PROJECT SUMMARY/ABSTRACT The success of mRNA vaccines in controlling the COVID 19 pandemic has confirmed the efficacy of mRNA and has also provided a blueprint on how to construct these vectors in terms of structure and cost. We have recently developed a new mRNA platform that, unlike current mRNA vaccines/therapeutics, does not require a 5’ cap to function, dramatically reducing the cost. More efficient at protein translation than canonical (capped) mRNA vectors, these mRNA vectors initiate translation from an internal ribosomal entry site (IRES) and contain a specially designed self-folding secondary structure to protect the 5’ end against degradation, significantly improving its stability and protein expression. The produced mRNA does not require any additional modifications to be functional. This makes this mRNA design attractive for use as a vaccine or therapeutic. In this STTR Phase I proposal, investigators at CompoVax and the University of South Alabama will test this (capless) mRNA design as a vaccine and compare it against a classical (capped) mRNA vaccine in mice. The vaccines will express either the SARS-CoV-2 spike protein or the Influenza A hemagglutinin surface protein. The proposal will provide evidence that this capless mRNA vaccine platform can generate a robust immune response and can be used as an affordable substitution to current mRNA vaccines and therapeutics.