AI Summary
This research focuses on the impact of incorporating the modified nucleoside N1-methyl-pseudouridine (1mΨ) into self-amplifying RNAs (saRNAs) used in vaccine platforms based on different positive-stranded RNA viruses. The study found that the effects of 1mΨ varied depending on the specific virus backbone, with impairments in different stages of the replication process observed. While TNCL and coxsackievirus B3 showed negative effects on replication and translation, respectively, Semliki forest virus did not show significant differences in in vitro studies. The study highlights the importance of considering the specific characteristics of different virus-based replicons when designing saRNA vaccines for potential immunization strategies.
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.
With the implementation of global immunization protocols against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including messenger RNA (mRNA) vaccines, during the COVID-19 pandemic,