Method of inducing the production of protective anti-hiv-1 antibodies

Abstract

The present invention relates, in general, to an immunogen for HIV vaccination and, in particular, to a method of inducing the production of protective anti-HIV antibodies by targeting B cell germline and clone intermediates using a combination of HIV envelope and non-HIV immunogens. The invention also relates to compositions suitable for use in such a method.

1 . A method of inducing the production in a subject of broadly neutralizing antibodies against HIV-1 comprising:
 i) administering to said subject a non-HIV-1 antigen that binds to a germline B cell receptor, said non-HIV-1 antigen being administered in an amount and under conditions such that intermediate clones of B cells are produced that secrete antibodies that cross-react with HIV-1 Env, and   ii) administering to said subject an HIV-1 antigen in an amount and under conditions such that naïve B cells or said intermediate clones of B cells are produced that secrete said broadly neutralizing anti-HIV-1 antibodies.   
     
     
         2 . The method according to  claim 1  wherein said subject is a human. 
     
     
         3 . The method according to  claim 1  wherein said non-HIV-1 antigen is a lipid. 
     
     
         4 . The method according to  claim 3  wherein said lipid is cardiolipin, phosphatidylserine, phosphatidylethanolamine, phosphatidylcholine, phosphotidylinositol, sphingomyelin, or derivative thereof. 
     
     
         5 . The method according to  claim 4  wherein said lipid is 1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-L-serine] (POPS), 1-palmitoyl-2-oleoyl-phosphatidylethanolamine (POPE), or dioleoyl phosphatidylethanolamine (DOPE). 
     
     
         6 . The method according to  claim 3  wherein said lipid is a hexagonal II phase of a phospholipid. 
     
     
         7 . The method according to  claim 1  wherein said non-HIV-1 antigen is phycoerythrin (PE), C-phycocyanin (C—PC), apoferritin, or anerobic or aerobic gut flora or component thereof. 
     
     
         8 . The method according to  claim 1  wherein said non-HIV antigen comprises the α subunit of RNA polymerase core protein of a bacteria or eukaryote. 
     
     
         9 . The method according to  claim 1  wherein said non-HIV antigen is kynureninase (KYNU) or antigenic fragment thereof. 
     
     
         10 . The method according to  claim 9  wherein said KYNU is recombinant KYNU expressed in CHO or 293T cells, or antigenic fragment thereof. 
     
     
         11 . The method according to  claim 1  further comprising administering an adjuvant. 
     
     
         12 . The method according to  claim 11  wherein said adjuvant is squalene based adjuvant, a TRL agonist, an oligonucletide (oCpGs) or R848. 
     
     
         13 . The method according to  claim 1  wherein said HIV-1 antigen is a membrane-proximal external region (MPER) antigen, or variant thereof. 
     
     
         14 . The method according to  claim 13  wherein said HIV-1 antigen is an immunogen shown in  FIG. 16B ,  16 C,  17 ,  18 ,  20 ,  25  or  26 . 
     
     
         15 . The method according to  claim 13  wherein said variant is a MPER epitope peptide with an L669S mutation. 
     
     
         16 . The method according to  claim 1  wherein said HIV-1 antigen is a transmitted founder HIV-1 Env, or antigenic fragment thereof. 
     
     
         17 . The method according to  claim 16  wherein said fragment comprises a portion of the CD4 binding site of gp120, an MPER sequence, or a portion of gp120 comprising the V2 or V3 region of gp120. 
     
     
         18 . The method according to  claim 1  wherein the method is effected by administering to said subject a prime immunization comprising said non-HIV-1 antigen followed by one or more boosts comprising said HIV-1 antigen. 
     
     
         19 . The method according to  claim 1  wherein said non-HIV-1 antigen comprises a lipid, a component of anaerobic or aerobic gut flora bacteria, phycobiliprotein, or KYNU or fragment thereof, and said HIV-1 antigen comprises an HIV-1 Env antigen selected from the group consisting of transmitted founder Env 1086.0 from Malawi, 089.0 from Malawi, 040_C9 from the U.S. and 63521 from a Clade B acute HIV-1 infected U.S. patient. 
     
     
         20 . The method according to  claim 1  wherein said non-HIV antigen or said HIV antigen comprises a protein and a DNA sequence encoding said protein is administered to said subject under conditions such that said DNA sequence is expressed and said protein is thereby produced. 
     
     
         21 . The method according to  claim 1  wherein A244gD+ envelope is administered as a prime and an envelope bound by CHO1, CHO2, CHO3, CHO4 or CHO5 is administered as a boost. 
     
     
         22 . The method according to  claim 1  wherein said non-HIV-1 antigen is present in a liposome with said HIV-1 antigen and at least one adjuvant. 
     
     
         23 . The method according to  claim 1  wherein said non-HIV-1 antigen is conjugated to said HIV-1 antigen and formulated with one or more adjuvants. 
     
     
         24 . An antibody selected from the group consisting of CHO1, CHO2, CHO3, CHO4, and CHO5, or antigen binding fragment thereof.