Tessy A H Hick, Corinne Geertsema, Wilson Nguyen, Cameron R Bishop, Linda van Oosten, Sandra R Abbo, Troy Dumenil, Frank J M van Kuppeveld, Martijn A Langereis, Daniel J Rawle, Bing Tang, Kexin Yan, Monique M van Oers, Andreas Suhrbier, Gorben P Pijlman
{"title":"Safety concern of recombination between self-amplifying mRNA vaccines and viruses is mitigated in vivo.","authors":"Tessy A H Hick, Corinne Geertsema, Wilson Nguyen, Cameron R Bishop, Linda van Oosten, Sandra R Abbo, Troy Dumenil, Frank J M van Kuppeveld, Martijn A Langereis, Daniel J Rawle, Bing Tang, Kexin Yan, Monique M van Oers, Andreas Suhrbier, Gorben P Pijlman","doi":"10.1016/j.ymthe.2024.06.019","DOIUrl":null,"url":null,"abstract":"<p><p>Self-amplifying mRNA (SAM) vaccines can be rapidly deployed in the event of disease outbreaks. A legitimate safety concern is the potential for recombination between alphavirus-based SAM vaccines and circulating viruses. This theoretical risk needs to be assessed in the regulatory process for SAM vaccine approval. Herein, we undertake extensive in vitro and in vivo assessments to explore recombination between SAM vaccine and a wide selection of alphaviruses and a coronavirus. SAM vaccines were found to effectively limit alphavirus co-infection through superinfection exclusion, although some co-replication was still possible. Using sensitive cell-based assays, replication-competent alphavirus chimeras were generated in vitro as a result of rare, but reproducible, RNA recombination events. The chimeras displayed no increased fitness in cell culture. Viable alphavirus chimeras were not detected in vivo in C57BL/6J, Rag1<sup>-/-</sup> and Ifnar<sup>-/-</sup> mice, in which high levels of SAM vaccine and alphavirus co-replicated in the same tissue. Furthermore, recombination between a SAM-spike vaccine and a swine coronavirus was not observed. In conclusion we state that although the ability of SAM vaccines to recombine with alphaviruses might be viewed as an environmental safety concern, several key factors substantially mitigate against in vivo emergence of chimeric viruses from SAM vaccine recipients.</p>","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":null,"pages":null},"PeriodicalIF":12.1000,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.ymthe.2024.06.019","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/17 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Self-amplifying mRNA (SAM) vaccines can be rapidly deployed in the event of disease outbreaks. A legitimate safety concern is the potential for recombination between alphavirus-based SAM vaccines and circulating viruses. This theoretical risk needs to be assessed in the regulatory process for SAM vaccine approval. Herein, we undertake extensive in vitro and in vivo assessments to explore recombination between SAM vaccine and a wide selection of alphaviruses and a coronavirus. SAM vaccines were found to effectively limit alphavirus co-infection through superinfection exclusion, although some co-replication was still possible. Using sensitive cell-based assays, replication-competent alphavirus chimeras were generated in vitro as a result of rare, but reproducible, RNA recombination events. The chimeras displayed no increased fitness in cell culture. Viable alphavirus chimeras were not detected in vivo in C57BL/6J, Rag1-/- and Ifnar-/- mice, in which high levels of SAM vaccine and alphavirus co-replicated in the same tissue. Furthermore, recombination between a SAM-spike vaccine and a swine coronavirus was not observed. In conclusion we state that although the ability of SAM vaccines to recombine with alphaviruses might be viewed as an environmental safety concern, several key factors substantially mitigate against in vivo emergence of chimeric viruses from SAM vaccine recipients.
自扩增 mRNA (SAM) 疫苗可在疾病爆发时迅速部署。一个合理的安全问题是基于α-病毒的 SAM 疫苗与循环病毒之间可能发生重组。这种理论上的风险需要在 SAM 疫苗审批的监管过程中进行评估。在此,我们进行了广泛的体外和体内评估,以探讨 SAM 疫苗与多种阿尔巴病毒和一种冠状病毒之间的重组。研究发现,SAM 疫苗能通过排除超级感染有效限制阿尔巴病毒的共感染,但仍有可能出现一些共复制。利用敏感的细胞检测法,在体外生成了具有复制能力的α-病毒嵌合体,这是罕见但可重复的 RNA 重组事件的结果。这些嵌合体在细胞培养中没有显示出更强的适应性。在 C57BL/6J、Rag1-/- 和 Ifnar-/- 小鼠体内检测不到可行的字母病毒嵌合体,在这些小鼠体内,高水平的 SAM 疫苗和字母病毒在同一组织中共同复制。此外,也没有观察到 SAM 疫苗和猪冠状病毒之间的重组。总之,我们认为,虽然 SAM 疫苗与α-病毒重组的能力可能被视为一种环境安全问题,但有几个关键因素可大大降低 SAM 疫苗受体体内出现嵌合病毒的可能性。
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.