orcid":false,"given":"Piercarlo","family":"Minoretti","sequence":"first","affiliation":[{"name":"Department of Social Sciences, Miguel de Cervantes European University (UEMC), 47012 Valladolid, Spain"},{"name":"Studio Minoretti, I-23848 Oggiono, LC, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3908-0290","authenticated-orcid":false,"given":"Enzo","family":"Emanuele","sequence":"additional","affiliation":[{"name":"2E Science, I-27038 Robbio, PV, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2200","DOI":"10.1016\/j.vaccine.2024.01.100","article-title":"COVID-19 vaccines and adverse events of special interest: A multinational Global Vaccine Data Network (GVDN) cohort study of 99 million vaccinated individuals","volume":"42","author":"Faksova","year":"2024","journal-title":"Vaccine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1016\/j.immuni.2005.06.008","article-title":"Suppression of RNA recognition by Toll-like receptors: The impact of nucleoside modification and the evolutionary origin of RNA","volume":"23","author":"Buckstein","year":"2005","journal-title":"Immunity"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1993","DOI":"10.1016\/j.immuni.2022.10.014","article-title":"Innate immune mechanisms of mRNA vaccines","volume":"55","author":"Verbeke","year":"2022","journal-title":"Immunity"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/s41586-021-03791-x","article-title":"Systems vaccinology of the BNT162b2 mRNA vaccine in humans","volume":"596","author":"Arunachalam","year":"2021","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/s41586-025-09655-y","article-title":"SARS-CoV-2 mRNA vaccines sensitize tumours to immune checkpoint blockade","volume":"647","author":"Grippin","year":"2025","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e70007","DOI":"10.1002\/wnan.70007","article-title":"Engineering lipid nanoparticles for mRNA immunotherapy","volume":"17","author":"Zwolsman","year":"2025","journal-title":"WIREs Nanomed. 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