Genetic adjuvants: A paradigm shift in vaccine development and immune modulation

The COVID-19 pandemic underscored the urgency of developing effective vaccines to combat infectious diseases, especially in vulnerable populations such as the elderly and immunocompromised. While recombinant protein vaccines offer safety, their poor immunogenicity highlights the need for advanced vaccination platforms. New genetic/nucleic acid vaccine formulations like plasmid DNA and mRNA showed efficiency and safety in preclinical and clinical studies; however, they demand innovative adjuvants because their mechanism of action differs from traditional protein vaccines. Genetic adjuvants-encoded by nucleic acids within DNA, RNA, or viral vectors-emerge as a promising solution by targeting and modulating specific immune pathways, including antigen presentation, T cell activation, and memory formation. These innovative adjuvants enhance vaccine efficacy by fine-tuning innate and adaptive immune responses, overcoming immune senescence, and addressing the challenges of CD8⁺ T cell activation in immunocompromised populations. This review explores the potential of genetically encoded adjuvants, including cytokines, chemokines, and other immune modulators. By comparing these adjuvants to traditional formulations, we highlight their capacity to address the limitations of modern vaccines while discussing their integration with emerging technologies like RNA-based vaccines. As genetic adjuvants advance toward clinical application, understanding their mechanisms and optimizing their delivery is pivotal to unlocking next-generation immunization strategies.