Self-amplifying mRNA vaccines: Mode of action, design, development and optimization.

The mRNA-based vaccines are quality-by-design (QbD) immunotherapies that provide safe, tunable, scalable, streamlined and potent treatment possibilities against different types of diseases. The self-amplifying mRNA (saRNA) vaccines, as a highly advantageous class of mRNA vaccines, are inspired by the intracellular self-multiplication nature of some positive-sense RNA viruses. Such vaccine platforms provide a relatively increased expression level of vaccine antigen(s) together with self-adjuvanticity properties. Lined with the QbD saRNA vaccines, essential optimizations improve the stability, safety, and immunogenicity of the vaccine constructs. Here, we elaborate on the concepts and mode-of-action of mRNA and saRNA vaccines, articulate the potential limitations or technical bottlenecks, and explain possible solutions or optimization methods in the process of their design and development.