Methods of treatment with compositions that include hemagglutinin
Methods that stimulate a protective immune response in a subject include a portion of a protein from a naturally occurring viral hemagglutinin, wherein the protein portion includes at least a portion of a globular head and at least a portion of at least one secondary structure that causes the globular head to essentially retain its tertiary structure, and wherein the protein portion lacks a transmembrane domain, a cytoplasmic domain and an HA2 subunit. Compositions administered to the subject can further include a carrier and can be administered in single or multiple doses.
1. A method of stimulating an immune response in a subject, comprising the step of administering to the subject a composition that includes at least one fusion protein comprising at least a portion of at least one flagellin that initiates an intracellular signal transduction pathway for a Toll-like Receptor and a portion of a protein of a naturally occurring influenza viral hemagglutinin, wherein the portion lacks a transmembrane domain, a cytoplasmic domain and an HA2 subunit and includes at least a portion of a globular head and at least a portion of at least one secondary structure having at least one β-sheet at a bottom of the portion of the globular head that causes the portion of the globular head to essentially retain its tertiary structure.
2. The method of claim 1 , wherein the composition administered to the subject further includes a carrier protein.
3. The method of claim 1 , wherein the fusion protein includes an amino acid linker between the flagellin and the portion of the naturally occurring influenza viral hemagglutinin.
4. The method of claim 1 , wherein the portion of the flagellin of the fusion protein administered to the subject includes at least one member selected from the group consisting of Salmonella typhimurium flagellin, an E coli flagellin, a S. muenchen flagellin, a Yersinia flagellin , a P. aeruginosa flagellin and a L. monocytogenes flagellin.
5. The method of claim 1 , wherein the portion of the protein of the naturally occurring influenza viral hemagglutinin of the fusion protein administered to the subject includes an HA1-1 portion of the naturally occurring influenza viral hemagglutinin.
6. The method of claim 5 , wherein the fusion protein includes an amino acid linker between the flagellin and the HA1-1 portion.
7. The method of claim 1 , wherein the portion of the protein of the naturally occurring influenza viral hemagglutinin of the fusion protein administered to the subject includes an HA1-2 portion of the naturally occurring influenza viral hemagglutinin.
8. The method of claim 7 , wherein the fusion protein includes an amino acid linker between the flagellin and the HA1-2 portion.
9. The method of claim 1 , wherein the portion of the protein of the naturally occurring influenza viral hemagglutinin of the fusion protein administered to the subject is not glycosylated.
10. The method of claim 1 , wherein the portion of the protein of the naturally occurring influenza viral hemagglutinin of the fusion protein administered to the subject further includes at least one β-sandwich at the bottom of the portion of the globular head.
11. The method of claim 10 , wherein the portion of the protein of the naturally occurring influenza viral hemagglutinin of the fusion protein administered to the subject further includes at least two β-strands at the bottom of the portion of the globular head.
12. The method of claim 1 , wherein the portion of the protein of the naturally occurring influenza viral hemagglutinin of the fusion protein administered to the subject is a portion of an influenza A viral hemagglutinin.
13. The method of claim 12 , wherein the influenza A viral hemagglutinin is at least one member selected from the group consisting of a H1, H2, H3, H5, H7 and H9 strain.
14. The method of claim 1 , wherein the portion of the protein of the naturally occurring influenza viral hemagglutinin of the fusion protein administered to the subject is a portion of an influenza B viral hemagglutinin.
15. The method of claim 14 , wherein the influenza A viral hemagglutinin includes at least one of an H3 and an H5 strain.
16. The method of claim 1 , wherein the portion of the protein of the naturally occurring influenza viral hemagglutinin of the fusion protein administered to the subject is a portion of an influenza C viral hemagglutinin.
17. The method of claim 1 , wherein the flagellin of the fusion protein administered to the subject is not glycosylated.
18. The method of claim 17 , wherein the portion of the protein of the naturally occurring influenza viral hemagglutinin of the fusion protein administered to the subject is not glycosylated.
