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.
摘要：
自扩增mRNA(SAM)疫苗可以在疾病爆发时快速部署。合理的安全问题是基于甲病毒的SAM疫苗和循环病毒之间的重组潜力。这种理论风险需要在SAM疫苗批准的监管过程中进行评估。在这里，我们进行了广泛的体外和体内评估，以探索SAM疫苗与多种甲病毒和冠状病毒之间的重组。发现SAM疫苗通过超感染排除有效地限制甲病毒共感染，尽管一些共同复制仍然是可能的。使用敏感的基于细胞的检测，复制能力的甲病毒嵌合体在体外产生，但可重现，RNA重组事件。嵌合体在细胞培养中没有显示出增加的适应性。在C57BL/6J体内未检测到有活力的甲病毒嵌合体，Rag1-/-和Ifnar-/-小鼠，其中高水平的SAM疫苗和甲病毒在同一组织中共同复制。此外，没有观察到SAM-spike疫苗和猪冠状病毒之间的重组。总之，尽管SAM疫苗与α病毒重组的能力可能被视为环境安全问题，几个关键因素在很大程度上缓解了SAM疫苗接受者体内嵌合病毒的出现。
