From prophylactic mRNA vaccines against viral infections to therapeutic applications: regulatory science considerations for expanding mRNA platforms

Abstract

Conventional non-amplifying messenger RNA (mRNA) and self-amplifying RNA (saRNA) medicines generally share a core linear RNA architecture—including a 5′ cap, untranslated regions, one or more open reading frames, and a poly(A) tail—and are commonly formulated with delivery systems such as lipid nanoparticles (LNPs) to enable transient intracellular expression of a target protein. Prophylactic mRNA vaccines are designed primarily to express infectious-disease antigens and generate protective immune memory, whereas mRNA therapeutics exert pharmacological effects intended to treat disease, suppress recurrence, replace proteins, modulate immunity, or deliver gene-editing enzymes. Thus, even products based on similar mRNA–LNP technology may have different regulatory classifications and evidence requirements according to their intended use and mechanism of action. The clinical and regulatory landscape has expanded beyond the first coronavirus disease 2019 vaccines to include respiratory syncytial virus and influenza mRNA vaccines, an influenza–coronavirus disease 2019 combination vaccine, an authorized saRNA vaccine, personalized cancer immunotherapies, protein-replacement therapies, in vivo cell programming, and gene-editing delivery systems. This review examines which prophylactic-vaccine evidence can support therapeutic development and where product-specific quality, nonclinical, clinical, and lifecycle evidence remains necessary. For prophylactic mRNA vaccines, major regulatory considerations include quality, immunogenicity, preventive efficacy, lot release, and safety surveillance after large-scale vaccination. For mRNA therapeutics, the principal issues include delivery to target tissues, function of the expressed product, repeat-dose safety, biodistribution, off-target risk, long-term follow-up, and patient-specific manufacture and traceability. In particular, although personalized mRNA cancer vaccines are commonly described as vaccines, they are closer in regulatory purpose to therapeutics that act on the basis of each patient’s tumor characteristics than to vaccines that prevent infectious disease. Antigen-selection algorithms, patient-specific sequence design, small-batch and multi-product manufacture, product–patient matching, clinical evaluation of combination strategies, manufacturing delays and analysis populations, and risk-based long-term postauthorization follow-up therefore require explicit regulatory consideration. Platform-level knowledge from prophylactic mRNA vaccine authorization can support therapeutic development, but regulatory questions may vary with each new product type; developers will need to track evolving regulatory instruments across jurisdictions and engage regulatory authorities early.