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1. WO2017136575 - COMPOSITIONS OF INFLUENZA HEMAGGLUTININ WITH HETEROLOGOUS EPITOPES AND/OR ALTERED MATURATION CLEAVAGE SITES

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Claims

1. A modified hemagglutinin (HA) protein of influenza A or B wherein an

immunodominant region of said HA protein contains a conserved alternative influenza epitope by insertion into said region or contains said epitope by replacing said region with said conserved alternative epitope of influenza.

2. The modified HA protein of claim 1 wherein the modified HA protein is contained in a live or attenuated virus or in a virus-like particle (VLP).

3. The modified HA protein of claim 2 which is contained in a live virus and the modified HA protein further comprises a modified maturation cleavage site (MCS) that is not cleaved by animal proteases.

4. The modified HA protein of claim 3 wherein the modified MCS has been cleaved by an appropriate protease.

5. The modified HA protein of any of claims 1-4 wherein the alternative epitope of influenza is an epitope from the stem domain of an influenza HA protein or is an epitope of the M2 influenza protein.

6. The modified HA protein of any of claims 1-4 wherein more than one

immunodominant region of said HA protein has been modified to contain an alternative influenza epitope.

7. The modified HA protein of claim 6 wherein at least some of the alternative influenza epitopes contained in each of said more than one immunodominant regions are different from each other.

8. A flu vaccine comprising the modified HA protein of any of claims 1-4.

9. A modified influenza virus wherein said virus comprises an influenza HA protein which has been modified to contain an MCS that is not cleaved by animal proteases.

10. The modified influenza virus of claim 9 wherein the MCS has been cleaved by an appropriate protease.

11. The modified influenza virus of claim 9 wherein the HA protein further contains a heterologous immunogenic epitope in at least one immunodominant region.

12. The modified influenza virus of claim 11 wherein the heterologous immunogenic epitope is of a tumor associated antigen or an epitope of a virus other than influenza or an alternate influenza epitope.

13. The modified influenza virus of claim 11 wherein more than one immunodominant region of said HA protein has been modified to contain a heterologous epitope.

14. The modified influenza virus of claim 13 wherein at least some of the heterologous epitopes contained in each of said more than one immunodominant regions are different from each other.

15. A modified HA protein modified to contain an MCS that is not cleaved by animal proteases and further contains a heterologous immunogenic epitope inserted in or that replaces at least one immunodominant region.

16. The modified HA protein of claim 15 wherein the MCS has been cleaved by an appropriate protease and/or wherein the heterologous immunogenic epitope is of a tumor associated antigen or an epitope of a virus other than influenza or an alternate influenza epitope.

17. A method to generate antibodies against flu which method comprises administering to a non-human subject the flu vaccine of claim 8.

18. The flu vaccine of claim 8 for use in a method to protect a subject against flu which method comprises administering said vaccine to said subject.

19. A method to generate antibodies against a desired antigen which method comprises administering to a subject the modified influenza virus of any of claims 9-14.

20. A nucleic acid encoding at least an effective portion of an influenza HA protein wherein a nucleotide sequence encoding an alternative epitope of an influenza protein is inserted into or replaces a nucleotide sequence encoding an immunodominant region of said HA protein.

21. The nucleic acid of claim 20 wherein a nucleotide sequence encoding the MCS is modified to encode MCS that is not cleaved by animal proteases.

22. The nucleic acid of claim 20 wherein more than one region encoding

immunodominant region of said HA protein has been modified to contain a nucleotide sequence encoding an alternative influenza epitope.

23. The nucleic acid of claim 21 wherein more than one region encoding

immunodominant region of said HA protein has been modified to contain a nucleotide sequence encoding an alternative influenza epitope.

24. A nucleic acid encoding at least an effective portion of an influenza HA protein wherein a nucleotide sequence encoding the MCS is modified to encode a MCS that is not cleaved by animal proteases.

25. The nucleic acid of claim 24 wherein a nucleotide sequence encoding a

heterologous epitope is inserted into or replaces a nucleotide sequence encoding an

immunodominant region of said HA protein.

26. The nucleic acid of claim 25 wherein more than one region encoding

immunodominant region of said HA protein has been modified to contain a nucleotide sequence encoding a heterologous epitope.

27. A nucleic acid that expresses in a recombinant host cell encoding the nucleotide sequence(s) of any of claims 20-26.

28. Recombinant host cells that contain the nucleic acid of claim 27.

29. A method to prepare the modified HA protein of claim 1 which method comprises culturing recombinant host cells comprising a nucleic acid encoding at least an effective portion of an influenza HA protein, wherein a nucleotide sequence encoding an alternative epitope of an influenza protein is inserted into or replaces a nucleotide sequence encoding an immunodominant region of said HA protein, under conditions wherein said nucleic acid is expressed and recovering the modified HA protein.

30. A method to prepare the modified HA protein of claim 3 which method comprises culturing recombinant host cells comprising a nucleic acid encoding at least an effective portion of an influenza HA protein wherein a nucleotide sequence encoding an alternative epitope of an influenza protein is inserted into or replaces a nucleotide sequence encoding an immunodominant region of said HA protein, and wherein a nucleotide sequence encoding the MCS is modified to encode an MCS that is not cleaved by animal proteases, under conditions wherein said nucleic acid is expressed and recovering the modified HA protein.

31. A method to prepare the modified influenza virus of claim 9 which method comprises culturing recombinant host cells comprising a nucleic acid of encoding at least an effective portion of an influenza HA protein, wherein a nucleotide sequence encoding the MCS is modified to encode an MCS that is not cleaved by animal proteases, under conditions wherein said nucleic acid is expressed and recovering the modified influenza virus.

32. A method to prepare the modified influenza virus of claim 11 which method comprises culturing recombinant host cells comprising a nucleic acid encoding at least an effective portion of an influenza HA protein, wherein a nucleotide sequence encoding the MCS is modified to encode an MCS that is not cleaved by animal proteases and wherein at least one nucleotide sequence encoding an immunodominant region of said HA protein has been modified to contain a nucleotide sequence encoding a heterologous epitope, under conditions wherein said nucleic acid is expressed and recovering the modified influenza virus.

33. A method to generate antibodies against flu which method comprises administering to a non-human subject the nucleic acid of any of claims 20-27.

34. The nucleic acid of any of claims 20-27 for use in a method to protect a subject against flu which method comprises administering said nucleic acid to said subject.

35. A method to generate antibodies against a desired antigen which method comprises administering to a subject the nucleic acid of any of claims 20-27.