IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-55843-9.html
   My bibliography  Save this article

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

Author

Listed:
  • Christian J. Maine

    (Replicate Bioscience Inc)

  • Shigeki J. Miyake-Stoner

    (Replicate Bioscience Inc)

  • Darina S. Spasova

    (Replicate Bioscience Inc)

  • Gaelle Picarda

    (Replicate Bioscience Inc)

  • Annie C. Chou

    (Replicate Bioscience Inc)

  • Emily D. Brand

    (Replicate Bioscience Inc)

  • Melanie D. Olesiuk

    (Replicate Bioscience Inc)

  • Christine C. Domingo

    (Replicate Bioscience Inc)

  • Hunter J. Little

    (Replicate Bioscience Inc)

  • Thomas T. Goodman

    (Replicate Bioscience Inc)

  • Jacqueline L. Posy

    (Replicate Bioscience Inc)

  • Jasmin Gonzalez

    (Replicate Bioscience Inc)

  • Terrina L. Bayone

    (Replicate Bioscience Inc)

  • Jessica Sparks

    (Replicate Bioscience Inc)

  • Ebony N. Gary

    (The Wistar Institute)

  • Zhi Xiang

    (The Wistar Institute)

  • Nicholas J. Tursi

    (The Wistar Institute
    University of Pennsylvania)

  • Casey E. Hojecki

    (The Wistar Institute)

  • Hildegund C. J. Ertl

    (The Wistar Institute)

  • David B. Weiner

    (The Wistar Institute)

  • Irafasha C. Casmil

    (University of British Columbia)

  • Anna K. Blakney

    (University of British Columbia)

  • Brandon Essink

    (Velocity Clinical Research)

  • Guillermo Somodevilla

    (Cordova Research Institute)

  • Nathaniel S. Wang

    (Replicate Bioscience Inc)

  • Andrew J. Geall

    (Replicate Bioscience Inc)

  • Zelanna Goldberg

    (Replicate Bioscience Inc)

  • Parinaz Aliahmad

    (Replicate Bioscience Inc)

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.

