Novel Composition

Abstract

The present invention relates to influenza vaccine formulations and vaccination regimes for immunising against influenza disease, their use in medicine, in particular their use in augmenting immune responses to various antigens, and to methods of preparation. In particular, the invention relates to multivalent influenza immunogenic compositions comprising an influenza antigen or antigenic preparation thereof from at least two influenza virus strains, at least one strain being associated with a pandemic outbreak or having the potential to be associated with a pandemic outbreak, in combination with an oil-in-water emulsion adjuvant.

1 . A multivalent influenza immunogenic composition comprising an influenza antigen or antigenic preparation thereof from at least two influenza virus strains, at least one strain being associated with a pandemic outbreak or having the potential to be associated with a pandemic outbreak, in combination with an oil-in-water emulsion adjuvant, wherein said oil-in-water emulsion adjuvant comprises a metabolisable oil, a sterol and an emulsifying agent. 
     
     
         2 . A composition according to  claim 1  wherein said sterol is alpha tocopherol. 
     
     
         3 . A composition according to  claim 1  or  claim 2  wherein said oil-in water emulsion contains oil droplets of which at least 70% by intensity are less than 1 μm in diameter. 
     
     
         4 . A composition according to any of  claims 1  to  3  wherein said oil-in water emulsion contains oil droplets of which at least 70% by intensity are less than 500 nm in diameter. 
     
     
         5 . A composition according to any of  claims 1  to  4  wherein said oil-in water emulsion contains oil droplets of which at least 80% by intensity are less than 300 nm in diameter. 
     
     
         6 . A composition according to any of  claims 1  to  5  wherein said oil-in water emulsion contains oil droplets of which at least 90% by intensity are in the range of 120 to 200 nm in diameter. 
     
     
         7 . A composition according to any of  claims 1  to  6  wherein said metabolisable oil is squalene. 
     
     
         8 . A composition according to any of  claims 1  to  7  wherein said metabolisable oil is present in an amount of 0.5% to 20% of the total volume of said immunogenic composition. 
     
     
         9 . A composition according to any of  claims 1  to  8  wherein said metabolisable oil is present in an amount of 1.0% to 10% of the total volume of said immunogenic composition. 
     
     
         10 . A composition according to any of  claims 1  to  9  wherein said metabolisable oil is present in an amount of 2.0% to 6.0% of the total volume of said immunogenic composition. 
     
     
         11 . A composition according to any of  claims 1  to  10  wherein the oil in water emulsion comprises a further sterol. 
     
     
         12 . A composition according to any of  claims 1  to  11  wherein said sterol is cholesterol. 
     
     
         13 . A composition according to any of  claims 1  to  12  wherein said alpha-tocopherol is present in an amount of 1.0% to 20% of the total volume of said immunogenic composition. 
     
     
         14 . A composition according to any of  claims 1  to  13  wherein said alpha-tocopherol is present in an amount of 1.0% to 5.0% of the total volume of said immunogenic composition. 
     
     
         15 . A composition according to any of  claims 1  to  14  wherein the ratio of squalene:alpha tocopherol is equal or less than 1. 
     
     
         16 . A composition according to any of  claims 1  to  15  wherein said emulsifying agent is Tween 80. 
     
     
         17 . A composition according to any of  claims 1  to  16  wherein said emulsifying agent is present at an amount of 0.01 to 5.0% by weight (w/w) of said immunogenic composition. 
     
     
         18 . A composition according to any of  claims 1  to  17  said emulsifying agent is present at an amount of 0.1 to 2.0% by weight (w/w) of said immunogenic composition. 
     
     
         19 . A composition according to any of  claims 1  to  18  wherein the immunogenic composition further comprises a TLR-4 ligand. 
     
     
         20 . A composition according to any of  claims 1  to  19  wherein said TLR-4 ligand is selected from the list consisting of: a non-toxic derivative of lipid A such as 3D-MPL; a synthetic derivative of lipid A; MDP; and RSV F protein. 
     
     
         21 . A composition according to any of  claims 1  to  20  wherein said lipid A derivative is 3D-MPL. 
     
     
         22 . A composition according to any of  claims 1  to  21  wherein 3D-MPL is present at an amount of 1 to 100 μg (w/v) per composition dose. 
     
     
         23 . A composition according to any of  claims 1  to  22  wherein 3D-MPL is present in an amount of 10 to 50 μg/ml. 
     
     
         24 . A composition according to any of  claims 1  to  22  wherein 3D-MPL is present in an amount of about 25 μg/ml 
     
     
         25 . A composition according to any of  claims 1  to  24  wherein said multivalent composition is a bivalent, trivalent or quadrivalent composition. 
     
     
         26 . A composition according to any of  claims 1  to  25  wherein said pandemic influenza virus strain is selected from the list consisting of: H5N1, H9N2, H7N7, H2N2 and H1N1. 
     
     
         27 . An immunogenic composition according to  claim 26  wherein at least two influenza virus strain is selected from the list consisting of: H5N1, H9N2, H7N7, H2N2 and H1N1. 
     
     
         28 . An immunogenic composition according to any of  claims 1  to  27 , wherein said antigen or antigenic composition contains between 1 to 15 μg of HA per influenza strain. 
     
     
         29 . An immunogenic composition according to  claim 28  wherein said antigen or antigenic composition contains a low dose of HA per influenza strain. 
     
     
         30 . An immunogenic composition according to  claim 29  wherein said antigen or antigenic composition contains between 2.5 to 7.5 μg of HA per strain. 
     
     
         31 . An immunogenic composition according to any of  claims 1  to  30 , wherein the antigen or antigen composition is in the form of: a purified whole influenza virus, a non-live influenza virus, or sub-unit component(s) of influenza virus. 
     
