Influenza vaccine

Abstract

The present invention relates to monovalent 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 monovalent influenza immunogenic compositions comprising an influenza antigen or antigenic preparation thereof from an influenza virus 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 comprising a metabolisable oil, a sterol or a tocopherol such as alpha tocopherol, and an emulsifying agent.

1 . A monovalent influenza vaccine composition comprising an influenza virus component which is a low dose of influenza virus antigen from an influenza virus strain that is associated with a pandemic outbreak or has the potential to be associated with a pandemic outbreak, in combination with a suitable adjuvant, wherein said low antigen dose is less than 15 μg of haemagglutinin per dose or no more than 15 μg per combined dose of vaccine, and wherein said adjuvant is an oil-in-water emulsion carrier comprising a metabolisable oil, alpha tocopherol and an emulsifier.  
     
     
         2 . A monovalent influenza vaccine composition comprising an influenza virus component which is a low dose of influenza virus antigen from an influenza virus strain that is associated with a pandemic outbreak or has the potential to be associated with a pandemic outbreak, in combination with a suitable adjuvant, wherein said low antigen dose is less than 15 μg of haemagglutinin per dose or no more than 15 μg per combined dose of vaccine, and wherein said adjuvant is an oil-in-water emulsion carrier comprising squalene and alpha tocopherol in a ratio which is equal or less than 1.  
     
     
         3 . A vaccine composition according to  claim 1  wherein the influenza virus antigen is in the form of purified whole or in the form of a split influenza virus.  
     
     
         4 . A vaccine composition according to  claim 1  wherein the said metabolisable oil is squalene.  
     
     
         5 . A vaccine composition according to  claim 1  wherein said emulsifier is Tween 80™.  
     
     
         6 . A vaccine composition according to  claim 1 , wherein said oil in water emulsion comprise from 2 to 10% squalene, from 2 to 10% alpha tocopherol and from 0.3 to 3% Tween 80.  
     
     
         7 . A vaccine composition according to  claim 1 , wherein said oil in water emulsion additionally comprise 3 De-O-acylated monophosphoryl lipid A (3D-MPL), or QS21.  
     
     
         8 . A vaccine composition according to  claim 7  wherein 3D-MPL and QS-21 are present at a range of 1 μg -100 μg, preferably 10 μg -50 μg per dose.  
     
     
         9 . A vaccine composition according to  claim 7  wherein 3D-MPL and QS-21 are both present and wherein the ratio of 3D-MPL: QS21 is 2.5:1 to 1:1.  
     
     
         10 . A vaccine composition according to  claim 1  wherein the low antigen dose is less than 15 μg of haemagglutinin per dose.  
     
     
         11 . A vaccine composition according to  claim 10  in which the low antigen dose is less than 10 μg of haemagglutinin per dose or per combined dose of vaccine.  
     
     
         12 . A vaccine composition according to  claim 11  in which the antigen dose is between 0.1 and 7.5 μg, or between 1 and 5 μg of haemagglutinin per dose or per combined dose of vaccine.  
     
     
         13 . A vaccine composition of  claim 1  which is egg-derived or cell culture-derived.  
     
     
         14 . A vaccine composition according to  claim 1  wherein the influenza virus antigen is substantially free of host cell contamination.  
     
     
         15 . A vaccine composition according to  claim 1  wherein the influenza virus component is purified by a method which includes a protease incubation step to digest non-influenza virus proteins.  
     
     
         16 . A kit comprising: 
 (i) a low dose of influenza virus antigen formulated with an adjuvant as defined in  claim 1  for parenteral administration; and    (ii) a low dose of influenza virus antigen for mucosal administration, in a mucosal delivery device such as an intranasal spray device,    wherein the influenza virus component which is an influenza virus antigen from an influenza virus strain that is associated with a pandemic outbreak, or has the potential to be associated with a pandemic outbreak, and wherein the low antigen dose is less than 15 μg of haemagglutinin per dose or no more than 15 μg per combined dose of vaccine.    
     
     
         17 . The kit according to  claim 16 , wherein the combined antigen dose of the parenteral and mucosal formulations is no more than 15 μg haemagglutinin.  
     
     
         18 . The kit according to  claim 17  wherein the combined antigen dose is less than 10 μg haemagglutinin.  
     
     
         19 . The kit according to  claim 17  wherein the influenza antigen in (i) is inactivated whole virus and the influenza antigen in (ii) is split virus.  
     
     
         20 . A method for the production of an influenza vaccine for a pandemic situation which method comprises admixing a influenza virus antigen from a single influenza virus strain that is associated with a pandemic outbreak or has the potential to be associated with a pandemic outbreak, with an adjuvant as defined in  claim 1  and providing vaccine lots or vaccine kits which contain less than 10 μg influenza haemagglutinin antigen per dose or no more than 15 μg haemagglutinin per combined dose.  
     
