 Safety and immunogenicity of an optimized self-replicating RNA platform for low dose or single dose vaccine applications: a randomized, open label Phase I study in healthy volunteersChristian J. Maine,
Shigeki J. Miyake-Stoner,
Darina S. Spasova,
Gaelle Picarda,
Annie C. Chou,
Emily D. Brand,
Melanie D. Olesiuk,
Christine C. Domingo,
Hunter J. Little,
Thomas T. Goodman,
Jacqueline L. Posy,
Jasmin Gonzalez,
Terrina L. Bayone,
Jessica Sparks,
Ebony N. Gary,
Zhi Xiang,
Nicholas J. Tursi,
Casey E. Hojecki,
Hildegund C. J. Ertl,
David B. Weiner,
Irafasha C. Casmil,
Anna K. Blakney,
Brandon Essink,
Guillermo Somodevilla,
Nathaniel S. Wang,
Andrew J. Geall,
Zelanna Goldberg and
Parinaz Aliahmad ()
Nature Communications, 2025, vol. 16, issue 1, 1-13 Abstract: Abstract Self-replicating RNA (srRNA) technology, in comparison to mRNA vaccines, has shown dose-sparing by approximately 10-fold and more durable immune responses. However, no improvements are observed in the adverse events profile. Here, we develop an srRNA vaccine platform with optimized non-coding regions and demonstrate immunogenicity and safety in preclinical and clinical development. Optimized srRNA vaccines generate protective immunity (according to the WHO defined thresholds) at doses up to 1,000,000-fold lower than mRNA in female mouse models of influenza and rabies. Clinically, safety and immunogenicity of RBI-4000, an srRNA vector encoding the rabies glycoprotein, was evaluated in a Phase I study (NCT06048770). RBI-4000 was able to elicit de novo protective immunity in the majority of healthy participants when administered at a dose of 0.1, 1, or 10 microgram (71%, 94%, 100%, respectively) in a prime-boost schedule. Similarly, we observe immunity above the WHO benchmark of protection following a single administration in most participants at both 1 and 10 microgram doses. There are no serious adverse events reported across all cohorts. These data establish the high therapeutic index of optimized srRNA vectors, demonstrating feasibility of both low dose and single dose approaches for vaccine applications. Date: 2025 Downloads: (external link) Related works: Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55843-9 Ordering information: This journal article can be ordered from DOI: 10.1038/s41467-025-55843-9 Access Statistics for this article Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie More articles in Nature Communications from Nature |
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