Live attenuated influenza virus vaccines by computer-aided rational design

Abstract

Influenza claims 250,000 - 500,000 lives annually worldwide. Despite existing vaccines and enormous efforts in biomedical research, these staggering numbers have not changed significantly over the last two decades1, motivating the search for new, more effective, vaccines that can be rapidly designed and easily produced. Using influenza virus strain A/PR/8/34, we describe a systematic, rational approach, termed Synthetic Attenuated Virus Engineering (SAVE), to develop new, efficacious live attenuated influenza virus vaccine candidates through genome-scale changes in codon pair bias. Attenuation is based on many hundreds of nucleotide changes across the viral genome, offering high genetic stability and a wide margin of safety. The method can be applied rapidly to any emerging influenza virus in its entirety, an advantage that is significant for dealing with seasonal epidemics and pandemic threats, such as H5N1- or 2009-H1N1 influenza.

Synthetic gene design—The rationale for codon optimization and implications for molecular pharming in plants

“…As discussed earlier, codon pair de-optimization has been used to synthesize novel viral vaccine candidates, validating that codon pair bias influences translational efficiency (Coleman et al 2008;Mueller et al 2010). Similarly, Moura et al considered 72 orthologous highly conserved genes from the three domains of life and showed that synonymous mutations were selected to maintain codon context biases (Moura et al 2011).…”

“…The approach, termed synthetic attenuated virus engineering (SAVE) has also been applied to influenza virus (Mueller et al 2010) and respiratory syncytial virus (Meng et al 2014).…”

Large-scale recoding of an arbovirus genome to rebalance its insect versus mammalian preference

“…We have been designing genes and viruses containing hundreds of unfavorable codon pairs, a process we call synthetic attenuated virus engineering. Recoded viral genomes are typically attenuated but strongly immunogenic in animals (16,22,23).…”

Constructing Orthogonal de Bruijn Sequences

“…In May 2010, Venter's group announced the first synthetic life form, a feat requiring synthesizing a 1.08 megabase bacterial chromosome [8]. The advent of cheap synthesis will have many exciting new applications throughout the life sciences (including our own work on synthetic vaccines [5,16,15]): the freedom to design new sequences to specification leads to a variety of new algorithmic problems on sequences.…”