US2013101614A1PendingUtilityA1

Novel live recombinant booster vaccine against tuberculosis

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Assignee: HORWITZ MARCUS APriority: Jun 15, 2010Filed: Jun 15, 2011Published: Apr 25, 2013
Est. expiryJun 15, 2030(~3.9 yrs left)· nominal 20-yr term from priority
Inventors:Marcus A. HorwitzQingmei Jia
A61K 2039/522C12N 1/36A61K 2039/545A61K 2039/55566A61K 39/04C12N 1/20A61K 2039/5555A61P 31/00C07K 2319/40A61K 2039/6037C07K 14/35A61K 2039/523C07K 14/195A61K 39/02A61P 31/10
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Claims

Abstract

Embodiments of the invention comprise an improved vaccine for generating an immune response and preventing or treating mycobacterial diseases such as tuberculosis in humans and animals. Embodiments of the invention also comprise a method for using the vaccine against such mycobacterial diseases.

Claims

exact text as granted — not AI-modified
1 . A composition of matter comprising attenuated  Listeria monocytogenes , wherein the  Listeria monocytogenes:    does not express a functional ActA protein (SEQ ID NO: 1); and   expresses  Mycobacterium tuberculosis  30 kDa antigen 85B protein (SEQ ID NO: 4).   
     
     
         2 . The composition of  claim 1 , wherein the  Listeria monocytogenes  further expresses at least one protein from the following group:
   Mycobacterium tuberculosis  12 kDa fragment of 16 kDa membrane protein (SEQ ID NO:5);     Mycobacterium tuberculosis  14 kDa MPT53 protein (SEQ ID NO: 6);     Mycobacterium tuberculosis  16 kDa MPT63 protein (SEQ ID NO: 7);     Mycobacterium tuberculosis  23 kDa SOD protein (SEQ ID NO: 8);     Mycobacterium tuberculosis  23.5 kDa MPT64 protein (SEQ ID NO: 9);     Mycobacterium tuberculosis  24 kDa MPT51 protein (SEQ ID NO: 10);     Mycobacterium tuberculosis  32 kDa antigen 85A protein (SEQ ID NO: 11);     Mycobacterium tuberculosis  32 kDa antigen 85C protein (SEQ ID NO: 12);     Mycobacterium tuberculosis  45 kDa MPT32 protein (SEQ ID NO: 13);     Mycobacterium tuberculosis  58 kDa glutamine synthetase protein (SEQ ID NO: 14);     Mycobacterium tuberculosis  71 kDa HSP 70 protein (SEQ ID NO: 15);     Mycobacterium tuberculosis  10.4 kDa EsxH protein (SEQ ID NO: 16);     Mycobacterium tuberculosis  14 kDa alpha crystalline homolog protein (SEQ ID NO: 17);     Mycobacterium tuberculosis  47 kDa isocitrate lysate protein (SEQ ID NO: 18);     Mycobacterium tuberculosis  7.6 kDa hypothetical protein (SEQ ID NO: 19);     Mycobacterium tuberculosis  80 kDa glcB protein (SEQ ID NO: 20);     Mycobacterium tuberculosis  110 kDa can protein (SEQ ID NO: 21); or     Mycobacterium tuberculosis  9.9 kDa ESAT-6 protein (SEQ ID NO: 22).   
     