     
         21 . A method according to  claim 20  wherein the antigen is highly purified.  
     
     
         22 . A method according to  claim 20  wherein the influenza virus antigen is in the form of whole or split influenza virus particles.  
     
     
         23 . The vaccine composition or kit or method according to  claim 1  wherein the influenza antigen is selected from an H2 antigen such as H2N2 and an H5 antigen such as H5N1.  
     
     
         24 . A method for producing influenza virus antigen for use in a vaccine, which method is according to  claim 20 , and comprises the step of incubating a mixture containing influenza virus particles with a protease to digest non-influenza virus proteins.  
     
     
         25 . A method according to  claim 24  wherein the protease digestion step is performed after the influenza virus antigen has been partially purified by one or more physical separation steps.  
     
     
         26 . A method according to  claim 24  wherein the protease digestion step is performed prior to a virus inactivation step.  
     
     
         27 . A method according to  claim 26  wherein the purification process comprises the steps of: 
 (i) providing a harvested mixture of cultured influenza virus and host proteins from a culture;    (ii) partially purifying the influenza virus in the mixture by one or more physical purification steps;    (iii) performing a protease digestion step on the partially purified mixture to digest host proteins;    (iv) inactivating the influenza virus;    (iv) further purifying the influenza virus by at least one filtration step.    
     
     
         28 . A method of manufacturing a vaccine lot or a vaccine kit for protection against influenza virus infection comprising the step of using below 10 μg, or below 8 μg, or from 1-7.5 μg, or from 1-5 μg of egg-derived influenza virus haemagglutinin antigen from a single strain of influenza associated with a pandemic outbreak or having the potential to be associated with a pandemic outbreak in combination with an adjuvant as defined in  claim 1 .  
     
     
         29 . The method according to  claim 28  for administration as a single dose or in more than one dose such as two doses.  
     
     
         30 . The method of no more than 15 μg, or below 10 μg, or below 8 μg, or from 1-7.5 μg, or from 1-5 μg of egg-derived influenza virus haemagglutinin antigen from a single strain of influenza associated with a pandemic outbreak or having the potential to be associated with a pandemic outbreak, in the manufacture of a two-dose vaccine for simultaneous parenteral and mucosal administration, wherein the haemaggutinin for parenteral administration has been formulated with an adjuvant as defined in  claim 1 .  
     
     
         31 . A monovalent influenza vaccine composition comprising a low amount of influenza virus antigen or antigenic preparation from an influenza virus strain that is associated with a pandemic or has the potential to be associated with a pandemic, in combination with an adjuvant, wherein said adjuvant is an oil-in-water emulsion comprising a metabolisable oil, a sterol or a tocopherol, and an emulsifying agent.  
     
     
         32 . A composition according to  claim 31  wherein said tocopherol is alpha tocopherol.  
     
     
         33 . A composition according to  claim 31  wherein said metabolisable oil is squalene.  
     
     
         34 . A composition according to  claim 31  wherein said metabolisable oil is present in an amount of 0.5% to 20% of the total volume of said immunogenic composition.  
     
     
         35 . A composition according to  claim 31  wherein said metabolisable oil is present in an amount of 1.0% to 10% of the total volume of said immunogenic composition.  
     
     
         36 . A composition according to  claim 31  wherein said metabolisable oil is present in an amount of 2.0% to 6.0% of the total volume of said immunogenic composition.  
     
     
         37 . A composition according to  claim 31  wherein said alpha-tocopherol is present in an amount of 1.0% to 20% of the total volume of said immunogenic composition.  
     
     
         38 . A composition according to  claim 31  wherein said alpha-tocopherol is present in an amount of 1.0% to 5.0% of the total volume of said immunogenic composition.  
     
     
         39 . A composition according to  claim 31  wherein the ratio of squalene: alpha tocopherol is equal or less than 1.  
     
     
         40 . A composition according to  claim 31  wherein said emulsifying agent is Tween 80.  
     
     
         41 . A composition according to  claim 31  wherein said emulsifying agent is present at an amount of 0.01 to 5.0% by weight (w/w) of said immunogenic composition.  
     
     
         42 . A composition according to  claim 31  wherein said emulsifying agent is present at an amount of 0.1 to 2.0% by weight (w/w) of said immunogenic composition.  
     
     
         43 . A composition according to  claim 31  wherein said antigen or antigenic composition contains a low amount of haemagglutinin (HA) antigen.  
     
     
         44 . A composition according to  claim 43  wherein the amount of HA antigen does not exceed 15 μg per dose.  
     
     
         45 . A composition according to  claim 44  wherein the amount of HA antigen does not exceed 10 μg, or 8 μg, or 4 μg, or 2 μg per dose.  
     
     
         46 . A composition according to  claim 43  wherein the amount of HA antigen is between 1-7.5 μg, or from 1-5 μg per dose.  
     
