Re-adenylation by TENT5A enhances efficacy of SARS-CoV-2 mRNA vaccines

Paweł S. Krawczyk, Michał Mazur, Wiktoria Orzeł, Olga Gewartowska, Sebastian Jeleń, Wiktor Antczak, Karolina Kasztelan, Aleksandra Brouze, Katarzyna Matylla-Kulińska, Natalia Gumińska, Bartosz Tarkowski, Ewelina P. Owczarek, Kamila Affek, Paweł Turowski, Agnieszka Tudek, Małgorzata Sroka, Tomasz Śpiewla, Monika Kusio-Kobiałka, Aleksandra Wesołowska, Dominika Nowis, Jakub Golab, Joanna Kowalska, Jacek Jemielity, Andrzej Dziembowski () and Seweryn Mroczek ()
Additional contact information
Paweł S. Krawczyk: International Institute of Molecular and Cell Biology
Michał Mazur: International Institute of Molecular and Cell Biology
Wiktoria Orzeł: International Institute of Molecular and Cell Biology
Olga Gewartowska: International Institute of Molecular and Cell Biology
Sebastian Jeleń: International Institute of Molecular and Cell Biology
Wiktor Antczak: International Institute of Molecular and Cell Biology
Karolina Kasztelan: International Institute of Molecular and Cell Biology
Aleksandra Brouze: International Institute of Molecular and Cell Biology
Katarzyna Matylla-Kulińska: International Institute of Molecular and Cell Biology
Natalia Gumińska: International Institute of Molecular and Cell Biology
Bartosz Tarkowski: International Institute of Molecular and Cell Biology
Ewelina P. Owczarek: International Institute of Molecular and Cell Biology
Kamila Affek: International Institute of Molecular and Cell Biology
Paweł Turowski: ExploRNA Therapeutics
Agnieszka Tudek: Institute of Biochemistry and Biophysics
Małgorzata Sroka: International Institute of Molecular and Cell Biology
Tomasz Śpiewla: University of Warsaw
Monika Kusio-Kobiałka: International Institute of Molecular and Cell Biology
Aleksandra Wesołowska: Medical University of Warsaw
Dominika Nowis: Medical University of Warsaw
Jakub Golab: Medical University of Warsaw
Joanna Kowalska: University of Warsaw
Jacek Jemielity: University of Warsaw
Andrzej Dziembowski: International Institute of Molecular and Cell Biology
Seweryn Mroczek: International Institute of Molecular and Cell Biology

Nature, 2025, vol. 641, issue 8064, 984-992

Abstract: Abstract Despite the widespread use of mRNA vaccines against COVID-19, little is known about the metabolism of therapeutic RNAs. Here we use nanopore sequencing1–3 to analyse individual therapeutic mRNA molecules, focusing on their poly(A) tails. We show that the Moderna mRNA-1273 vaccine4 has a poly(A) tail of around 100 nucleotides, followed by an mΨCmΨAG sequence. In cell lines, mRNA-1273 undergoes rapid degradation initiated by mΨCmΨAG removal, followed by CCR4–NOT-mediated deadenylation. However, in medically relevant preclinical models, particularly in macrophages, mRNA-1273 poly(A) tails are extended to up to 200 nucleotides by the TENT5A poly(A) polymerase5–7, which is induced by the vaccine. Re-adenylation, which stabilizes target mRNAs, is consistently observed in synthetic mRNAs that encode proteins targeted to the endoplasmic reticulum, such as ovalbumin or antigens from Zika virus8 or the malaria parasite9. The extent of re-adenylation varies: the BioNTech–Pfizer BNT162b2 vaccine10 shows less potent re-adenylation than mRNA-1273, which correlates with a smaller proportion of membrane-associated BNT162b2. This highlights the crucial role of spatial accessibility to ER-resident TENT5A in determining re-adenylation efficiency. In vivo, TENT5A is expressed in immune cells that take up mRNA vaccine, and TENT5A deficiency reduces specific immunoglobulin production for mRNA vaccines after immunization in mice. Overall, our findings reveal a principle for enhancing the efficacy of therapeutic mRNAs, paving the way for improvement.

Date: 2025
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DOI: 10.1038/s41586-025-08842-1

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