Live attenuated influenza virus vaccines by computer-aided rational design

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Abstract
Live attenuated viruses make more effective vaccines than newer protein subunit or recombinant DNA vaccines, but the traditional passaging methods used to generate them often fail to produce a suitable mutant. Mueller et al. improve the production of live attenuated influenza virus by extensive manipulation of codon-pair bias across the genome, which minimizes the risk of reversion to a virulent form. Despite existing vaccines and enormous efforts in biomedical research, influenza annually claims 250,000–500,000 lives worldwide1, motivating the search for new, more effective vaccines that can be rapidly designed and easily produced. We applied the previously described synthetic attenuated virus engineering (SAVE)2 approach to influenza virus strain A/PR/8/34 to rationally design live attenuated influenza virus vaccine candidates through genome-scale changes in codon-pair bias. As attenuation is based on many hundreds of nucleotide changes across the viral genome, reversion of the attenuated variant to a virulent form is unlikely. Immunization of mice by a single intranasal exposure to codon pair–deoptimized virus conferred protection against subsequent challenge with wild-type (WT) influenza virus. The method can be applied rapidly to any emerging influenza virus in its entirety, an advantage that is especially relevant when dealing with seasonal epidemics and pandemic threats, such as H5N1- or 2009-H1N1 influenza.