     
         47 . A composition according to  claim 46  wherein the amount of HA antigen contains between 2.5 to 7.5 μg of HA per strain.  
     
     
         48 . A composition according to  claim 31  wherein said pandemic influenza virus strain is selected from the list consisting of: H5N1, H9N2, H7N7, H2N2 and H1N1.  
     
     
         49 . A composition according to  claim 48  wherein said pandemic influenza virus strain is selected from the list consisting of: H5N1, H9N2, H7N7, H2N2 and H1N1.  
     
     
         50 . A composition according to  claim 31 , 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.  
     
     
         51 . A composition according to  claim 50  wherein said non-live influenza virus is a split influenza virus.  
     
     
         52 . A composition as claimed in  claim 31  wherein said influenza antigen or antigenic composition is derived from cell culture or produced in embryonic eggs.  
     
     
         53 . A composition as claimed in  claim 31  for use in medicine.  
     
     
         54 . A kit comprising a low amount of influenza virus antigen or antigenic preparation and an oil-in-water adjuvant as defined in  claim 31 .  
     
     
         55 . A kit according to  claim 54  wherein said antigen is HA.  
     
     
         56 . A kit according to  claim 55  wherein said amount of HA is as defined in  claims 14  to  17 .  
     
     
         57 . A method for the production of an influenza vaccine composition for a pandemic situation or a pre-pandemic situation which method comprises admixing an egg-derived or a cell culture-derived influenza virus antigen from a single influenza virus strain that is associated with a pandemic or has the potential to be associated with a pandemic, with an an oil-in-water emulsion adjuvant and providing vaccine lots or vaccine kits which contain no more than 15 μg influenza haemagglutinin antigen per dose.  
     
     
         58 . A method as claimed in  claim 57  wherein the oil-in-water emulsion adjuvant is as defined in  claim 31 .  
     
     
         59 . A method of manufacturing an immunogenic composition as claimed in  claim 31  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, iii) an improved humoral response comprising the step of using (a) a low amount of an influenza virus antigen or antigenic preparation thereof from a single strain of influenza associated with a pandemic or having the potential to be associated with a pandemic, and (b) an oil-in-water emulsion adjuvant.  
     
     
         60 . The method according to  claim 59  wherein said CD4 T-cell immune response involves the induction of a cross-reactive CD4 T helper response or the induction of a cross-reactive humoral immune response.  
     
     
         61 . The method of (a) a low amount of a pandemic influenza virus antigen or antigenic preparation thereof influenza virus haemagglutinin antigen from a single strain of influenza associated with a pandemic or having the potential to be associated with a pandemic, and (b) an oil-in-water emulsion adjuvant as defined in  claim 31  in the manufacture of a vaccine lot or a vaccine kit for protection against influenza virus infection.  
     
     
         62 . The method according to  claim 59  wherein said immune response or protection meets all three EU regulatory criteria for influenza vaccine efficacy.  
     
     
         63 . The method according to  claim 59  wherein said immune response or protection meets is obtained after one or two doses of vaccine.  
     
     
         64 . The method according to  claim 59  wherein said vaccine is administered parenterally.  
     
     
         65 . A method as claimed in  claim 57  or use as claimed in any of  claims 29  to  34  wherein said HA antigen amount is as defined in  claim 44 .  
     
     
         66 . The method 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  claim 1 .  
     
     
         67 . The method according to  claim 65  wherein the composition used for the revaccination contains an adjuvant.  
     
     
         68 . The method according to  claim 67  wherein said adjuvant is an oil-in-water emulsion adjuvant.  
     
     
         69 . The method according to  claim 66  wherein said immunogenic composition for revaccination contains an influenza virus or antigenic preparation thereof which is associated with a pandemic or has the potential to be associated with a pandemic.  
     
     
         70 . The method according to  claim 69  wherein said pandemic strain is selected from the list consisting of: H5N1, H9N2, H7N7, H2N2 and H1N1.  
     
     
         71 . The method according to  claim 69  wherein said immunogenic composition for revaccination contains an influenza virus or antigenic preparation thereof which shares common CD4 T-cell epitopes or common B cell epitopes with the influenza virus or antigenic preparation thereof used for the first vaccination.  
     
     
         72 . The method according to  claim 66  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.  
     
     
         73 . The method of an antigen or antigenic preparation from a first influenza strain in the manufacture of an immunogenic composition as claimed in  claim 1  for protection against influenza infections caused by a variant influenza strain.  
     
     
         74 . The method according to  claim 73  wherein the first influenza strain is associated with a pandemic outbreak or has the potential to be associated with a pandemic outbreak.  
     
     
         75 . The method according to  claim 73  wherein the variant influenza strain is associated with a pandemic outbreak or has the potential to be associated with a pandemic outbreak.