19. The method of claim 1 , wherein the fusion protein is administered to the subject in a single dose.
20. The method of claim 19 , wherein the single dose is administered to the subject intramuscularly.
21. The method of claim 1 , wherein the fusion protein is administered to the subject in multiple doses.
22. The method of claim 21 , wherein the multiple doses are administered to the subject intramuscularly.
23. The method of claim 1 , wherein:
i) the flagellin and the portion of the naturally occurring influenza viral hemagglutinin of the fusion protein administered to the subject includes an amino acid linker between the flagellin and the portion of the naturally occurring influenza viral hemagglutinin; and
ii) the naturally occurring influenza viral hemagglutinin is a H3 strain of influenza A.
24. The method of claim 23 , wherein the fusion protein administered to the subject is not glycosylated.
25. The method of claim 24 , wherein the portion of the protein of the naturally occurring influenza viral hemagglutinin of the fusion protein administered to the subject further includes at least one β-sandwich at the bottom of the portion of the globular head.
26. The method of claim 25 , wherein the portion of the protein of the naturally occurring influenza viral hemagglutinin of the fusion protein administered to the subject further includes at least two β-strands at the bottom of the portion of the globular head.
27. The method of claim 1 , wherein administration of the composition stimulates a protective immune response in the subject.
28. The method of claim 1 , further including administering a Toll-like Receptor 9 agonist to the subject.
29. The method of claim 28 , wherein the Toll-like Receptor 9 agonist administered to the subject is CpG.
30. The method of claim 1 , further including administering to the subject a Toll-like Receptor 3 agonist, a Toll-like Receptor 7 agonist or a Toll-like Receptor 8 agonist.
31. The method of claim 1 , further including administering to the subject a fusion protein that includes at least one flagellin that initiates an intracellular signal transduction pathway for a Toll-like Receptor and a portion of an influenza matrix 2 protein.
32. The method of claim 31 , wherein the portion of the influenza matrix 2 protein of the fusion protein administered to the subject is at least one ectodomain peptide of the matrix 2 protein.
33. The method of claim 32 , wherein the portion of the influenza matrix 2 protein of the fusion protein administered to the subject includes four ectodomain peptides of the matrix 2 protein.
34. The method of claim 5 , further including administering a Toll-like Receptor 9 agonist to the subject.
35. The method of claim 34 , wherein the Toll-like Receptor 9 agonist administered to the subject is CpG.
36. The method of claim 5 , further including administering to the subject a Toll-like Receptor 3 agonist, a Toll-like Receptor 7 agonist or a Toll-like Receptor 8 agonist.
37. The method of claim 5 , further including administering to the subject a fusion protein that includes at least one flagellin that initiates an intracellular signal transduction pathway for a Toll-like Receptor and a portion of an influenza matrix 2 protein.
38. The method of claim 37 , wherein the portion of the influenza matrix 2 protein of the fusion protein administered to the subject is at least one ectodomain peptide of the matrix 2 protein.
39. The method of claim 38 , wherein the portion of the influenza matrix 2 protein of the fusion protein administered to the subject includes four ectodomain peptides of the matrix 2 protein.
40. The method of claim 7 , further including administering a Toll-like Receptor 9 agonist to the subject.
41. The method of claim 40 , wherein the Toll-like Receptor 9 agonist administered to the subject is CpG.
42. The method of claim 7 , further including administering to the subject a Toll-like Receptor 3 agonist, a Toll-like Receptor 7 agonist or a Toll-like Receptor 8 agonist.
43. The method of claim 7 , further including administering to the subject a fusion protein that includes at least one flagellin that initiates an intracellular signal transduction pathway for a Toll-like Receptor and a portion of an influenza matrix 2 protein.
44. The method of claim 43 , wherein the portion of the influenza matrix 2 protein of the fusion protein administered to the subject is at least one ectodomain peptide of the matrix 2 protein.
45. The method of claim 44 , wherein the portion of the influenza matrix 2 protein of the fusion protein administered to the subject includes four ectodomain peptides of the matrix 2 protein.