1mΨ influences the performance of various positive-stranded RNA virus-based replicons

• Published in: Scientific reports Vol. 14; no. 1; pp. 17634 - 13
• Main Authors: Miyazato, Paola, Noguchi, Takafumi, Ogawa, Fumiyo, Sugimoto, Takeshi, Fauzyah, Yuzy, Sasaki, Ryo, Ebina, Hirotaka
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31-07-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/326/590; 631/326/596; Animals; DNA-directed RNA polymerase; Enterovirus B, Human - genetics; Enterovirus B, Human - physiology; Humanities and Social Sciences; Humans; Immune response; Immunogenicity; Innate immunity; Modified nucleosides; mRNA stability; multidisciplinary; N1-Methyl-pseudouridine; Nodavirus; Positive-Strand RNA Viruses - genetics; Pseudouridine - metabolism; Replication; Replicon - genetics; Replicons; RNA polymerase; RNA Stability; RNA viruses; RNA, Viral - genetics; RNA-Dependent RNA Polymerase - genetics; RNA-Dependent RNA Polymerase - metabolism; RNA-directed RNA polymerase; Science; Science (multidisciplinary); Semliki forest virus - genetics; Vaccines; Viral replication; Virus Replication; Viruses; Modified nucleosides; Viral replication; N1-Methyl-pseudouridine; Replicons; Nodavirus
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-68617-y

Self-amplifying RNAs (saRNAs) are versatile vaccine platforms that take advantage of a viral RNA-dependent RNA polymerase (RdRp) to amplify the messenger RNA (mRNA) of an antigen of interest encoded within the backbone of the viral genome once inside the target cell. In recent years, more saRNA vaccines have been clinically tested with the hope of reducing the vaccination dose compared to the conventional mRNA approach. The use of N1-methyl-pseudouridine (1mΨ), which enhances RNA stability and reduces the innate immune response triggered by RNAs, is among the improvements included in the current mRNA vaccines. In the present study, we evaluated the effects of this modified nucleoside on various saRNA platforms based on different viruses. The results showed that different stages of the replication process were affected depending on the backbone virus. For TNCL, an insect virus of the
Alphanodavirus
genus, replication was impaired by poor recognition of viral RNA by RdRp. In contrast, the translation step was severely abrogated in coxsackievirus B3 (CVB3), a member of the
Picornaviridae
family. Finally, the effects of 1mΨ on Semliki forest virus (SFV), were not detrimental in in vitro studies, but no advantages were observed when immunogenicity was tested in vivo.