Targeted suppression of type 1 interferon signaling during RNA delivery enhances vaccine-elicited immunity

Kim, B. J.; Hosn, R. R.; Remba, T. K.; Dye, J.; Mak, H. H.; Jeong, J. Y.; Cornwall-Brady, M.; Abraham, W.; Maiorino, L.; Melo, M. B.; Li, B.; Zhang, Y.; Dong, Y.; Irvine, D. J.

doi:10.1101/2025.03.09.642244

bioRxiv · 10.1101/2025.03.09.642244

Targeted suppression of type 1 interferon signaling during RNA delivery enhances vaccine-elicited immunity

Kim, B. J.·Hosn, R. R.·Remba, T. K.·Dye, J.·Mak, H. H.·Jeong, J. Y.·Cornwall-Brady, M.·Abraham, W.·Maiorino, L.·Melo, M. B.·Li, B.·Zhang, Y.·Dong, Y.·Irvine, D. J.

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Abstract

RNA vaccines have emerged as a breakthrough technology, and one promising modality employs alphavirus-derived self-replicating RNA (repRNA) to express vaccine antigens. However, both the lipid nanoparticles (LNP) commonly used to deliver RNA and virus-like amplification of repRNAs trigger innate immune recognition, especially via type I interferon (IFN) signaling. To modulate IFN responses during vaccination, we formulated LNPs co-delivering antigen-encoding RNA together with siRNA targeting the interferon-/{beta} receptor-1 (IFNAR1). siRNA-mediated repression of IFNAR1 increased antigen expression from repRNAs by >10-fold, increased immune cell infiltration, and increased antigen presenting cell activation in the injection site and draining lymph nodes. Compared to repRNA alone, siRNA/repRNA co-delivery increased serum antibody titers >10-fold, dramatically augmented antigen-specific germinal center (GC) B cell responses, and primed 4.4-fold more antigen-specific T cells. Ifnar1 silencing by siRNA co-delivery similarly enhanced mRNA vaccines. Thus, siRNA co-delivery is a readily translatable approach to substantially enhance the immunogenicity of RNA vaccines.

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Kim, B. J., Hosn, R. R., Remba, T. K., Dye, J., Mak, H. H., Jeong, J. Y., Cornwall-Brady, M., Abraham, W., Maiorino, L., Melo, M. B., Li, B., Zhang, Y., Dong, Y., Irvine, D. J.. 2025-03-10. Targeted suppression of type 1 interferon signaling during RNA delivery enhances vaccine-elicited immunity. https://doi.org/10.1101/2025.03.09.642244

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