A novel deep generative model for mRNA vaccine development: Designing 5' UTRs with <i>N</i>1-methyl-pseudouridine modification.

Tang, Xiaoshan; Huo, Miaozhe; Chen, Yuting; Huang, Hai; Qin, Shugang; Luo, Jiaqi; Qin, Zeyi; Jiang, Xin; Liu, Yongmei; Duan, Xing; Wang, Ruohan; Chen, Lingxi; Li, Hao; Fan, Na; He, Zhongshan; He, Xi; Shen, Bairong; Li, Shuai Cheng; Song, Xiangrong

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

Tang, Xiaoshan; Huo, Miaozhe; Chen, Yuting; Huang, Hai; Qin, Shugang; Luo, Jiaqi; Qin, Zeyi; Jiang, Xin; Liu, Yongmei; Duan, Xing; Wang, Ruohan; Chen, Lingxi; Li, Hao; Fan, Na; He, Zhongshan; He, Xi; Shen, Bairong; Li, Shuai Cheng; Song, Xiangrong.

Afiliación

Tang X; Institute of Systems Genetics, Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.
Huo M; Department of Computer Science, City University of Hong Kong, Hong Kong 99907, China.
Chen Y; Institute of Systems Genetics, Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.
Huang H; Institute of Systems Genetics, Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.
Qin S; Institute of Systems Genetics, Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.
Luo J; Department of Computer Science, City University of Hong Kong, Hong Kong 99907, China.
Qin Z; Department of Biology, Brandeis University, Boston, MA 02453, USA.
Jiang X; Institute of Systems Genetics, Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.
Liu Y; Institute of Systems Genetics, Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.
Duan X; Institute of Systems Genetics, Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.
Wang R; Department of Computer Science, City University of Hong Kong, Hong Kong 99907, China.
Chen L; Department of Computer Science, City University of Hong Kong, Hong Kong 99907, China.
Li H; Institute of Systems Genetics, Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.
Fan N; Institute of Systems Genetics, Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.
He Z; Institute of Systems Genetics, Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.
He X; Institute of Systems Genetics, Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.
Shen B; Institute of Systems Genetics, Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.
Li SC; Department of Computer Science, City University of Hong Kong, Hong Kong 99907, China.
Song X; Institute of Systems Genetics, Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610000, China.

Acta Pharm Sin B ; 14(4): 1814-1826, 2024 Apr.

Article en En | MEDLINE | ID: mdl-38572113

ABSTRACT

ABSTRACT

Efficient translation mediated by the 5' untranslated region (5' 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 5' UTR. We discovered that the optimal 5' UTR for m1Ψ-modified mRNA (m1Ψ-5' UTR) differs significantly from its unmodified counterpart, highlighting the need for a specialized tool for designing m1Ψ-5' UTRs rather than directly utilizing high-expression endogenous gene 5' UTRs. In response, we developed a novel machine learning-based tool, Smart5UTR, which employs a deep generative model to identify superior m1Ψ-5' 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 5' UTRs, greatly benefiting mRNA vaccine development. Notably, Smart5UTR-designed superior 5' 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 5' UTRs.

Palabras clave

5' UTR; COVID-19; Machine learning; N1-Methyl-pseudouridine; SARS-CoV-2; Sequence design; mRNA design; mRNA vaccine

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