Self-amplifying RNA—opportunities and challenges

Messenger (m)RNA vaccines have made great strides in the past 5 years, highlighted by the rapid development of effective vaccines against SARS-CoV-2. mRNA vaccines have distinct advantages over other vaccine platforms, including modular design, rapid development, cell free manufacture, and the ability to express antigen genes of interest in situ resulting in efficacious immunogenicity, including for traditionally challenging membrane proteins [1]. The insights and technologies behind mRNA vaccines are now expanding to additional platform technologies, including other large RNA modalities such as self-amplifying RNA (saRNA). The first saRNA vaccine human drug product was recently approved, demonstrating the progress of this platform for clinical applications [2,3]. This commentary will focus on design and performance differences between conventional mRNA, as a reference point, and saRNA. Current challenges will be highlighted along with ongoing areas of improvement including saRNA design, production, and innate activation.

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