Vaccine against beta-herpesvirus infection and use thereof

Abstract

The present invention is related to a beta-herpesvirus, wherein the beta-herpesvirus is spread-deficient.

We claim: 
     
         1 . A recombinant beta-herpesvirus, wherein the beta-herpesvirus is spread-deficient. 
     
     
         2 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus is endotheliotropic and/or has a wild type-like virion surface. 
     
     
         3 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus is endotheliotropic and has a wild type-like virion surface. 
     
     
         4 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus is suitable to or capable of inducing an immune response, wherein the immune response comprises neutralizing antibodies against beta-herpesvirus and CD4 +  and CD8 +  T-cells directed against epitopes of beta-herpesvirus. 
     
     
         5 . The beta-herpesvirus according to  claim 4 , wherein the immune response comprises induction of neutralizing antibodies against a wild type beta-herpesvirus, wherein said antibodies are capable of inhibiting said wild type beta-herpesvirus from infecting endothelial cells and/or epithelial cells. 
     
     
         6 . The beta-herpesvirus according to  claim 5 , wherein beta-herpesvirus which is prevented from infecting endothelial cells and/or epithelial cells by the neutralizing antibodies, is preferably a human pathogen. 
     
     
         7 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus is a human beta-herpesvirus. 
     
     
         8 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus is a cytomegalovirus. 
     
     
         9 . The beta-herpesvirus according to  claim 7 , wherein the beta-herpesvirus is a human cytomegalovirus. 
     
     
         10 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus is deficient in at least one gene product involved in primary and/or secondary envelopment. 
     
     
         11 . The beta-herpesvirus according to  claim 10 , wherein the at least one gene product is involved in primary envelopment. 
     
     
         12 . The beta-herpesvirus according to  claim 11 , wherein the at least one gene product is encoded by a gene selected from the group comprising UL50 and UL 53 and homologs of each thereof. 
     
     
         13 . The beta-herpesvirus according to  claim 10 , wherein the at least one gene product is involved in secondary envelopment. 
     
     
         14 . The beta-herpesvirus according to  claim 13 , wherein the at least one gene product is encoded by a gene selected from the group comprising UL94 and UL99 and homologs each thereof. 
     
     
         15 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 122630 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 123668 to 181652 of the nucleotide sequence according to SEQ ID NO: 20 and a third nucleotide sequence represented by nucleotides 189192 to 233681 of the nucleotide sequence according to SEQ ID NO: 20 and wherein nucleotide 122630 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 123668 of the nucleotide sequence according to SEQ ID NO: 20 and wherein nucleotide 181652 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 189192 of the nucleotide sequence according to SEQ ID NO: 20. 
     
     
         16 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 122630 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 123668 to 181652 of the nucleotide sequence according to SEQ ID NO: 20, a third nucleotide sequence represented by nucleotides 189192 to 233681 of the nucleotide sequence according to SEQ ID NO: 20 and a fourth nucleotide sequence comprising a nucleotide sequence according to SEQ ID NO: 34. 
     
     
         17 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 122630 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 123668 to 130670 of the nucleotide sequence according to SEQ ID NO: 20, a third nucleotide sequence represented by nucleotides 131243 to 181652 of the nucleotide sequence according to SEQ ID NO: 20 and a fourth nucleotide sequence represented by nucleotides 189192 to 233681 of the nucleotide sequence according to SEQ ID NO: 20 and wherein nucleotide 122630 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 123668 of the nucleotide sequence according to SEQ ID NO: 20, wherein the nucleotide 130670 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to the nucleotide 131243 of the nucleotide sequence according to SEQ ID NO: 20 and wherein the nucleotide 181652 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to the nucleotide 189192 of the nucleotide sequence according to SEQ ID NO: 20. 
     
