Compositions and methods for treating an active mycobacterium tuberculosis infection

Abstract

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.

What is claimed is: 
     
         1 . A method for treating an active tuberculosis infection in a mammal, the method
 comprising the step of administering to a mammal 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 antigen Rv1813, Rv3620, and Rv2608 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 combination of antigens.   
     
     
         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% identity to the combination of antigens. 
     
     
         3 . The method of  claim 2 , wherein the  Mycobacterium  antigen Rv2608, Rv3619, Rv3620 and Rv1813 are  M. tuberculosis  antigen Rv2608, Rv3619, Rv3620 and Rv1813. 
     
     
         4 . The method of  claim 3 , 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 . The method of  claim 3 , 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. 
     
     
         6 . The method of  claim 1 , wherein the therapeutic vaccine comprises a fusion polypeptide comprising (a) a combination of  Mycobacterium  antigen Rv2608, Rv3620 and Rv1813, or (b) a sequence having at least 90% identity to the combination of antigens. 
     
     
         7 . The method of  claim 6 , wherein the  Mycobacterium  antigen Rv2608, Rv3620 and Rv1813 are  M. tuberculosis  antigen Rv2608, Rv3620 and Rv1813. 
     
     
         8 . The method of  claim 6 , 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 any one of  claims 1 - 8 , wherein the active tuberculosis infection is an active primary infection of  M. tuberculosis.    
     
     
         10 . The method of any one of  claims 1 - 8 , wherein the active tuberculosis infection is a reactivation tuberculosis infection. 
     
     
         11 . The method of any one of  claims 1 - 8 , wherein the active tuberculosis infection is associated with a clinical symptom of weakness, fatigue, fever, chills, weight loss, loss of appetite, anorexia, night sweats, or any combination thereof. 
     
     
         12 . The method of any one of  claims 1 - 8 , wherein the active tuberculosis infection is a pulmonary active TB infection. 
     
     
         13 . The method of  claim 12 , wherein the pulmonary active tuberculosis infection is associated with a clinical symptom of persistent cough, thick mucus, chest pain, hemoptysis, or any combination thereof. 
     
     
         14 . The method of any one of  claims 1 - 8 , wherein the active tuberculosis infection is characterized by Mtb bacteria which proliferate, reproduce, expand or actively multiply at an exponential, logarithmic, or semilogrithmic rate in an organ of the mammal. 
     
     
         15 . The method of any one of  claims 1 - 8 , wherein the active tuberculosis infection is identified using an assay selected from the group consisting of an acid fast staining (AFS) assay; a bacterial culture assay; an IGR test; a skin test; and intracellular cytokine staining of whole blood or isolated PBMC following antigen stimulation. 
     
     
         16 . The method of any one of  claims 1 - 8 , wherein the mammal is infected with a multidrug resistant (MDR)  M. tuberculosis.    
     
     
         17 . The method of any one of  claims 1 - 16 , wherein the mammal was previously immunized with Bacillus Calmette-Guerin (BCG). 
     
     
         18 . The method of any one of  claims 1 - 17 , wherein the mammal is a human. 
     
     
         19 . The method of any one of  claims 1 - 18 , wherein the one or more chemotherapeutic agents is isoniazid, rifampin, or a combination thereof. 
     
     
         20 . The method of any one of  claims 1 - 19 , wherein the mammal is first administered one or more chemotherapeutic agents over a period of time and subsequently administered the therapeutic vaccine. 
     
     
         21 . The method of any one of  claims 1 - 19 , wherein the mammal is first administered the therapeutic vaccine and subsequently administered one or more chemotherapeutic agents over a period of time. 
     
     
         22 . The method of any one of  claims 1 - 19 , wherein administration of the one or more chemotherapeutic agents and the therapeutic vaccine is concurrent. 
     
     
         23 . The method of any one of  claims 1 - 22 , further comprising administering the therapeutic vaccine to the mammal one or more subsequent times, wherein a tuberculosis infection remaining in the mammal at the one or more subsequent times may or may not be an active tuberculosis infection. 
     
     
         24 . The method of any one of  claims 1 - 23 , wherein the vaccine further comprises an adjuvant. 
     
     
         25 . The method of  claim 24 , 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. 
       
     
     
         26 . The method of  claim 25 , 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. 
     
     
         27 . The method of  claim 25 , wherein R 1 , R 3 , R 5  and R 6  are C 11  alkyl; and R 2  and R 4  are C 13  alkyl. 
     
     
         28 . The method of  claim 25 , wherein R 1 , R 3 , R 5  and R 6  are C 11  alkyl; and R 2  and R 4  are C 9  alkyl. 
     
     
         29 . A method for reducing the time course of chemotherapy against an active tuberculosis infection, the method comprising administering to a mammal having an active tuberculosis infection an immunologically effective amount of a therapeutic vaccine in conjunction with the chemotherapy, wherein the vaccine comprises a pharmaceutical composition comprising an isolated fusion polypeptide, wherein the fusion polypeptide comprises (a) a combination of antigen Rv1813, Rv3620, and Rv2608 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 combination of antigens; and wherein the vaccine induces an immune response against tuberculosis, thereby providing for a reduced time course of the chemotherapy against an active tuberculosis infection. 
     
     
         30 . The method of  claim 29 , 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 a sequence at least 90% identity to the combination of antigens. 
     
     
         31 . The method of  claim 30 , wherein the  Mycobacterium  antigen Rv2608, Rv3619,
 Rv3620 and Rv1813 are  M. tuberculosis  antigen Rv2608, Rv3619, Rv3620 and Rv1813.   
     
     
         32 . The method of  claim 31 , wherein the fusion polypeptide comprises a sequence set forth in SEQ ID NO:1, or a sequence having at least 90% identity thereto. 
     
     
         33 . The method of  claim 31 , wherein the fusion polypeptide comprises a sequence set forth in SEQ ID NO:2, or a sequence having at least 90% identity thereto. 
     
     
         34 . The method of  claim 29 , wherein the therapeutic vaccine comprises a fusion polypeptide comprising (a) a combination of  Mycobacterium  antigen Rv2608, Rv3620 and Rv1813, or (b) a sequence having a sequence at least 90% identity to the combination of antigens. 
     
     
         35 . The method of  claim 34 , wherein the  Mycobacterium  antigen Rv2608, Rv3620 and Rv1813 are  M. tuberculosis  antigen Rv2608, Rv3620 and Rv1813. 
     
     
         36 . The method of  claim 35 , wherein the fusion polypeptide comprises a sequence set forth in SEQ ID NO:3 or 4, or a sequence having at least 90% identity to SEQ ID NO:3 or SEQ ID NO:4. 
     
     
         37 . The method of any one of  claims 29 - 36 , wherein the time course of the chemotherapy is shortened to no more than about 3 months, about 5 months, or about 7 months. 
     
     
         38 . The method of any one of  claims 29 - 37 , wherein the vaccine further comprises an adjuvant. 
     
     
         39 . The method of  claim 38 , 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. 
       
     
     
         40 . The method of  claim 39 , 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. 
     
     
         41 . The method of  claim 39 , wherein R 1 , R 3 , R 5  and R 6  are C 11  alkyl; and R 2  and R 4  are C 13  alkyl. 
     
     
         42 . The method of  claim 40 , wherein R 1 , R 3 , R 5  and R 6  are C 11  alkyl; and R 2  and R 4  are C 9  alkyl.