Proteosome influenza vaccine

Abstract

Improved forms of vaccines which comprise proteosomes and protein antigens are described. Vaccines which contain influenza HA as the antigen are used for illustration as to demonstrate efficacy. Improvements in the preparation of the vaccines themselves and the proteosome component are also included.

1 .- 12 . (canceled) 
     
     
         13 . An immunogenic composition comprising at least one inactivated influenza virus antigen formulated with an adjuvant comprising a preparation of at least one outer membrane protein of a gram negative bacteria. 
     
     
         14 . The immunogenic composition of  claim 13 , wherein the inactivated influenza virus antigen comprises a split influenza virus antigen comprising hemagglutinin (HA). 
     
     
         15 . The immunogenic composition of  claim 13 , wherein the at least one inactivated influenza virus antigen is formulated with the adjuvant in the substantial absence of detergent. 
     
     
         16 . The immunogenic composition of  claim 13 , wherein the adjuvant comprises a preparation of hydrophobic particles comprising the at least one outer membrane protein of the gram negative bacteria. 
     
     
         17 . The immunogenic composition of  claim 16 , wherein the adjuvant comprises a preparation of proteosomes. 
     
     
         18 . The immunogenic composition of  claim 13 , wherein the at least one outer membrane protein of the gram negative bacteria is from a  Neisseria  species. 
     
     
         19 . The immunogenic composition of  claim 18 , wherein the at least one outer membrane protein of the gram negative bacteria is from  Neisseria meningitidis.    
     
     
         20 . The immunogenic composition of  claim 13 , wherein the ratio of outer membrane proteins to HA in the inactivated influenza virus antigen is at least 1:1. 
     
     
         21 . The immunogenic composition of  claim 20 , wherein the ratio is greater than 2:1. 
     
     
         22 . The immunogenic composition of  claim 13 , wherein the immunogenic composition comprises a multi-valent influenza preparation. 
     
     
         23 . The immunogenic composition of  claim 22 , wherein the immunogenic composition comprises a trivalent influenza preparation. 
     
     
         24 . The immunogenic composition of  claim 13 , wherein the at least one inactivated influenza virus antigen in the immunogenic composition comprises about 15 μg of HA. 
     
     
         25 . The immunogenic composition of  claim 24 , wherein the immunogenic composition comprises about 15 μg of HA of each of a plurality of inactivated influenza virus antigens. 
     
     
         26 . The immunogenic composition of  claim 13 , wherein the at least one inactivated influenza virus antigen in the immunogenic composition comprises less than about 15 μg of HA. 
     
     
         27 . The immunogenic composition of  claim 13 , wherein the at least one inactivated influenza virus antigen in the immunogenic composition comprises about 30 μg of HA. 
     
     
         28 . The immunogenic composition of  claim 13 , wherein the outer membrane proteins are in the form of particles with a median size of between about 150 and 1000 nM as measured by light scattering. 
     
     
         29 . A method for eliciting an immune response against influenza in a subject comprising administering to the subject the immunogenic composition of  claim 13 . 
     
     
         30 . The method of  claim 29 , wherein the immunogenic composition is administered intranasally. 
     
     
         31 . A method of preparing an influenza vaccine comprising the steps of:
 providing a mixture comprising at least one inactivated influenza virus antigen and a preparation comprising outer membrane proteins of a gram negative bacteria in the presence of detergent; and   removing detergent from the mixture by at least one of diafiltration and ultrafiltration to obtain a substantially detergent-free composition comprising the at least one inactivated influenza virus and outer membrane proteins; and   formulating the substantially detergent-free composition into a vaccine.   
     
     
         32 . The method of  claim 31 , further comprising filtering the substantially detergent-free composition with a filter comprising a pore size of at least 0.2μ and no more than 0.8μ in diameter. 
     
     
         33 . The method of  claim 31 , wherein the mixture provided comprises a ratio of the preparation of outer membrane proteins to inactivated influenza antigen of at least 1:1. 
     
     
         34 . The method of  claim 31 , wherein the mixture provided comprises a ratio of the preparation of outer membrane proteins to inactivated influenza antigen of greater than 2:1. 
     
     
         35 . The method of  claim 31 , comprising providing the mixture by
 treating an inactivated influenza virus with a detergent thereby providing a split influenza virus antigen; and   mixing the split influenza virus antigen with the preparation comprising outer membrane proteins of a gram negative bacteria in the presence of a detergent.   
     
     
         36 . A method of preparing an immunogenic composition against influenza comprising the steps of:
 providing a preparation of live influenza virus;   inactivating the live influenza virus in the preparation to produce an inactivated influenza virus;   treating the inactivated influenza virus with a detergent thereby providing a split influenza virus antigen;   mixing the split influenza virus antigen with a preparation comprising outer membrane proteins of a gram negative bacteria in the presence of a detergent;   removing detergent from the mixture by at least one of filtration step to obtain a substantially detergent-free composition comprising the at least one split influenza virus antigen and outer membrane proteins; and   formulating the substantially detergent-free composition into a vaccine.