Programmable genetic vaccines: Improving immune responses through co-delivery of antigens and immunomodulators

The field of genetic vaccines has emerged as a transformative area in immunology, particularly with the advent of platforms delivering engineered nucleic acids, such as RNA, DNA, and viral or bacterial vectors. These next-generation vaccines have demonstrated exceptional adaptability, rapid development cycles, and a high degree of modularity, distinguishing them from traditional protein-based or inactivated approaches. While considerable progress has been made in antigen selection and optimization, a critical challenge remains: how best to modulate the immune system in situ to achieve robust, durable, and targeted responses, especially in the context of complex infectious diseases and cancer. Recent studies highlight the promise of incorporating genetic adjuvants—genes encoding immune modulators—directly into vaccine constructs, offering refined control over the magnitude and quality of immune activation.Despite notable advances, questions persist regarding the mechanisms by which co-encoded immunomodulators shape immune landscapes and how these programmable designs can overcome barriers like immune tolerance or non-responsiveness. Empirical and translational research suggests that embedding cytokines, chemokines, costimulatory molecules, or checkpoint inhibitors within the genetic payload can enhance not only the potency but also the specificity and persistence of immune protection. Yet, significant knowledge gaps remain about the best strategies to balance efficacy and safety, the comparative advantages of various immunomodulatory combinations, and the clinical translation of these innovative constructs. Greater mechanistic understanding and real-world data are urgently needed to unlock the full therapeutic potential of programmable genetic vaccines.This Research Topic aims to bring together leading scientists and clinicians to explore the design, function, and translational potential of genetic vaccines that co-deliver antigens and immunomodulatory genes. The goal is to clarify how such co-encoded factors can be leveraged to boost vaccine efficacy, to dissect the molecular and cellular pathways involved, and to highlight solutions for overcoming immune resistance or achieving longer-lasting immunity. We encourage submissions that integrate experimental insights, preclinical validation, or clinical findings, particularly those that address safety, regulatory considerations, and the real-world impact of these programmable solutions.Contributions should focus on the development, mechanistic analysis, or clinical evaluation of genetic vaccines featuring co-delivery of antigens and immune modulators, rather than antigen discovery or predictive computational approaches. To gather further insights into these evolving strategies, we welcome articles addressing, but not limited to, the following themes:o Design and engineering of genetic vaccines encoding immunomodulatorso Mechanistic insights into adjuvants’ effects on innate and adaptive immunityo Comparative studies of different genetic adjuvant strategieso Challenges and solutions in regulating immune potency and safety of combination vaccineso Clinical and translational advances, including trial data and real-world applicationsPlease note: Manuscripts primarily centered on antigen discovery, computational epitope prediction, or reverse vaccinology methodologies are outside the scope of this Research TopicPlease note that Dr. Hildegund CJ Ertl is a Founder at Virion Therapeutics and a Scientific Advisory Board (SAB) member at Rhygaze. Topic editors: Hildegund CJ Ertl, Hanseul Oh, Mohsen Mohammadi Source: https://www.frontiersin.org/research-topics/82061/programmable-genetic-vaccines-improving-immune-responses-through-co-delivery-of-antigens-and-immunomodulators