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-including 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)-may 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-namely, (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-comprising target trial emulation, Mendelian randomization, and pragmatic trial design-are 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.
