Application of self-amplifying mRNA technology in the development of infectious disease vaccines
The mRNA vaccine has become a promising platform for prevention and treatment of infectious diseases due to its advantages of high efficacy,low risk of genetic integration and rapid development cycle.The current mRNA technologies include three types of synthetic RNAs which are conventional linear mRNA,circular RNA and self-amplifying mRNA(saRNA).Both conventional linear mRNA and circular RNA are non-amplifying,and the protein expression levels depend on the amount of RNAs delivered into cells.Therefore,high mRNA doses and repetitive vaccination of the conventional mRNA vaccines are often required to induce adequate immune responses.saRNAs are derived from the genomes of positive-strand RNA viruses in which the coding sequences of viral structural proteins are replaced by a heterologous gene of interest(GOI).saRNAs carry the viral replicase genes and therefore maintain self-replicative activity in the host cells,leading to enhanced and lasting expression of the GOI.It has been reported that compared to the conventional mRNA vaccines,lower doses of saRNAs can provide similar expression levels of the antigens and stimulate equivalent or even more potent immune responses in vivo.Therefore,compared to conventional mRNA vaccines,the saRNA-based vaccines have potential to decrease the initial RNA dosage and immunization frequency,thereby minimizing the potential side effects associated with the delivery materials and also making the vaccination less costly.However,the development of saRNA vaccines faces greater challenges than conventional mRNA vaccines.Due to the large size of the genome,the synthesis and delivery of saRNA is more difficult than that of conventional mRNA.In addition,the self-replicating property of saRNAs also increases their innate immunogenicity,which may lead to degradation of saRNAs and interfere with the therapeutic outcome of GOI.In recent years,tremendous efforts have been put into the optimization of saRNA synthesis,vector design and delivery systems to overcome these issues,and the relevant advances have facilitated the development of saRNA vaccines.Several saRNA vaccine candidates against a variety of infectious diseases have been reported to show protective effects in preclinical studies,and the vaccines against rabies virus and SARS-CoV-2 have been subjected to clinical trials,demonstrating the superior potential of saRNA vaccines in combating infectious diseases.In this review,we described the technologies that support the development of saRNA vaccines,including their mechanism of action,the in vitro RNA synthesis,the progress in the delivery systems,and the strategies of vector optimization in the effort to increase the efficiency of saRNA vaccines.We provided a detailed overview of the developing saRNA vaccine candidates against various virus infections,and summarized the general design strategies for saRNA vaccines against viral diseases.In addition to the application in vaccines,we have also proposed other directions for saRNA in the prevention and treatment of infectious diseases.
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