Suggested Citation

  • 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 &, 2025. "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, Nature, vol. 16(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55843-9
    DOI: 10.1038/s41467-025-55843-9
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-55843-9
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-025-55843-9?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Ugur Sahin & Petra Oehm & Evelyna Derhovanessian & Robert A. Jabulowsky & Mathias Vormehr & Maike Gold & Daniel Maurus & Doreen Schwarck-Kokarakis & Andreas N. Kuhn & Tana Omokoko & Lena M. Kranz & Mu, 2020. "An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma," Nature, Nature, vol. 585(7823), pages 107-112, September.
    2. Luis A. Rojas & Zachary Sethna & Kevin C. Soares & Cristina Olcese & Nan Pang & Erin Patterson & Jayon Lihm & Nicholas Ceglia & Pablo Guasp & Alexander Chu & Rebecca Yu & Adrienne Kaya Chandra & There, 2023. "Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer," Nature, Nature, vol. 618(7963), pages 144-150, June.
    3. Mai Komori & Takuto Nogimori & Amber L. Morey & Takashi Sekida & Keiko Ishimoto & Matthew R. Hassett & Yuji Masuta & Hirotaka Ode & Tomokazu Tamura & Rigel Suzuki & Jeff Alexander & Yasutoshi Kido & K, 2023. "saRNA vaccine expressing membrane-anchored RBD elicits broad and durable immunity against SARS-CoV-2 variants of concern," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Dwight Koeberl & Andreas Schulze & Neal Sondheimer & Gerald S. Lipshutz & Tarekegn Geberhiwot & Lerong Li & Rajnish Saini & Junxiang Luo & Vanja Sikirica & Ling Jin & Min Liang & Mary Leuchars & Steph, 2024. "Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia," Nature, Nature, vol. 628(8009), pages 872-877, April.
    5. Sebastian Kreiter & Mathias Vormehr & Niels van de Roemer & Mustafa Diken & Martin Löwer & Jan Diekmann & Sebastian Boegel & Barbara Schrörs & Fulvia Vascotto & John C. Castle & Arbel D. Tadmor & Step, 2015. "Erratum: Mutant MHC class II epitopes drive therapeutic immune responses to cancer," Nature, Nature, vol. 523(7560), pages 370-370, July.
    6. Sebastian Kreiter & Mathias Vormehr & Niels van de Roemer & Mustafa Diken & Martin Löwer & Jan Diekmann & Sebastian Boegel & Barbara Schrörs & Fulvia Vascotto & John C. Castle & Arbel D. Tadmor & Step, 2015. "Mutant MHC class II epitopes drive therapeutic immune responses to cancer," Nature, Nature, vol. 520(7549), pages 692-696, April.
    7. Amy R. Rappaport & Sue-Jean Hong & Ciaran D. Scallan & Leonid Gitlin & Arvin Akoopie & Gregory R. Boucher & Milana Egorova & J. Aaron Espinosa & Mario Fidanza & Melissa A. Kachura & Annie Shen & Glori, 2022. "Low-dose self-amplifying mRNA COVID-19 vaccine drives strong protective immunity in non-human primates against SARS-CoV-2 infection," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Szymon J. Szymura & Lin Wang & Tiantian Zhang & Soung-chul Cha & Joo Song & Zhenyuan Dong & Aaron Anderson & Elizabeth Oh & Vincent Lee & Zhe Wang & Sapna Parshottam & Sheetal Rao & Jasper B. Olsem & , 2024. "Personalized neoantigen vaccines as early intervention in untreated patients with lymphoplasmacytic lymphoma: a non-randomized phase 1 trial," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Ariel Isser & Aliyah B. Silver & Hawley C. Pruitt & Michal Mass & Emma H. Elias & Gohta Aihara & Si-Sim Kang & Niklas Bachmann & Ying-Yu Chen & Elissa K. Leonard & Joan G. Bieler & Worarat Chaisawangw, 2022. "Nanoparticle-based modulation of CD4+ T cell effector and helper functions enhances adoptive immunotherapy," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Jim Middelburg & Marjolein Sluijter & Gaby Schaap & Büşra Göynük & Katy Lloyd & Vitalijs Ovcinnikovs & Gijs G. Zom & Renoud J. Marijnissen & Christianne Groeneveldt & Lisa Griffioen & Gerwin G. W. San, 2024. "T-cell stimulating vaccines empower CD3 bispecific antibody therapy in solid tumors," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Laura Y. Zhou & Fei Zou & Wei Sun, 2023. "Prioritizing candidate peptides for cancer vaccines through predicting peptide presentation by HLA‐I proteins," Biometrics, The International Biometric Society, vol. 79(3), pages 2664-2676, September.
