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 volunteers
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-codi...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-55843-9 |
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| author | Christian 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 Parinaz Aliahmad |
| author_facet | Christian 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 Parinaz Aliahmad |
| author_sort | Christian J. Maine |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ef6eba9fcb8f48bda92cdacfb069e641 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-ef6eba9fcb8f48bda92cdacfb069e6412025-01-12T12:29:43ZengNature PortfolioNature Communications2041-17232025-01-0116111310.1038/s41467-025-55843-9Safety 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. Maine0Shigeki J. Miyake-Stoner1Darina S. Spasova2Gaelle Picarda3Annie C. Chou4Emily D. Brand5Melanie D. Olesiuk6Christine C. Domingo7Hunter J. Little8Thomas T. Goodman9Jacqueline L. Posy10Jasmin Gonzalez11Terrina L. Bayone12Jessica Sparks13Ebony N. Gary14Zhi Xiang15Nicholas J. Tursi16Casey E. Hojecki17Hildegund C. J. Ertl18David B. Weiner19Irafasha C. Casmil20Anna K. Blakney21Brandon Essink22Guillermo Somodevilla23Nathaniel S. Wang24Andrew J. Geall25Zelanna Goldberg26Parinaz Aliahmad27Replicate Bioscience IncReplicate Bioscience IncReplicate Bioscience IncReplicate Bioscience IncReplicate Bioscience IncReplicate Bioscience IncReplicate Bioscience IncReplicate Bioscience IncReplicate Bioscience IncReplicate Bioscience IncReplicate Bioscience IncReplicate Bioscience IncReplicate Bioscience IncReplicate Bioscience IncThe Vaccine & Immunotherapy Center, The Wistar InstituteThe Vaccine & Immunotherapy Center, The Wistar InstituteThe Vaccine & Immunotherapy Center, The Wistar InstituteThe Vaccine & Immunotherapy Center, The Wistar InstituteThe Vaccine & Immunotherapy Center, The Wistar InstituteThe Vaccine & Immunotherapy Center, The Wistar InstituteMichael Smith Laboratories, School of Biomedical Engineering, University of British ColumbiaMichael Smith Laboratories, School of Biomedical Engineering, University of British ColumbiaVelocity Clinical ResearchCordova Research InstituteReplicate Bioscience IncReplicate Bioscience IncReplicate Bioscience IncReplicate Bioscience IncAbstract 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.https://doi.org/10.1038/s41467-025-55843-9 |
| spellingShingle | Christian 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 Parinaz Aliahmad 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 volunteers Nature Communications |
| title | 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 volunteers |
| title_full | 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 volunteers |
| title_fullStr | 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 volunteers |
| title_full_unstemmed | 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 volunteers |
| title_short | 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 volunteers |
| title_sort | 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 volunteers |
| url | https://doi.org/10.1038/s41467-025-55843-9 |
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