FcRn-targeted mucosal vaccination against influenza infections
Disclosed are peptides comprising a monomeric Fc fragment of an immunoglobulin recognized by a neonatal receptor (FcRn); an influenza HA protein; and a trimerization domain. Disclosed are compositions comprising one or more of the peptides described herein. Disclosed are nucleic acid sequences capable of encoding any one of the peptides described herein. Disclosed are methods for eliciting a protective immune response against influenza comprising administering to a subject an effective amount of a composition comprising a monomeric Fc fragment of an immunoglobulin recognized by a FcRn; an influenza HA protein; and a trimerization domain, wherein the administering is to a mucosal epithelium. Disclosed are methods of treating a subject exposed to influenza or at risk of being exposed to influenza comprising administering to the subject an effective amount of a composition comprising a monomeric Fc fragment of an immunoglobulin recognized by a FcRn; an influenza HA protein; and a trimerization domain, wherein the administering is to a mucosal epithelium.
1. A peptide comprising
a monomeric IgG Fc fragment of an immunoglobulin recognized by a neonatal receptor (FcRn), wherein the monomeric Fc fragment comprises one or more mutations in the CH2 domain, wherein the one or more mutations ablate C1q binding to the IgG Fc fragment, wherein the one or more mutations in the CH2 domain comprise a mutation of a Lys residue at a position that corresponds to amino acid 108 of SEQ ID NO:2;
an influenza HA protein comprising HA1 and HA2; and
a trimerization domain.
2. The peptide of claim 1 , wherein the trimerization domain is a T4 fibritin trimerization domain.
3. The peptide of claim 2 , wherein the T4 fibritin trimerization domain is foldon.
4. The peptide of claim 1 , wherein the monomeric IgG Fc fragment of an immunoglobulin recognized by a FcRn is conjugated to the amino or carboxy terminal end of the influenza HA protein.
5. The peptide of claim 1 further comprising one or more linkers.
6. The peptide of claim 5 , wherein at least one of the one or more linkers is between the influenza HA protein and the monomeric IgG Fc fragment of an immunoglobulin recognized by a FcRn.
7. The peptide of claim 5 , wherein at least one of the one or more linkers is between the trimerization domain and the monomeric IgG Fc fragment of an immunoglobulin recognized by a FcRn.
8. The peptide of claim 5 , wherein the one or more linkers comprises a GS-linker.
9. The peptide of claim 1 , wherein the monomeric Fc fragment of an immunoglobulin recognized by a FcRn comprises one or more mutations in the cysteine residues responsible for dimer formation.
10. The peptide of claim 1 , wherein the influenza HA protein is a non-cleavable HA0 protein, wherein the non-cleavable HA0 protein cannot be cleaved into HA1 and HA2.
11. The peptide of claim 10 , wherein the non-cleavable HA0 protein comprises mutations at the cleavage site of wild type HA0, wherein the mutations are SIQS→QRET, amino acids 321-325 of SEQ ID NO:6.
12. A composition comprising the peptide of claim 1 .
13. The composition of claim 12 , wherein the composition is a vaccine.
14. The composition of claim 12 further comprising a pharmaceutically acceptable carrier.
15. A nucleic acid sequence which encodes the peptide of claim 1 .
16. A method for eliciting a protective immune response against influenza comprising administering to a subject an effective amount of a composition comprising the peptide of claim 1 , wherein the administering is to a mucosal epithelium.
17. The method of claim 16 , wherein the trimerization domain is a T4 fibritin trimerization domain.
18. The method of claim 16 , wherein the mucosal epithelium is selected from the group consisting of: lungs, intestines, trachea, colon, nasal tissue, and vaginal tissue.
19. The method of claim 16 , wherein the administering is intranasal administering.
20. The method of claim 16 , wherein an adjuvant is further administered with the composition.
21. The method of claim 20 , wherein the adjuvant is CpG or MPL.
22. A method of treating a subject exposed to influenza or at risk of being exposed to influenza comprising administering to the subject an effective amount of a composition comprising the peptide of claim 1 , wherein the administering is to a mucosal epithelium.