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

John S Tregoning; David C Stirling; Ziyin Wang; Katie E Flight; Jonathan C Brown; Anna K Blakney; Paul F McKay; Robert F Cunliffe; Valarmathy Murugaiah; Christopher B Fox; Mitchell Beattie; Ying K Tam; Cecilia Johansson; Robin J Shattock

doi:10.1016/j.omtn.2022.11.024

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

Mol Ther Nucleic Acids. 2022 Dec 5:31:29-42. doi: 10.1016/j.omtn.2022.11.024. eCollection 2023 Mar 14.

Authors

Affiliations

¹ Department of Infectious Disease, Imperial College London, St. Mary's Campus, London, UK.
² IDRI, Seattle, WA, USA.
³ Department of Global Health, University of Washington, Seattle, WA, USA.
⁴ Acuitas Therapeutics, 6190 Agronomy Road, Ste 405, Vancouver, BC, Canada.
⁵ National Heart and Lung Institute, Imperial College London, St. Mary's Campus, London, UK.

Abstract

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.

Keywords: MT: Oligonucleotides: Therapies and Applications; formulation; inflammation; influenza; pandemic; sensing; vaccine.