Proteinaceous adjuvants

Abstract

A modulated immune response to an antigen is achieved by coadministering the antigen and a genetically-detoxified pertussis holotoxin, particularly one retaining its immunogenicity, to a host. The modulated immune response enables immunogenic compositions, including multivalent pediatric vaccines, such as DTP, to be provided which produce a modulated immune response in the absence of extrinsic adjuvants, such as alum. The adjuvanting effect achieved by the genetically-detoxified pertussis holotoxin enables at least the same level of adjuvanting effect to be achieved as previously attained by alum, without the undesirable side effects thereof.

What we claim is:  
     
         1 . An immunogenic composition, which comprises: 
 a genetically-detoxified pertussis holotoxin, and    at least one other, non-Bordetella, antigen, wherein said genetically-detoxified pertussis holotoxin is present in an amount sufficient to modulate an immune response to said other antigen in the absence of an extrinsic adjuvant.    
     
     
         2 . The composition of  claim 1  wherein said immune response is selected from a humoral response, a cellular response and both a humoral and a cellular response.  
     
     
         3 . The composition of  claim 1  wherein said modulated immune response to said other antigen is selected from an enhanced IgG response, a cellular response and both an enhanced IgG and a cellular response.  
     
     
         4 . The composition of  claim 1  wherein said other antigen provides a protective immune response to at least one pathogen.  
     
     
         5 . The composition of  claim 4  wherein said pathogen is selected from the group consisting of bacterial, viral and parasitic pathogens.  
     
     
         6 . The composition of  claim 5  wherein said at least one pathogen is selected from the group consisting of  Corynebacterium diphtheria, Clostridium tetani,  paramyxoviridae, haemophilus, influenza, hepatitis, meningococci, streptococci, schistosoma and trypanosoma.  
     
     
         7 . The composition of  claim 6  wherein said genetically-detoxified pertussis holotoxin is immunoprotective.  
     
     
         8 . The composition of  claim 4  wherein said other antigen is a cancer-associated antigen.  
     
     
         9 . The composition of claim a wherein said cancer is selected from melanoma, bladder, lung, cervical and prostate cancer.  
     
     
         10 . The composition of  claim 1  wherein such other antigen comprises inactivated tumor cells or membrane fraction thereof.  
     
     
         11 . The composition of  claim 10  wherein said cells are inactivated by irradiation.  
     
     
         12 . The composition of  claim 1  wherein at least one amino acid is removed or replaced in said genetically-detoxified pertussis holotoxin.  
     
     
         13 . The composition of  claim 12  wherein multiple amino acids are removed and replaced in said genetically-detoxified pertussis holotoxin.  
     
     
         14 . The composition of  claim 12  or  13  wherein said at least one amino acid is selected from the group consisting of (S1) ARG 9 , ARG 13 , TRP 26 , ARG 58  and GLU 129 .  
     
     
         15 . The composition of  claim 13  wherein said multiple amino acids are (S1) ARG 9 , GLU 129 .  
     
     
         16 . The composition of  claim 15  wherein said multiple amino acids are replaced (S1) ARG 9  to LYS 9  and GLU 129  to GLY 129 .  
     
     
         17 . The composition of  claim 1  wherein said genetically-detoxified pertussis holotoxin is selected from those listed in Tables 1a, 2 and 3.  
     
     
         18 . The composition of  claim 1  containing at least one additional Bordetella antigen.  
     
     
         19 . The composition of  claim 18  wherein said Bordetella antigen is selected from the group consisting of agglutinogens, FHA and pertactin.  
     
     
         20 . The immunogenic composition of  claim 1  which is formulated in the substantial absence of an extrinsic adjuvant as a vaccine for human or animal administration.  
     
     
         21 . The immunogenic composition of  claim 20  wherein said composition exhibits a decreased IgE response.  
     
     
         22 . The immunogenic composition of  claim 1  which is formulated in the substantial absence of alum as a multivalent vaccine comprising said genetically-detoxified pertussis holotoxin in an immunoprotective form and amount and diphtheria toxoid and tetanus toxoid as said at least one other, non-Bordetella, antigen.  
     
     
         23 . The immunogenic composition of  claim 22  which further comprises at least an additional Bordetella antigen.  
     
     
         24 . The immunogenic composition of  claim 23  wherein said additional Bordetella antigen is selected from the group consisting of agglutinogens, FHA and pertactin.  
     
     
         25 . A method of obtaining a modulated immune response to an antigen in a host, which comprises: 
 administering at least one non-Bordetella antigen to said host, and    coadministering to said host a genetically-detoxified holotoxin in an amount sufficient to modulate an immune response to said other antigen in the absence of an extrinsic adjuvant.    
     
     
         26 . The method of  claim 25  wherein said immune response is selected from a humoral response, a cellular response and both a humoral and a cellular response.  
     
     
         27 . The method of  claim 25  wherein said modulated immune response to said non-Bordetella antigen is selected from an enhanced IgG response, a cellular response and both an enhanced IgG and a cellular response.  
     
     
         28 . The method of  claim 25  wherein said administration and coadministration are effected by administering a composition as claimed in  claim 1  to  22  to said host in the absence of an extrinsic adjuvant.  
     
     
         29 . The method of  claim 25  wherein said host is a human.