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AssigneeSanofi Pasteur Limited
InventorsTod Strugnell, Eliud Oloo
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The present invention provides, among other things, a novel and improved method for generating “mosaic” influenza antigenic polypeptides including hemagglutinin (HA) and neuraminidase (NA) polypeptides based on unique combination of epitope patterns that maximize exposure to epitopes present across multiple HA or NA sequences and therefore improved influenza strain coverage. In particular, the present invention provides engineered influenza B hemagglutinin (HA) polypeptides that are comprised of novel combinations of protective epitopes and antigenic regions from multiple influenza B viral strains. Such engineered HA polypeptides have improved properties over HA polypeptides developed through conventional approaches that rely on consensus alignments of viral sequences.
A method of engineering a mosaic influenza hemagglutinin (HA) polypeptide, comprising
A method of engineering a mosaic influenza hemagglutinin (HA) polypeptide, comprising
The method of any preceding claim, wherein the selecting step further comprises ranking the selected sequences by sequence identity, geographical location and/or isolation date of the type or subtype of influenza virus.
The method of any preceding claim, wherein the obtaining step further comprises identifying redundant sequences by screening the HA amino acid sequences for those with greater than 99.9% sequence identity, and removing all but one of the redundant sequences.
The method of any preceding claims, wherein the obtaining step comprises obtaining 100-5000 HA amino acid sequences from multiple circulating influenza strains.
The method of any preceding claims, wherein the obtaining step comprises obtaining all publicly available HA amino acid sequences.
The method of any preceding claims, further comprising:
The method of any of the preceding claims, wherein the epitopes are neutralizing epitopes.
The method of any of the preceding claims, wherein the epitopes are discontinuous epitopes.
The method of any of the preceding claims, wherein the epitopes are B cell epitopes.
The method of any of the preceding claims, wherein the particular type and/or subtype of influenza virus is a type A influenza virus.
A method of engineering a mosaic influenza neuraminidase (NA) polypeptide, comprising:
A method of engineering a mosaic influenza neuraminidase (NA) polypeptide, comprising:
An engineered mosaic influenza hemagglutinin (HA) polypeptide comprising a mosaic amino acid sequence pattern defined by amino acid substitutions at residues 110, 140, 141, 143, 145, 146, 153, 154, 155, 156, 165, 174, 175, 176, 177, 179, 180, 181, 209, 210, 211, 212, 215, 216, 217, 228, 258, 259, 279 or a subset thereof, in the receptor binding site (RBS), as indexed by reference to a B/Brisbane/60/2008 amino acid sequence.
An engineered mosaic influenza hemagglutinin (HA) polypeptide comprising a mosaic amino acid sequence pattern defined by amino acid substitutions 110F, 140I, 141D/N, 143E, 145A, 146P, 153G, 154T, 155S, 156G/R, 165S/I/N, 174A, 175V, 176P, 177K, 179D, 180N/S, 181N, 209H, 210S, 211D, 212N/D, 215Q, 216M, 217K/V, 228F, 258S, 259G, 279Q, or a subset thereof in the receptor binding site (RBS), as indexed by reference to a B/Brisbane/60/2008 amino acid sequence.
An engineered mosaic influenza hemagglutinin (HA) polypeptide comprising an amino acid sequence at least 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:40, wherein the amino acid sequence is not a naturally-occurring sequence.
An engineered mosaic influenza hemagglutinin (HA) polypeptide comprising an amino acid sequence at least 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:
An engineered mosaic influenza hemagglutinin (HA) polypeptide comprising an amino acid sequence at least 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:
An engineered mosaic influenza hemagglutinin (HA) polypeptide comprising an amino acid sequence at least 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:
An engineered mosaic influenza hemagglutinin (HA) polypeptide comprising an amino acid sequence at least 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:
An engineered mosaic influenza hemagglutinin (HA) polypeptide comprising an amino acid sequence at least 90%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:
Dependencies are inferred from the claim text.