     
         3 . The composition of  claim 1 , wherein the  Listeria monocytogenes  further expresses: 
       at least one protein from group A:
   Mycobacterium tuberculosis  12 kDa fragment of 16 kDa membrane protein (SEQ ID NO:5); 
   Mycobacterium tuberculosis  14 kDa MPT53 protein (SEQ ID NO: 6); 
   Mycobacterium tuberculosis  16 kDa MPT63 protein (SEQ ID NO: 7); 
   Mycobacterium tuberculosis  23 kDa SOD protein (SEQ ID NO: 8); 
   Mycobacterium tuberculosis  23.5 kDa MPT64 protein (SEQ ID NO: 9); 
   Mycobacterium tuberculosis  24 kDa MPT51 protein (SEQ ID NO: 10); 
   Mycobacterium tuberculosis  32 kDa antigen 85A protein (SEQ ID NO: 11); 
   Mycobacterium tuberculosis  32 kDa antigen 85C protein (SEQ ID NO: 12); 
   Mycobacterium tuberculosis  45 kDa MPT32 protein (SEQ ID NO: 13); 
   Mycobacterium tuberculosis  58 kDa glutamine synthetase protein (SEQ ID NO: 14); 
   Mycobacterium tuberculosis  71 kDa HSP 70 protein (SEQ ID NO: 15); 
   Mycobacterium tuberculosis  10.4 kDa EsxH protein (SEQ ID NO: 16); 
   Mycobacterium tuberculosis  80 kDa glcB protein (SEQ ID NO: 20); 
   Mycobacterium tuberculosis  110 kDa can protein (SEQ ID NO: 21); or 
   Mycobacterium tuberculosis  9.9 kDa ESAT-6 protein (SEQ ID NO: 22); at least one protein from group B: 
   Mycobacterium tuberculosis  14 kDa alpha crystalline homolog protein (SEQ ID NO: 17); 
   Mycobacterium tuberculosis  47 kDa isocitrate lysate protein (SEQ ID NO: 18); or 
   Mycobacterium tuberculosis  7.6 kDa hypothetical protein (SEQ ID NO: 19). 
 
     
     
         4 . The composition of  claim 1 , wherein the  Listeria monocytogenes:    does not express a functional InlB protein (SEQ ID NO: 2); and/or   expresses prfA protein having a G155S substitution mutation (SEQ ID NO: 3).   
     
     
         5 . The composition of  claim 1 , further comprising at least one of a pharmaceutically acceptable carrier or an adjuvant. 
     
     
         6 . The composition of  claim 1 , further comprising a buffer system. 
     
     
         7 . The composition of  claim 1 , wherein the  Mycobacterium tuberculosis  30 kDa antigen 85B protein is fused in frame with a heterologous protein sequence. 
     
     
         8 . The composition of  claim 1 , wherein the  Mycobacterium tuberculosis  30 kDa antigen 85B protein is coupled to a heterologous protein sequence comprising the N-terminal 100 amino acids of the ActA protein. 
     
     
         9 . The composition of  claim 4 , wherein the expression of the  Mycobacterium tuberculosis  30 kDa antigen 85B protein is controlled by an actA promoter. 
     
     
         10 . A method of generating an antibody to a  Mycobacterium tuberculosis  30 kDa antigen 85B protein (SEQ ID NO: 4) comprising the steps of:
 immunizing a mammal with a composition of matter comprising attenuated  Listeria monocytogenes , wherein the  Listeria monocytogenes:      does not express a functional ActA protein (SEQ ID NO: 1); and   expresses  Mycobacterium tuberculosis  30 kDa antigen 85B protein (SEQ ID NO: 4); such that an antibody to a  Mycobacterium tuberculosis  30 kDa antigen 85B protein is generated.   
     
     
         11 . The method of  claim 10 , further comprising immunizing the mammal with  Mycobacterium bovis  strain Bacille Calmette-Guérin (BCG). 
     
     
         12 . The method of  claim 11 , wherein the BCG is used in a primary immunization and the attenuated  Listeria monocytogenes  is used in a booster immunization. 
     
     
         13 . The method of  claim 10 , wherein the  Listeria monocytogenes:    does not express a functional InlB protein (SEQ ID NO: 2); and/or   expresses prfA protein having a G155S substitution mutation (SEQ ID NO: 3).   
     
     
         14 . The method of  claim 10 , wherein the mammal is immunized intranasally, subcutaneously, intradermally, intramuscularly or orally. 
     
     
         15 . The method of  claim 10 , wherein the mammal is a guinea pig or a mouse. 
     
     
         16 . The method of  claim 10 , wherein the mammal is a human. 
     
