Patent
The present invention provides Listeria that are attenuated for entry into non-phagocytic cells as well as a variety of methods of inducing immune responses involving administering compositions comprising the attenuated Listeria . Some of the attenuated Listeria are mutant Listeria that comprise at least one mutation in a gene encoding an invasin, such as an internalin. Some of the attenuated Listeria are further attenuated for cell-to-cell spread. Pharmaceutical compositions and vaccines useful in the methods of the invention are further provided. Methods of making and improving vaccines are also provided.
1. An isolated Listeria monocytogenes bacterium which comprises:
(a) a deletion in the genomic actA and inlB genes of the bacterium whereby the bacterium does not express ActA or InlB proteins;
(b) a functional genomic inlA gene whereby the bacterium expresses InlA protein; and
(c) a nucleic acid sequence encoding a non- Listerial polypeptide operably linked to a promoter sequence directing expression of the polypeptide whereby the bacterium expresses the non- Listerial polypeptide.
2. A composition comprising (a) the Listeria bacterium of claim 1 , and (b) an adjuvant.
3. A method of inducing an immune response in a host to a non- Listerial antigen comprising administering to the host an effective amount of a composition comprising the Listeria bacterium of claim 1 , wherein the non- Listerial polypeptide comprises the non- Listerial antigen.
4. A method of expressing a non- Listerial polypeptide in a host, comprising administering to the host an effective amount of a composition comprising the Listeria bacterium of claim 1 expressing the non- Listerial polypeptide.
5. An isolated professional antigen-presenting cell comprising the Listeria bacterium of claim 1 .
6. The method of claim 4 , wherein the host is selected on the basis of a diagnosis of cancer in the host.
7. The method of claim 4 , wherein the host is selected on the basis of a need for protection against a disease in the host.
8. The method of claim 7 , wherein the disease is an infectious disease.
9. The method of claim 7 , wherein the disease is cancer.
10. A pharmaceutical composition comprising (a) the Listeria bacterium of claim 1 , and (b) a pharmaceutically acceptable carrier.
11. The method of claim 4 , wherein the host is selected on the basis of a diagnosis of an infectious disease in the host.