The development of vaccines has significantly reduced the global burden of infectious diseases. Among various vaccine platforms, DNA vaccines stand out for their stability, while mRNA vaccines are recognized for their efficient antigen expression, as demonstrated during the SARS-CoV-2 pandemic. Despite these advances, challenges remain, including the induction of long-lasting immunity, safety concerns, and the need to broaden T cell responses.
Self-amplifying RNA (saRNA) vaccines, inspired by the replication machinery of alphaviruses, have emerged as a promising alternative due to its high efficiency. In saRNA vaccine design, the non-structural replication elements are retained, while the structural protein coding sequences are replaced with an antigen of interest. This design enables efficient intracellular RNA amplification and enhanced antigen expression compared with conventional non-replicating RNA vaccines. However, saRNA platforms also face challenges, including recombination events, cytopathogenicity, and RNA instability.
We have discovered one specific virus which exhibits no recombination events of a duplicated fluorescent transgene over 14 in vitro passages while other members of the family typically recombine in less than 5 passages. We are currently optimizing a saRNA backbone version based on this virus for use in a pathogen-agnostic vaccine platform. On going optimizations include production, packaging and safety, and will then be evaluated for in vivo immunogenicity. Ultimately, this work provides insights to advance the design of safer and cost-efficient saRNA-based vaccines and therapeutics, expanding their potential clinical applications.