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Cited by 47RNA and protein synthesis mechanismsSARS-CoV-2 and COVID-19 Researchvaccines and immunoinformatics approaches

A novel deep generative model for mRNA vaccine development: Designing 5′ UTRs with N1-methyl-pseudouridine modification

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Tang, Xiaoshan, Huo, Miaozhe, Chen, Yuting, Huang, Hai, Qin, Shugang, Luo, Jiaqi, Qin, Zeyi, Jiang, Xin +11 more·2024·Acta Pharmaceutica Sinica B
DOI 10.1016/j.apsb.2023.11.003PMC PMC10985129
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Abstract

Efficient translation mediated by the 5ʹ untranslated region (5ʹ UTR) is essential for the robust efficacy of mRNA vaccines. However, the N1-methyl-pseudouridine (m1Ψ) modification of mRNA can impact the translation efficiency of the 5ʹ UTR. We discovered that the optimal 5ʹ UTR for m1Ψ-modified mRNA (m1Ψ–5ʹ UTR) differs significantly from its unmodified counterpart, highlighting the need for a specialized tool for designing m1Ψ–5ʹ UTRs rather than directly utilizing high-expression endogenous gene 5ʹ UTRs. In response, we developed a novel machine learning-based tool, Smart5UTR, which employs a deep generative model to identify superior m1Ψ–5ʹ UTRs in silico. The tailored loss function and network architecture enable Smart5UTR to overcome limitations inherent in existing models. As a result, Smart5UTR can successfully design superior 5ʹ UTRs, greatly benefiting mRNA vaccine development. Notably, Smart5UTR-designed superior 5ʹ UTRs significantly enhanced antibody titers induced by COVID-19 mRNA vaccines against the Delta and Omicron variants of SARS-CoV-2, surpassing the performance of vaccines using high-expression endogenous gene 5ʹ UTRs.

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  • In mRNA vaccines, use of different 5′ UTR sequences can substantially enhance immunological properties, including increased antibody titers and improved T-cell responses.

    “In the setting of mRNA vaccines, the use of different 5′ UTR sequences can substantially enhance immunological properties, including increased antibody titers and improved T-cell responses [18,19].”

    From Identification of novel 5’ UTR variants for enhanced mRNA translation and vaccine immunogenicity (2026) · cites this paper as [19]

    The Results section reports substantially higher antibody titers in mice given COVID-19 mRNA vaccines with Smart5UTR-designed 5′ UTRs than with the comparator 5′ UTR. It reports antibody responses, but does not establish the claimed improvement in T-cell responses; the demonstrated finding is also specific to these vaccines in mice. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Several synthetic 5′ UTR sequences have demonstrated strong performance.

    “However, several synthetic sequences have also demonstrated strong performance [14,19].”

    From Identification of novel 5’ UTR variants for enhanced mRNA translation and vaccine immunogenicity (2026) · cites this paper as [19]

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Research works printed but not linked: 31

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Authors
Tang, X., Huo, M., Chen, Y., Huang, H., Qin, S., Luo, J., Qin, Z., Jiang, X., Liu, Y., Duan, X., Wang, R., Chen, L., Li, H., Fan, N., He, Z., He, X., Shen, B., Li, S. C., & Song, X.
Affiliations
  • Sichuan University (CN)
  • City University of Hong Kong (HK)
  • Brandeis University (US)
Corresponding author
  • Shen, Bairong
  • Li, Shuai Cheng
  • Song, Xiangrong
ORCID
Venue
Acta Pharmaceutica Sinica B
Publisher
Elsevier BV
Published
2024-04
Volume
14
Issue
4
Pages
1814-1826
ISSN
2211-3835 (ISSN-L)
DOI
10.1016/j.apsb.2023.11.003
PMC
PMC10985129
OpenAlex
W4388378396
Cited by
47
References
4
Citations by year
2026: 24 · 2025: 18 · 2024: 5
FWCI
4.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Pharmaceutica Sinica B (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • CityU Scholars (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Zhejiang University
  • Sichuan Province Science and Technology Support Program (2018ZX09201018, 2022YFH0001, 2021YFH0003)
  • West China Hospital, Sichuan University (2018ZX09201018)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
mRNA vaccine design, 5' untranslated region, deep generative models, translation efficiency, COVID-19 mRNA vaccine, Omicron variant, Delta variant, antibody titers

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