Mechanisms and durability of humoral and cellular immunity elicited by self-amplifying mRNA (sa-mRNA) platforms

Self-amplifying messenger RNA (sa-mRNA) platforms represent a transformative evolution in vaccinology. By leveraging intracellular replication machinery, sa-mRNA vaccines sustain antigen expression at significantly lower RNA doses than conventional modified mRNA or protein-subunit platforms. Emerging evidence indicates that intracellular replication dynamics and innate pattern-recognition receptor pathways, particularly RIG-I and MDA5, critically regulate both the magnitude and longevity of the immune response.Despite rapid clinical development and recent regulatory approvals, key questions remain regarding the long-term kinetics of sa-mRNA-induced protection. Elucidating the mechanisms governing germinal center dynamics, memory B-cell maintenance, durable neutralizing antibody titers, and polyfunctional T-cell longevity is essential for optimizing next-generation RNA therapeutics. This Research Topic provides a dedicated forum to synthesize current insights into the immunological persistence, safety, and comparative advantages of sa-mRNA platforms.This Research Topic aims to uncover the immunological and molecular mechanisms driving long-term protection following sa-mRNA vaccination. We seek contributions that clarify how vector design, innate sensing, and antigen presentation shape durable memory B and T cell populations. Additionally, this collection will address critical translational questions, including booster durability, cross-variant neutralization decay, heterologous priming strategies, and real-world clinical effectiveness compared to traditional vaccine modalities.We welcome Original Research, Review, Mini-Review, Perspective, Brief Research Report, and Methods articles. Topics of interest include, but are not limited to:- Innate Sensing and Antigen Persistence: We welcome studies elucidating the molecular mechanisms of intracellular RNA replication and RIG-I/MDA5 signaling, and how these pathways influence the duration and amplitude of antigen expression.- Humoral Immune Dynamics: We welcome studies characterizing the kinetics of antibody persistence, neutralizing antibody decay, germinal center reaction longevity, and memory B-cell pool establishment.- Cellular Immune Durability: We welcome studies examining the phenotype, longevity, tissue residency, and polyfunctionality of CD4+ and CD8+ T-cell responses elicited by sa-mRNA compared to conventional platforms.- Comparative Platform Evaluations: We welcome studies presenting head-to-head assessments of sa-mRNA against standard mRNA, viral-vector, or protein-subunit vaccines, including heterologous prime-boost regimens.- Translational and Clinical Insights: We welcome studies reporting correlates of protection, durability of variant cross-neutralization, safety and reactogenicity profiles over extended follow-up, and co-administration compatibility.Please note that submissions should focus on the immunological and molecular mechanisms of sa-mRNA platforms; content on-topic but not focused on immune mechanisms is outside the scope of this Research Topic.----Topic Editors Igor Smolenov and Simone Pecetta are employees of Arcturus Therapeutics and the GSK group of companies, respectively, and each holds stock/stock options in their respective employer. The other Topic Editors declare no competing interests with regard to the Research Topic subject. Topic editors: Igor Smolenov, Ken J. Ishii, Simone Pecetta, Robin John Shattock Source: https://www.frontiersin.org/research-topics/84060/mechanisms-and-durability-of-humoral-and-cellular-immunity-elicited-by-self-amplifying-mrna-sa-mrna-platforms