US2020113998A1PendingUtilityA1

Hbv vaccine

38
Assignee: UNIV OXFORD INNOVATION LTDPriority: Apr 10, 2017Filed: Apr 10, 2018Published: Apr 16, 2020
Est. expiryApr 10, 2037(~10.7 yrs left)· nominal 20-yr term from priority
Inventors:Eleanor BarnesSenthil Chinnakannan
C12N 2710/10041A61K 2039/5256C12N 2730/10134A61K 39/12C12N 2710/24041A61K 39/39C12N 7/00C07K 14/005C12N 2710/24134A61K 39/292A61K 2039/55516C12N 2800/107C07K 2319/50C07K 2319/00C12N 2730/10122C12N 2710/10343A61P 37/04A61P 31/20A61P 1/16C12N 9/22C12Y 301/26004C12Y 207/07049C12N 9/1276C12N 15/86
38
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Claims

Abstract

The invention relates to a multi-HBV immunogen viral vector vaccine comprising: a viral vector comprising an immunogen expression cassette, wherein the expression of a protein encoded by the expression cassette is arranged to be driven by a promoter, wherein the immunogen expression cassette encodes: a) HBV Core; b) a modified HBV polymerase (Pmut), wherein the modification is a mutation to wild-type HBV polymerase to substantially remove polymerase function; c) HBV surface antigen (HbsAg); and d) an intergenic sequence that is arranged to cause expression of at least the HBV surface antigen (HbsAg) as a separate protein from the HBV core and the modified HBV polymerase (Pmut), wherein the intergenic sequence is downstream (3′) of the sequences encoding the HBV core and the modified HBV polymerase (Pmut) and upstream (5′) of the sequence encoding the HBV surface antigen (HbsAg); and related compositions, vaccination methods and methods of treatment or prophylaxis of HBV infection.

Claims

exact text as granted — not AI-modified
1 . A multi-HBV immunogen viral vector vaccine comprising:
 a viral vector comprising an immunogen expression cassette, wherein the expression of a protein encoded by the expression cassette is arranged to be driven by a promoter, wherein the immunogen expression cassette encodes:   a) HBV Core;   b) a modified HBV polymerase (P mut ), wherein the modification is a mutation to wild-type HBV polymerase to substantially remove polymerase function;   c) HBV surface antigen (HbsAg); and   d) an intergenic sequence that is arranged to cause expression of at least the HBV surface antigen (HbsAg) as a separate protein from the HBV core and the modified HBV polymerase (P mut ),   wherein the intergenic sequence is downstream (3′) of the sequences encoding the HBV core and the modified HBV polymerase (P mut ) and upstream (5′) of the sequence encoding the HBV surface antigen (HbsAg).   
     
     
         2 . The multi-HBV immunogen viral vector vaccine according to  claim 1 , wherein the intergenic sequence comprises a cleavage domain, an IRES (Internal Ribosomal Entry Site), a splicing signal, or a secondary promoter. 
     
     
         3 . The multi-HBV immunogen viral vector vaccine according to  claim 1 , wherein the intergenic sequence comprises a cleavage domain;
 optionally wherein the cleavage domain comprises a ribosome skipping cleavage domain;   further optionally, wherein the cleavage domain comprises or consists of Furin-2A (F2A) peptide sequence or a functional variant thereof.   
     
     
         4 . The multi-HBV immunogen viral vector vaccine according to  claim 1 , wherein the intergenic sequence comprises a secondary promoter to promote expression of at least the surface antigen (HbsAg). 
     
     
         5 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the immunogen expression cassette further encodes HBV Pre-Core (PreC). 
     
     
         6 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the immunogen expression cassette further encodes HBV PreS1, and/or a truncated form thereof. 
     
     
         7 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the immunogen expression cassette further encodes HBV PreS2. 
     
     
         8 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the immunogen expression cassette encodes HBV Pre-Core (PreC) and HBV PreS1, and a truncated form of PreS1. 
     
     
         9 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the immunogen expression cassette is capable of expressing HBV e-Antigen. 
     
