The disclosed compositions and methods provide an approach for the rational development of a live attenuated virus to be used as a vaccine, vaccine seed strain, therapy, and/or research tool. Methods are disclosed to generate a virus that is phenotypically wild-type but genetically attenuated. The virus would 'look' like the pathogenic virus and, upon vaccination, the initial viral infection would be largely, if not fully, indistinguishable from that initiated by its pathogenic counterpart, leading to the most relevant and robust immune response. However, because the genome is attenuated, the viruses generated by the initial round of infection would be phenotypically attenuated. This approach can be applied to any virus that, upon the introduction of select mutations, can be propagated with an organism or system that utilizes an alternative genetic code.