     
         17 . The method of  claim 10 , wherein the  Listeria monocytogenes  further expresses at least one protein from the following group:
   Mycobacterium tuberculosis  12 kDa fragment of 16 kDa membrane protein (SEQ ID NO:5);     Mycobacterium tuberculosis  14 kDa MPT53 protein (SEQ ID NO: 6);     Mycobacterium tuberculosis  16 kDa MPT63 protein (SEQ ID NO: 7);     Mycobacterium tuberculosis  23 kDa SOD protein (SEQ ID NO: 8);     Mycobacterium tuberculosis  23.5 kDa MPT64 protein (SEQ ID NO: 9);     Mycobacterium tuberculosis  24 kDa MPT51 protein (SEQ ID NO: 10);     Mycobacterium tuberculosis  32 kDa antigen 85A protein (SEQ ID NO: 11);     Mycobacterium tuberculosis  32 kDa antigen 85C protein (SEQ ID NO: 12);     Mycobacterium tuberculosis  45 kDa MPT32 protein (SEQ ID NO: 13);     Mycobacterium tuberculosis  58 kDa glutamine synthetase protein (SEQ ID NO: 14);     Mycobacterium tuberculosis  71 kDa HSP 70 protein (SEQ ID NO: 15);     Mycobacterium tuberculosis  10.4 kDa EsxH protein (SEQ ID NO: 16);     Mycobacterium tuberculosis  14 kDa alpha crystalline homolog protein (SEQ ID NO: 17);     Mycobacterium tuberculosis  47 kDa isocytrate lysate protein (SEQ ID NO: 18);     Mycobacterium tuberculosis  7.6 kDa hypothetical protein (SEQ ID NO: 19);     Mycobacterium tuberculosis  80 kDa glcB protein (SEQ ID NO: 20);     Mycobacterium tuberculosis  110 kDa can protein (SEQ ID NO: 21); or     Mycobacterium tuberculosis  9.9 kDa ESAT-6 protein (SEQ ID NO: 22).   
     
     
         18 . The method of  claim 10 , wherein the  Listeria monocytogenes  further expresses at least one protein from group A:
   Mycobacterium tuberculosis  12 kDa fragment of 16 kDa membrane protein (SEQ ID NO:5);     Mycobacterium tuberculosis  14 kDa MPT53 protein (SEQ ID NO: 6);     Mycobacterium tuberculosis  16 kDa MPT63 protein (SEQ ID NO: 7);     Mycobacterium tuberculosis  23 kDa SOD protein (SEQ ID NO: 8);     Mycobacterium tuberculosis  23.5 kDa MPT64 protein (SEQ ID NO: 9);     Mycobacterium tuberculosis  24 kDa MPT51 protein (SEQ ID NO: 10);     Mycobacterium tuberculosis  32 kDa antigen 85A protein (SEQ ID NO: 11);     Mycobacterium tuberculosis  32 kDa antigen 85C protein (SEQ ID NO: 12);     Mycobacterium tuberculosis  45 kDa MPT32 protein (SEQ ID NO: 13);     Mycobacterium tuberculosis  58 kDa glutamine synthetase protein (SEQ ID NO: 14);     Mycobacterium tuberculosis  71 kDa HSP 70 protein (SEQ ID NO: 15);     Mycobacterium tuberculosis  10.4 kDa EsxH protein (SEQ ID NO: 16);     Mycobacterium tuberculosis  80 kDa glcB protein (SEQ ID NO: 20);     Mycobacterium tuberculosis  110 kDa can protein (SEQ ID NO: 21); or     Mycobacterium tuberculosis  9.9 kDa ESAT-6 protein (SEQ ID NO: 22); at least one protein from group B:     Mycobacterium tuberculosis  14 kDa alpha crystalline homolog protein (SEQ ID NO: 17);     Mycobacterium tuberculosis  47 kDa isocytrate lysate protein (SEQ ID NO: 18); or     Mycobacterium tuberculosis  7.6 kDa hypothetical protein (SEQ ID NO: 19).   
     
     
         19 . The method of  claim 10 , wherein the  Mycobacterium tuberculosis  30 kDa antigen 85B protein is coupled to a heterologous protein sequence comprising the N-terminal 100 amino acids of the ActA protein. 
     
     
         20 . The method of  claim 19 , wherein the expression of the  Mycobacterium tuberculosis  30 kDa antigen 85B protein is controlled by an ActA promoter.

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