     
         10 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the HBV Core and modified polymerase (Pmut) are arranged to be expressed as a fusion protein. 
     
     
         11 . The multi-HBV immunogen viral vector vaccine according to  claims 5  to  10 , wherein the HBV Pre-core, HBV Core and modified polymerase (Pmut) are arranged to be expressed as a fusion protein. 
     
     
         12 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the immunogen expression cassette does not encode HBV X protein. 
     
     
         13 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the immunogen expression cassette comprises nucleic acid comprising the sequence of:
 SEQ ID NO: 46 (SIi-HBV-CPmutS) or a variant thereof;   SEQ ID NO: 47 (SIi-HBV-SCPmut) or a variant thereof;   SEQ ID NO: 48 (SIi-HBV-CPmutPreS-S(sh)) or a variant thereof;   SEQ ID NO: 49 (SIi-HBV-CPmutPreS-TPA-S(sh)) or a variant thereof; SEQ ID NO: 24 (MVA-SIi-HBV-PreS-Pmut-C-S(sh)) or a variant thereof; or   SEQ ID NO: 27 or SEQ ID NO: 58 (MVA-SIi-HBV-PreS-Pmut-C-TPA-S(sh)) or a variant thereof.   
     
     
         14 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the viral vector encodes the amino acid sequence of:
 SEQ ID NO: 3 (SIi-HBV-CPmutS) or a variant thereof.   SEQ ID NO: 11 (SIi-HBV-SCPmut) or a variant thereof.   SEQ ID NO: 13 (SIi-HBV-CPmutPreS-S(sh)) or a variant thereof.   SEQ ID NO: 25 (SIi-HBV-CPmutPreS-TPA-S(sh)) or a variant thereof.   SEQ ID NO: 23 (MVA-SIi-HBV-PreS-Pmut-C-S(sh)) or a variant thereof.   SEQ ID NO: 26 (MVA-SIi-HBV-PreS-Pmut-C-TPA-S(sh)) or a variant thereof.   
     
     
         15 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the viral vector comprises an adenovirus vector or Modified Vaccinia Ankara (MVA) vector. 
     
     
         16 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the viral vector may comprise a group E simian adenovirus vector. 
     
     
         17 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the promoter is encoded in the immunogen expression cassette, for example the promoter may be encoded at, or adjacent to, the 5′ end of the immunogen expression cassette; or
 wherein the promoter may be encoded as part of the viral vector nucleic acid outside of the immunogen expression cassette. 
 
     
     
         18 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the promoter promotes the expression of all the encoded protein of the immunogen expression cassette. 
     
     
         19 . The multi-HBV immunogen viral vector vaccine according to  claims 1  to  17 , wherein the immunogen expression cassette comprises a secondary promoter, wherein the promoter is a primary promoter that is arranged to promote expression of at least the HBV core and modified polymerase (Pmut), and not the HBV surface antigen (HbsAg) which is arranged to be promoted separately by the secondary promoter. 
     
     
         20 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the promoter comprises a CMV promoter or a pox viral promoter. 
     
     
         21 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the HBV Core comprises or consists of a full length wild-type HBV Core sequence. 
     
     
         22 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the modified HBV polymerase (P mut ) is not a truncated form of HBV polymerase (i.e. it is full length relative to wildtype HBV polymerase). 
     
     
         23 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the modified HBV polymerase (P mut ) comprises or consists of the sequence of SEQ ID NO: 8 or a variant thereof. 
     
     
         24 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the HbsAg comprises or consists of a full length wild-type HbsAg sequence, or a variant thereof. 
     
     
         25 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the immunogen expression cassette encodes a truncated form of HBV PreS1 and the truncated PreS1 is arranged to be expressed a fusion protein with the HBV surface antigen (S/HbsAg). 
     
     
         26 . The multi-HBV immunogen viral vector vaccine according to  claim 25 , further comprising a linker sequence provided between the truncated PreS1 and surface antigen (S/HbsAg). 
     
     
         27 . The multi-HBV immunogen viral vector vaccine according to  claim 25  or  26 , wherein the truncated PreS1 with a fused surface antigen is encoded downstream (3′) of the intergenic sequence. 
     
