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

• Published in: Molecular therapy. Nucleic acids Vol. 31; pp. 29 - 42
• Main Authors: Tregoning, John S., Stirling, David C., Wang, Ziyin, Flight, Katie E., Brown, Jonathan C., Blakney, Anna K., McKay, Paul F., Cunliffe, Robert F., Murugaiah, Valarmathy, Fox, Christopher B., Beattie, Mitchell, Tam, Ying K., Johansson, Cecilia, Shattock, Robin J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.03.2023; American Society of Gene & Cell Therapy; Elsevier
• Subjects: formulation; inflammation; influenza; MT: Oligonucleotides: Therapies and Applications; Original; pandemic; sensing; vaccine; influenza; MT: Oligonucleotides: Therapies and Applications; sensing; vaccine; inflammation; formulation; pandemic
• ISSN: 2162-2531; 2162-2531
• DOI: 10.1016/j.omtn.2022.11.024

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. [Display omitted] RNA vaccines were a vital part of the pandemic response. But further research is required to broaden their usage. In the current study, we investigated the interplay of RNA vaccine-induced inflammation and the downstream adaptive response. We show that acute inflammation after immunization is required for protective antibody responses.