Listeria-based adjuvants
This invention provides methods and compositions for using Listeria monocytogenes as an adjuvant for enhancing immune responses in a subject.
1. A method of reconstituting an immune response in a subject in an antigen-independent manner, the method comprising the step of administering a live attenuated recombinant Listeria strain to said subject, wherein said Listeria strain comprises a mutation or a deletion of a genomic internalin C (inlC) gene, and wherein said administration reconstitutes an immune response in the subject in an antigen-independent manner.
2. The method of claim 1 , wherein said Listeria strain comprises a nucleic acid molecule, wherein said nucleic acid molecule comprises a first open reading frame encoding a non-hemolytic LLO protein or immunogenic fragment thereof, an N-terminal ActA fragment or a truncated ActA, or a PEST amino acid sequence selected from the group consisting of SEQ ID NO: 8-19.
3. The method of claim 2 , wherein said Listeria over expresses and secretes said non-hemolytic LLO protein or immunogenic fragment thereof, said N-terminal ActA fragment or a truncated ActA, or said PEST amino acid sequence selected from the group consisting of SEQ ID NO: 8-19.
4. The method of claim 1 , wherein said recombinant Listeria further comprises a mutation or a deletion of a genomic Act A gene, a PlcA gene, PrfA gene or a PlcB gene.
5. The method of claim 2 , wherein said nucleic acid molecule further comprises a second open reading frame encoding a metabolic enzyme, wherein said metabolic enzyme complements an endogenous gene that is lacking in the chromosome of said recombinant Listeria strain.
6. The method of claim 5 , wherein said metabolic enzyme encoded by said second open reading frame is an alanine racemase enzyme or a D-amino acid transferase enzyme.
7. The method of claim 2 , wherein said nucleic acid molecule is integrated into the Listeria genome.
8. The method of claim 2 , wherein said nucleic acid molecule is in a plasmid that is stably maintained in said recombinant Listeria vaccine strain in the absence of antibiotic selection.
9. The method of claim 1 , wherein said subject is an adult human, a child or a non-human mammal.
10. The method of claim 1 , wherein said method facilitates recovery of immune responses in an antigen-independent manner following a cytotoxic treatment in said subject.
11. The method of claim 1 , wherein the Listeria strain is used alone or is combined with an additional adjuvant.
12. The method of claim 11 , wherein said additional adjuvant is a non-nucleic acid adjuvant including aluminum adjuvant, Freund's adjuvant, MPL, emulsion, GM-CSF, QS21, SBAS2, CpG-containing oligonucleotide, a nucleotide molecule encoding an immune-stimulating cytokine, comprises a bacterial mitogen, or a bacterial toxin.
13. The method of claim 1 , wherein said method enables the treatment of a disease.
14. The method of claim 13 , wherein said disease is a tumor or a cancer, or an infectious disease.
15. The method of claim 14 , wherein said method increases the ratio of CD8+/T regulatory cells in said tumor.