Compositions and methods for treating an active
The present disclosure relates to methods and compositions for treating a active tuberculosis infection and methods and compositions for improving the efficacy of chemotherapy regimens against active tuberculosis infection. The present disclosure relates to methods of treating an active M. tuberculosis infection or an active infection resulting from reactivation of a latent infection in a mammal and to methods of improving the efficacy of chemotherapy regimens against active M. tuberculosis infection.
1. A method for treating an active tuberculosis infection in a human, the method comprising the step of administering to a human having an active tuberculosis infection an immunologically effective amount of a therapeutic vaccine in conjunction with one or more chemotherapeutic agents, wherein the vaccine comprises a pharmaceutical composition comprising an isolated fusion polypeptide, wherein the fusion polypeptide comprises (a) a combination of the Rv1813, Rv3620, and Rv2608 antigens from a Mycobacterium species of a tuberculosis complex and the antigens are covalently linked, or (b) a sequence having at least 90% identity to the sequence of the fusion polypeptide; and wherein the active tuberculosis infection is characterized by Mycobacterium tuberculosis bacteria that proliferate, reproduce, expand, or actively multiply at an exponential, logarithmic, or semilogarithmic rate in an organ of the human or wherein the active tuberculosis infection is associated with a clinical symptom.
2. The method of claim 1 , wherein the therapeutic vaccine comprises a fusion polypeptide comprising (a) a combination of Mycobacterium antigen Rv2608, Rv3619, Rv3620, and Rv1813, or (b) a sequence having at least 90% sequence identity to the sequence of the fusion polypeptide.
3. The method of claim 2 , wherein the Mycobacterium antigens Rv2608, Rv3619, Rv3620 and Rv1813 are M. tuberculosis antigens Rv2608, Rv3619, Rv3620 and Rv1813.
4. The method of claim 1 , wherein the fusion polypeptide comprises the amino acid sequence set forth in SEQ ID NO:1, or a sequence having at least 90% identity thereto.
5. A method for treating an active tuberculosis infection in a human, the method comprising the step of administering to a human having an active tuberculosis infection an immunologically effective amount of a therapeutic vaccine in conjunction with one or more chemotherapeutic agents, wherein the vaccine comprises a pharmaceutical composition comprising an isolated fusion polypeptide, wherein the fusion polypeptide comprises the amino acid sequence set forth in SEQ ID NO:2, or a sequence having at least 90% identity thereto, and wherein the active tuberculosis infection is characterized by Mycobacterium tuberculosis bacteria that proliferate, reproduce, expand, or actively multiply at an exponential, logarithmic, or semilogarithmic rate in an organ of the human or wherein the active tuberculosis infection is associated with a clinical symptom.
6. The method of claim 1 , wherein the combination of Mycobacterium antigen consists of Rv2608, Rv3620 and Rv1813.
7. The method of claim 6 , wherein the Mycobacterium antigens Rv2608, Rv3620 and Rv1813 are M. tuberculosis antigens Rv2608, Rv3620 and Rv1813.
8. The method of claim 1 , wherein the fusion polypeptide comprises the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:4, or a sequence having at least 90% identity to SEQ ID NO:3 or SEQ ID NO:4.
9. The method of claim 1 , wherein the active tuberculosis infection is an active primary infection of M. tuberculosis.
10. The method of claim 1 , wherein the active tuberculosis infection is a reactivation tuberculosis infection.
11. The method of claim 1 , wherein the human is infected with a multidrug resistant (MDR) M. tuberculosis.
12. The method of claim 1 , wherein the human was previously immunized with Bacillus Calmette-Guerin (BCG).
13. The method of claim 1 , wherein the one or more chemotherapeutic agents is isoniazid, rifampin, amikacin, aminosalicylic acid, capreomycin, cycloserine, ethambutol, ethionamide, kanamycin, pyrazinamide, rifapentine, rifabutin, streptomycin, ofloxacin, ciprofloxacin, clarithromycin, azithromycin, fluoroquinolones, or a combination thereof.
14. The method of claim 1 , wherein the human is first administered one or more chemotherapeutic agents over a period of time and subsequently administered the therapeutic vaccine.
15. The method of claim 1 , wherein the human is first administered the therapeutic vaccine and subsequently administered one or more chemotherapeutic agents over a period of time.
16. The method of claim 1 , wherein administration of the one or more chemotherapeutic agents and the therapeutic vaccine is concurrent.
17. The method of claim 1 , further comprising administering the therapeutic vaccine to the human one or more subsequent times, wherein a tuberculosis infection remaining in the human at the one or more subsequent times may or may not be an active tuberculosis infection.
18. The method of claim 1 , wherein the vaccine further comprises an adjuvant.
19. The method of claim 18 , wherein the adjuvant is GLA, having the following structure:
wherein R 1 , R 3 , R 5 , and R 6 are C 11 -C 20 alkyl; and R 2 and R 4 are C 9 -C 20 alkyl.
20. The method of claim 19 , wherein R 1 , R 3 , R 5 , and R 6 are C 11-14 alkyl; and R 2 and R 4 are C 12-15 alkyl.
21. The method of claim 19 , wherein R 1 , R 3 , R 5 and R 6 are C 11 alkyl; and R 2 and R 4 are C 13 alkyl.
22. The method of claim 19 , wherein R 1 , R 3 , R 5 and R 6 are C 11 alkyl; and R 2 and R 4 are C 9 alkyl.
23. The method of claim 1 , wherein a N-terminal leader sequence or a transmembrane domain of Rv1813has been removed.
24. The method of claim 2 , wherein a N-terminal leader sequence or a transmembrane domain of Rv1813 has been removed.
25. The method of claim 6 , wherein a N-terminal leader sequence or a transmembrane domain of Rv1813 has been removed.