Reducing cell intrinsic immunity to mRNA vaccine alters adaptive immune responses in mice.

Autor:	Wang Z; Department of Infectious Disease, Imperial College London, London W2 1PG, UK., Jacobus EJ; BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany., Stirling DC; Department of Infectious Disease, Imperial College London, London W2 1PG, UK., Krumm S; BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany., Flight KE; Department of Infectious Disease, Imperial College London, London W2 1PG, UK., Cunliffe RF; Department of Infectious Disease, Imperial College London, London W2 1PG, UK., Mottl J; BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany., Singh C; Department of Infectious Disease, Imperial College London, London W2 1PG, UK., Mosscrop LG; Department of Infectious Disease, Imperial College London, London W2 1PG, UK., Santiago LA; BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany., Vogel AB; BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany., Kariko K; BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany., Sahin U; BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany., Erbar S; BioNTech SE, An der Goldgrube 12, 55131 Mainz, Germany., Tregoning JS; Department of Infectious Disease, Imperial College London, London W2 1PG, UK.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2023 Oct 05; Vol. 34, pp. 102045. Date of Electronic Publication: 2023 Oct 05 (Print Publication: 2023).
DOI:	10.1016/j.omtn.2023.102045
Abstrakt:	The response to mRNA vaccines needs to be sufficient for immune cell activation and recruitment, but moderate enough to ensure efficacious antigen expression. The choice of the cap structure and use of N1-methylpseudouridine (m1Ψ) instead of uridine, which have been shown to reduce RNA sensing by the cellular innate immune system, has led to improved efficacy of mRNA vaccine platforms. Understanding how RNA modifications influence the cell intrinsic immune response may help in the development of more effective mRNA vaccines. In the current study, we compared mRNA vaccines in mice against influenza virus using three different mRNA formats: uridine-containing mRNA (D1-uRNA), m1Ψ-modified mRNA (D1-modRNA), and D1-modRNA with a cap1 structure (cC1-modRNA). D1-uRNA vaccine induced a significantly different gene expression profile to the modified mRNA vaccines, with an up-regulation of Stat1 and RnaseL , and increased systemic inflammation. This result correlated with significantly reduced antigen-specific antibody responses and reduced protection against influenza virus infection compared with D1-modRNA and cC1-modRNA. Incorporation of m1Ψ alone without cap1 improved antibodies, but both modifications were required for the optimum response. Therefore, the incorporation of m1Ψ and cap1 alters protective immunity from mRNA vaccines by altering the innate immune response to the vaccine material. Competing Interests: E.J.J., S.K., J.M., L.A.S., A.B.V., K.K., U.S., and S.E. are employees at BioNTech SE (Mainz, Germany). U.S. is cofounder and management board member of BioNTech SE (Mainz, Germany). A.B.V., K.K., U.S., and S.E. are inventors on patents and patent applications related to RNA technology. A.B.V., K.K., U.S., and S.E. hold securities from BioNTech SE. (© 2023 The Authors.)
Databáze:	MEDLINE
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