Attenuation of human respiratory syncytial virus by genome scale codon-pair deoptimization
AssigneesThe United States of America, AS Represented By the Secretary, Department of He, The Research Foundation for The State University of New York
InventorsPeter L. COLLINS, Cyril LE NOUEN, Linda G. BROCK, Ursula J. BUCHHOLZ, Joshua Marc DINAPOLI, Steffen MUELLER, Eckard WIMMER
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Abstract
Described herein are RSV polynucleotide sequences that make use of multiple codons that are containing silent nucleotide substitutions engineered in multiple locations in the genome, wherein the substitutions introduce a numerous synonymous codons into the genome. Due to the large number of defects involved, the attenuated viruses disclosed herein provide a means of producing attenuated, live vaccines against RSV.
Claims51
A recombinant polynucleotide encoding a respiratory syncytial virus (RSV) amino acid sequence of a parent RSV, comprising a nucleotide sequence that has from about 77% to about 93% identity with the corresponding nucleotide sequence of the parent virus genome.
A recombinant polynucleotide encoding at least two RSV proteins having amino acid sequences of a parent RSV, comprising separate nucleotide sequences encoding each of the RSV proteins that have from about 77% to about 93% identity with the corresponding nucleotide sequence of the parent virus genome.
A recombinant RSV genome or antigenome comprising the genome encoded by pRSV_Min A, pRSV_Min B, pRSV_Min L, pRSV_Min FLC, pRSV_Min L_N, pRSV_Min L_p, pRSV_Min L_M21, pRSV_Min L_NP, pRSV_Min L_NM21, pRSV_Min L_PM21, or pRSV_Min L_NPM21.
A recombinant RSV genome or antigenome comprising a nucleotide change in one or more of the following:
- a. a change in the codon encoding amino acid 136 of the N protein,
- b. a change in the codon encoding amino acid 114 of the P protein, or
- c. a change in the codon encoding amino acid 88 of the M2-1 protein.
The recombinant RSV genome or antigenome of claim 52, wherein any one of said nucleotide changes causes an amino acid other than:
- a. lysine to be encoded at position 136 of the N protein,
- b. glutamic acid to be encoded at position 114 of the P protein, or
- c. asparagine to be encoded at position 88 of the M2-1 protein.
The recombinant RSV genome or antigenome of claim 53, wherein arginine is encoded at position 136 of the N protein, valine is encoded at position 114 of the P protein, and/or lysine is encoded at position 88 of the M2-1 protein.
Dependencies are inferred from the claim text.