| Summary: | <p>Abstract</p> <p>Background</p> <p>Viral diversity is a key problem for the design of effective and universal vaccines. Virtually, a vaccine candidate including most of the diversity for a given epitope would force the virus to create escape mutants above the viability threshold or with a high fitness cost.</p> <p>Presentation of the hypothesis</p> <p>Therefore, I hypothesize that priming the immune system with polyvalent vaccines where each single vehicle generates and displays multiple antigen variants <it>in vivo</it>, will elicit a broad and long-lasting immune response able to avoid viral escape.</p> <p>Testing the hypothesis</p> <p>To this purpose, I propose the use of yeasts that carry virus-like particles designed to pack the antigen-coding RNA inside and replicate it via RNA-dependent RNA polymerase. This would produce diversity <it>in vivo </it>limited to the target of interest and without killing the vaccine vehicle.</p> <p>Implications of the hypothesis</p> <p>This approach is in contrast with peptide cocktails synthesized <it>in vitro </it>and polyvalent strategies where every cell or vector displays a single or definite number of mutants; but similarly to all them, it should be able to overcome original antigenic sin, avoid major histocompatibility complex restriction, and elicit broad cross-reactive immune responses. Here I discuss additional advantages such as minimal global antagonism or those derived from using a yeast vehicle, and potential drawbacks like autoimmunity. Diversity generated by this method could be monitored both genotypically and phenotypically, and therefore selected or discarded before use if needed.</p>
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