     
         32 . An immunogenic composition according to  claim 31  wherein said non-live influenza virus is a split influenza virus. 
     
     
         33 . A method for the production of an influenza immunogenic composition for a pandemic situation which method comprises admixing influenza virus antigen or antigenic preparation from at least two influenza virus strains, at least one of which is associated with a pandemic outbreak or has the potential to be associated with a pandemic outbreak, with an oil-in-water emulsion. 
     
     
         34 . A method as claimed in  claim 33  wherein the oil-in-water emulsion adjuvant is as defined in any of  claims 1  to  18 . 
     
     
         35 . A method according to  claim 34  wherein the oil-in-water emulsion further comprises a TLR-4 adjuvant. 
     
     
         36 . A method according to  claim 35  wherein the TLR-4 adjuvant is as defined in any of  claims 19  to  24 . 
     
     
         37 . An immunogenic composition as claimed in any of  claims 1 - 32  for use in medicine. 
     
     
         38 . The use of (a) an influenza virus or antigenic preparation thereof, and (b) an oil-in-water emulsion adjuvant in the manufacture of an immunogenic composition as claimed in any of  claims 1  to  32  for inducing at least one of i) an improved CD4 T-cell immune response, ii) an improved B cell memory response, against said virus or antigenic composition in a human. 
     
     
         39 . The use of an influenza virus or antigenic preparation thereof and an oil-in-water emulsion adjuvant in the preparation of an immunogenic composition as claimed in any of  claims 1  to  32  for vaccination of human elderly against influenza. 
     
     
         40 . The use according to  claim 39  wherein the composition induces at least one of i) an improved CD4 T-cell immune response, ii) an improved B-memory cell response, against said virus or antigenic composition in said elderly subject. 
     
     
         41 . The use according to any of  claims 38  to  40  wherein the administration of said immunogenic composition induces both an improved CD4 T-cell immune response and an improved B-memory cell response. 
     
     
         42 . The use according to any of  claims 38  and  40  to  41  wherein said CD4 T-cell immune response involves the induction of a cross-reactive CD4 T helper response. 
     
     
         43 . The use according to any of  claims 38  to  42  wherein the target population is above 50 years of age. 
     
     
         44 . The use according to  claim 43  wherein the target population elderly above 65 years of age. 
     
     
         45 . The use of an influenza virus or antigenic preparation thereof in the manufacture of an immunogenic composition for revaccination of humans previously vaccinated with an immunogenic composition as claimed in any of  claims 1  to  32 . 
     
     
         46 . The use according to  claim 45  wherein the composition used for the revaccination contains an additional adjuvant. 
     
     
         47 . The use according to  claim 46  wherein said adjuvant is selected from the list consisting of: oil-in-water emulsion adjuvant, aluminium adjuvant, a TLR-4 ligand, a saponin. 
     
     
         48 . The use according to any of  claims 28  to  30  wherein said oil-in-water emulsion adjuvant is as defined in any of  claims 2  to  18  and the TLR-4 ligand is as defined in any of  claims 19  to  24 . 
     
     
         49 . The use according to any of  claims 45  to  48  wherein said immunogenic composition for revaccination contains an influenza virus or antigenic preparation thereof which shares common CD4 T-cell epitopes with the split influenza virus or split virus antigenic preparation thereof used for the first vaccination. 
     
     
         50 . The use according to any of  claim 45  to  49  wherein the immunological response following revaccination is any or two or all of the following: an improved CD4 response against the influenza virus or antigenic preparation thereof, or an improved humoral response or an improved B cell memory response. 
     
     
         51 . The use according to any of  claims 45  to  50  wherein the influenza antigen or antigenic preparation thereof is from at least two different influenza strains. 
     
     
         52 . The use according to  claim 51  wherein the influenza antigen or antigenic preparation thereof is from three different influenza strains. 
     
     
         53 . The use according to any of  claims 45  to  52  wherein said immunogenic composition for revaccination contains at least one influenza strain which is associated with a pandemic outbreak or has the potential to be associated with a pandemic outbreak. 
     
     
         54 . The use according to  claim 53  wherein said pandemic strain is selected from the list consisting of: H5N1, H9N2, H7N7, H2N2 and H1N1. 
     
     
         55 . The use according to any of  claim 45  to  54  wherein the first vaccination is made with an influenza composition containing an influenza strain that could potentially cause a pandemic outbreak and the re-vaccination is made with an influenza composition containing a circulating pandemic strain. 
     
     
         56 . The use according to any of  claims 45  to  55  wherein said immunogenic composition contains a low dose of HA antigen. 
     
     
         57 . The use according to any of  claims 45  to  56  wherein said influenza antigen or antigenic preparation thereof is egg-derived or tissue-culture derived. 
     
     
         58 . The use of an antigen or antigenic preparation from a first influenza strain in the manufacture of an immunogenic composition as claimed in any of  claims 1  to  32  for protection against influenza infections caused by a variant influenza strain. 
     
     
         59 . The use according to  claim 58  wherein the first influenza strain is associated with a pandemic outbreak or has the potential to be associated with a pandemic outbreak. 
     
     
         60 . The use according to  claim 58  wherein the variant influenza strain is associated with a pandemic outbreak or has the potential to be associated with a pandemic outbreak. 
     
     
         61 . The use according to  claim 59  or  60  wherein said pandemic strain is selected from the list consisting of: H5N1, H9N2, H7N7, H2N2 and H1N1. 
     
     
         62 . The use according to any of  claims 45  to  61  wherein said influenza antigen is selected from the list consisting of: a split influenza virus, a whole influenza virus, a sub-unit influenza virus, an influenza virosome, and antigenic preparation thereof.