    5. Mitchell Emmers & Marij J. P. Welters & Michelle V. Dietz & Saskia J. Santegoets & Sanne Boekesteijn & Anouk Stolk & Nikki M. Loof & Daphne W. Dumoulin & Annemarie L. Geel & Lauri C. Steinbusch & A. R, 2025. "TEIPP-vaccination in checkpoint-resistant non-small cell lung cancer: a first-in-human phase I/II dose-escalation study," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    6. Julia Velz & Lena K. Freudenmann & Gioele Medici & Marissa Dubbelaar & Malte Mohme & David R. Ghasemi & Jonas Scheid & Daniel J. Kowalewski & Angelica B. Patterson & Anna M. Zeitlberger & Katrin Lamsz, 2025. "Mapping naturally presented T cell antigens in medulloblastoma based on integrative multi-omics," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    7. Qing Li & Hao Zeng & Ting Liu & Peipei Wang & Rui Zhang & Binyan Zhao & Tang Feng & Yuling Yang & Jiumei Wu & Yue Zheng & Bailing Zhou & Yang Shu & Heng Xu & Li Yang & Zhenyu Ding, 2024. "A dendritic cell vaccine for both vaccination and neoantigen-reactive T cell preparation for cancer immunotherapy in mice," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    8. Xinyuan Lei & Hsinyu Lin & Jieqi Wang & Zhanpeng Ou & Yi Ruan & Ananthan Sadagopan & Weixiong Chen & Shule Xie & Baisheng Chen & Qunxing Li & Jue Wang & Huayue Lin & Xiaofeng Zhu & Xiaoqing Yuan & Tia, 2022. "Mitochondrial fission induces immunoescape in solid tumors through decreasing MHC-I surface expression," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    9. Yuwei Li & Maoxin Fang & Haotian Yu & Xianglei Wang & Shiyao Xue & Zeze Jiang & Zixuan Huang & Shaoqin Rong & Xiaoli Wei & Zhigang Lu & Min Luo, 2025. "Neoantigen enriched biomimetic nanovaccine for personalized cancer immunotherapy," Nature Communications, Nature, vol. 16(1), pages 1-15, December.
    10. Laurel B. Darragh & Jacob Gadwa & Tiffany T. Pham & Benjamin Court & Brooke Neupert & Nicholas A. Olimpo & Khoa Nguyen & Diemmy Nguyen & Michael W. Knitz & Maureen Hoen & Sophia Corbo & Molishree Josh, 2022. "Elective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    11. Kevin B. Weyant & Ayomide Oloyede & Sukumar Pal & Julie Liao & Mariela Rivera-De Jesus & Thapakorn Jaroentomeechai & Tyler D. Moeller & Steven Hoang-Phou & Sean F. Gilmore & Riya Singh & Daniel C. Pan, 2023. "A modular vaccine platform enabled by decoration of bacterial outer membrane vesicles with biotinylated antigens," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    12. Yonger Xue & Xucheng Hou & Yichen Zhong & Yuebao Zhang & Shi Du & Diana D. Kang & Leiming Wang & Chang Wang & Haoyuan Li & Siyu Wang & Zhengwei Liu & Meng Tian & Kaiyuan Guo & Dinglingge Cao & Binbin , 2025. "LNP-RNA-mediated antigen presentation leverages SARS-CoV-2-specific immunity for cancer treatment," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    13. Jinhao Que & Guangfu Xue & Tao Wang & Xiyun Jin & Zuxiang Wang & Yideng Cai & Wenyi Yang & Meng Luo & Qian Ding & Jinwei Zhang & Yilin Wang & Yuexin Yang & Fenglan Pang & Yi Hui & Zheng Wei & Jun Xion, 2025. "Identifying T cell antigen at the atomic level with graph convolutional network," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    14. Wojciech Barczak & Simon M. Carr & Geng Liu & Shonagh Munro & Annalisa Nicastri & Lian Ni Lee & Claire Hutchings & Nicola Ternette & Paul Klenerman & Alexander Kanapin & Anastasia Samsonova & Nicholas, 2023. "Long non-coding RNA-derived peptides are immunogenic and drive a potent anti-tumour response," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    15. Aneesh Vijayan & Ronald Vogels & Rachel Groppo & Yi Jin & Selina Khan & Mirjam Kampen & Sytze Jorritsma & Satish Boedhoe & Miranda Baert & Harry Diepen & Harmjan Kuipers & Jan Serroyen & Jorge Reyes- , 2024. "A self-amplifying RNA RSV prefusion-F vaccine elicits potent immunity in pre-exposed and naïve non-human primates," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    16. Wanbo Tai & Shengyong Feng & Benjie Chai & Shuaiyao Lu & Guangyu Zhao & Dong Chen & Wenhai Yu & Liting Ren & Huicheng Shi & Jing Lu & Zhuming Cai & Mujia Pang & Xu Tan & Penghua Wang & Jinzhong Lin & , 2023. "An mRNA-based T-cell-inducing antigen strengthens COVID-19 vaccine against SARS-CoV-2 variants," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    17. Matthew P. Morrow & Elisabeth Gillespie & Albert Sylvester & Milan R. Amin & Peter C. Belafsky & Simon R. Best & Aaron D. Friedman & Adam M. Klein & David G. Lott & Ted Mau & Randal C. Paniello & Seth, 2025. "DNA immunotherapy for recurrent respiratory papillomatosis (RRP): phase 1/2 study assessing efficacy, safety, and immunogenicity of INO-3107," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    18. Paula M. Cevaal & Stanislav Kan & Bridget M. Fisher & Michael A. Moso & Abigail Tan & Haiyin Liu & Abdalla Ali & Kiho Tanaka & Rory A. Shepherd & Youry Kim & Jesslyn Ong & Denzil L. Furtado & Marvin H, 2025. "Efficient mRNA delivery to resting T cells to reverse HIV latency," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    19. Marco Notaro & Maristella Borghetti & Chiara Bresesti & Giovanna Giacca & Thomas Kerzel & Carl Mirko Mercado & Stefano Beretta & Marco Monti & Ivan Merelli & Silvia Iaia & Marco Genua & Andrea Annoni , 2025. "In vivo armed macrophages curb liver metastasis through tumor-reactive T-cell rejuvenation," Nature Communications, Nature, vol. 16(1), pages 1-24, December.
    20. Wanzun Lin & Li Chen & Haojiong Zhang & Xianxin Qiu & Qingting Huang & Fangzhu Wan & Ziyu Le & Shikai Geng & Anlan Zhang & Sufang Qiu & Long Chen & Lin Kong & Jiade J. Lu, 2023. "Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-55843-9. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.