     
         28 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the expression cassette encodes a NΔPreS1 and PreS2 fusion sequence. 
     
     
         29 . The multi-HBV immunogen viral vector vaccine according to  claim 28 , wherein the encoded NΔPreS1 and PreS2 fusion sequence is encoded upstream (5′) of the intergenic sequence. 
     
     
         30 . The multi-HBV immunogen viral vector vaccine according to  claim 29 , wherein the encoded NΔPreS1 and PreS2 fusion sequence is further fused with the modified polymerase (Pmut). 
     
     
         31 . The multi-HBV immunogen viral vector vaccine according to  claim 30 , wherein a linker sequence is provided between the PreS2 and modified polymerase (Pmut). 
     
     
         32 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein the immunogen expression cassette further encodes a peptide adjuvant. 
     
     
         33 . The multi-HBV immunogen viral vector vaccine according to  claim 32 , wherein the peptide adjuvant comprises TPA (tissue plasminogen activator) or a human or non-human invariant chain (Ii), or a fragment thereof. 
     
     
         34 . The multi-HBV immunogen viral vector vaccine according to any preceding claim, wherein linker residues are encoded between one or more, or all, of the protein/antigen sequences that are provided in a fusion protein. 
     
     
         35 . A nucleic acid comprising or consisting of an HBV immunogen expression cassette, wherein the immunogen expression cassette encodes:
 a) HBV Core;   b) a modified HBV polymerase (P mut ), wherein the modification is a mutation to wild-type HBV polymerase to substantially remove polymerase function;   c) HBV surface antigen (HbsAg); and   d) an intergenic sequence that is arranged to cause expression of at least the HBV surface antigen (HbsAg) as a separate protein from the HBV core and the modified HBV polymerase (P mut ),   wherein the intergenic sequence is downstream (3′) of the sequences encoding the HBV core and the modified HBV polymerase (P mut ) and upstream (5′) of the sequence encoding the HBV surface antigen (HbsAg).   
     
     
         36 . The nucleic acid according to  claim 35 , wherein the immunogen expression cassette further encodes a promoter. 
     
     
         37 . The nucleic acid according to  claim 35  or  36 , wherein the immunogen expression cassette is isolated or provided in a non-viral vector. 
     
     
         38 . A composition comprising the viral vector according to any of  claims 1  to  34  or the nucleic acid according to any of  claims 35  to  37 , optionally wherein the composition is a pharmaceutically acceptable composition. 
     
     
         39 . The composition according to any of  claim 38 , further comprising another therapeutically or prophylactically active ingredient and/or an adjuvant. 
     
     
         40 . The composition according to  claim 38  or  39 , wherein the composition comprises a pharmaceutically acceptable carrier and/or wherein the composition is a vaccine composition. 
     
     
         41 . The composition according to any of  claims 38  to  40 , the viral vector according to any of  claims 1  to  34  or the nucleic acid according to any of  claims 35  to  37 , for use in the prophylaxis or treatment of HBV infection in a subject; optionally wherein the use is as a vaccine. 
     
     
         42 . A method of treatment or prophylaxis of HBV infection comprising the administration of the composition according to any of  claims 38  to  40 , the viral vector according to any of  claims 1  to  34  or the nucleic acid according to any of  claims 35  to  37 , to a subject. 
     
     
         43 . The composition for the use according to  claim 41  of the method according to  claim 42 , wherein the use or administration is in combination with the use or administration of another therapeutically or prophylactically active ingredient. 
     
     
         44 . A prime boost vaccination kit comprising
 a prime vaccination comprising the composition according to any of  claims 38  to  40 , the viral vector according to any of  claims 1  to  34  or the nucleic acid according to any of  claims 35  to  37 ; and   a boost vaccination comprising the composition according to any of  claims 38  to  40 , the viral vector according to any of  claims 1  to  34  or the nucleic acid according to any of  claims 35  to  37 .   
     
     
         45 . The prime and boost vaccination kit according to  claim 44 , wherein the prime and boost vaccinations comprise different viral vectors.

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