Formulation, inflammation, and RNA sensing impact the immunogenicity of self-amplifying RNA vaccines.

Autor:	Tregoning JS; Department of Infectious Disease, Imperial College London, St. Mary's Campus, London, UK., Stirling DC; Department of Infectious Disease, Imperial College London, St. Mary's Campus, London, UK., Wang Z; Department of Infectious Disease, Imperial College London, St. Mary's Campus, London, UK., Flight KE; Department of Infectious Disease, Imperial College London, St. Mary's Campus, London, UK., Brown JC; Department of Infectious Disease, Imperial College London, St. Mary's Campus, London, UK., Blakney AK; Department of Infectious Disease, Imperial College London, St. Mary's Campus, London, UK., McKay PF; Department of Infectious Disease, Imperial College London, St. Mary's Campus, London, UK., Cunliffe RF; Department of Infectious Disease, Imperial College London, St. Mary's Campus, London, UK., Murugaiah V; Department of Infectious Disease, Imperial College London, St. Mary's Campus, London, UK., Fox CB; IDRI, Seattle, WA, USA.; Department of Global Health, University of Washington, Seattle, WA, USA., Beattie M; Acuitas Therapeutics, 6190 Agronomy Road, Ste 405, Vancouver, BC, Canada., Tam YK; Acuitas Therapeutics, 6190 Agronomy Road, Ste 405, Vancouver, BC, Canada., Johansson C; National Heart and Lung Institute, Imperial College London, St. Mary's Campus, London, UK., Shattock RJ; Department of Infectious Disease, Imperial College London, St. Mary's Campus, London, UK.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2022 Dec 05; Vol. 31, pp. 29-42. Date of Electronic Publication: 2022 Dec 05 (Print Publication: 2023).
DOI:	10.1016/j.omtn.2022.11.024
Abstrakt:	To be effective, RNA vaccines require both in situ translation and the induction of an immune response to recruit cells to the site of immunization. These factors can pull in opposite directions with the inflammation reducing expression of the vaccine antigen. We investigated how formulation affects the acute systemic cytokine response to a self-amplifying RNA (saRNA) vaccine. We compared a cationic polymer (pABOL), a lipid emulsion (nanostructured lipid carrier, NLC), and three lipid nanoparticles (LNP). After immunization, we measured serum cytokines and compared the response to induced antibodies against influenza virus. Formulations that induced a greater cytokine response induced a greater antibody response, with a significant correlation between IP-10, MCP-1, KC, and antigen-specific antibody titers. We then investigated how innate immune sensing and signaling impacted the adaptive immune response to vaccination with LNP-formulated saRNA. Mice that lacked MAVS and are unable to signal through RIG-I-like receptors had an altered cytokine response to saRNA vaccination and had significantly greater antibody responses than wild-type mice. This indicates that the inflammation induced by formulated saRNA vaccines is not solely deleterious in the induction of antibody responses and that targeting specific aspects of RNA vaccine sensing might improve the quality of the response. Competing Interests: R.S., P.M., and A.B. are associated with Vaxequity global health and have stocks in it; M.B. and Y.T. are employed by Acuitas; C.F. was employed by IDRI. (© 2022 The Authors.)
Databáze:	MEDLINE
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