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Live attenuated influenza virus vaccines by computer-aided rational design


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.

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Figure 1: Characterization in tissue culture of synthetic codon pair–deoptimized influenza viruses.
Figure 2: Attenuation of codon pair–deoptimized influenza virus PR83F in BALB/c mice.
Figure 3: Immune responses and protection.

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The authors are indebted to A. García-Sastre and P. Palese for sharing with us their 8-plasmid system for PR8, antibodies, and information. We thank A. Paul and J. Cello for comments on the manuscript. Supported by National Institutes of Health grants AI075219 and AI15122 (EW) and a TRO-Fusion Award by Stony Brook University (S.M. and S.S.).

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Authors and Affiliations



S.M. designed and carried out the majority of the study and wrote the paper. J.R.C. and A.N. carried out experiments contributing to Figures 1c and 2. D.P., C.B.W. and S.S. developed computer design and analysis algorithms. B.F. and E.W. contributed to the design of the study and writing of the paper.

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Correspondence to Steffen Mueller.

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All authors declare they have a patent pending relating to certain aspects of this work.

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Mueller, S., Coleman, J., Papamichail, D. et al. Live attenuated influenza virus vaccines by computer-aided rational design. Nat Biotechnol 28, 723–726 (2010).

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