     
         18 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 58442 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 59623 to 181652 of the nucleotide sequence according to SEQ ID NO: 20 and a third nucleotide sequence represented by nucleotides 189192 to 233681 of the nucleotide sequence according to SEQ ID NO: 20 and wherein nucleotide 58442 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 59623 of the nucleotide sequence according to SEQ ID NO: 20 and wherein nucleotide 181652 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to the nucleotide 189192 of the nucleotide sequence according to SEQ ID NO: 20. 
     
     
         19 . The beta-herpesvirus according to  claim 1 , wherein nucleotide 58442 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 1 of the nucleotide sequence according to SEQ ID NO: 32, wherein nucleotide 179 of the nucleotide sequence according to SEQ ID NO: 32 is covalently linked to nucleotide 59623 of the nucleotide sequence according to SEQ ID NO: 20 and wherein nucleotide 181652 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 189192 of the nucleotide sequence according to SEQ ID NO: 20. 
     
     
         20 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 62129 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 63261 to 181652 of the nucleotide sequence according to SEQ ID NO: 20 and a third nucleotide sequence represented by nucleotides 189192 to 233681 of the nucleotide sequence according to SEQ ID NO: 20 and wherein nucleotide 62129 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 63261 of the nucleotide sequence according to SEQ ID NO: 20 and wherein the nucleotide 181652 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to the nucleotide 189192 of the nucleotide sequence according to SEQ ID NO: 20. 
     
     
         21 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 62129 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 63261 to 181652 of the nucleotide sequence according to SEQ ID NO: 20, a third nucleotide sequence represented by nucleotides 189192 to 233681 of the nucleotide sequence according to SEQ ID NO: 20 and a fourth nucleotide sequence comprising a nucleotide sequence according to SEQ ID NO: 33. 
     
     
         22 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 58442 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 59623 to 62129 of the nucleotide sequence according to SEQ ID NO: 20, a third nucleotide sequence represented by nucleotides 63261 to 181652 of the nucleotide sequence according to SEQ ID NO: 20, a fourth nucleotide sequence represented by nucleotides 189192 to 233681 of the nucleotide sequence according to SEQ ID NO: 20, a fifth nucleotide sequence comprising a nucleotide sequence according to SEQ ID NO: 32 and a sixth nucleotide sequence comprising a nucleotide sequence according to SEQ ID NO: 33. 
     
     
         23 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus comprises human cytomegalovirus. 
     
     
         24 . The beta-herpesvirus according to  claim 1 , wherein the beta herpesvirus comprises the nucleotide sequence according to SEQ ID NO: 23. 
     
     
         25 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus is deficient in at least one gene product encoded by an immune evasive gene. 
     
     
         26 . The beta-herpesvirus according to  claim 25 , wherein the at least one gene product encoded by an immune evasive gene is selected from the group comprising gene products regulating MHC class I presentation and gene products regulating NK cell response. 
     
     
         27 . The beta-herpesvirus according to  claim 26 , wherein the at least one gene product encoded by an immune evasive gene is a gene product regulating MHC class I presentation. 
     
     
         28 . The beta-herpesvirus according to  claim 27 , wherein the gene product regulating MHC class I presentation comprises human cytomegalovirus. 
     
     
         29 . The beta-herpesvirus according to  claim 26 , wherein the at least one gene product encoded by an immune evasive gene is a gene product regulating NK cell response. 
     
     
         30 . The beta-herpesvirus according to  claim 29 , wherein the gene product regulating NK cell response is selected from the group comprising gene products encoded by the genes UL40, UL16 and UL18. 
     
     
         31 . The beta-herpesvirus according to  claim 1 , wherein the beta-herpesvirus encodes a heterologous nucleic acid. 
     
     
         32 . The beta-herpesvirus according to  claim 34 , wherein the heterologous nucleic acid is a functional nucleic acid, preferably selected from the group comprising antisense molecules, ribozymes and RNA interference mediating nucleic acids. 
     
     
         33 . The beta-herpesvirus according to  claim 31 , wherein the nucleic acid is a nucleic acid coding for a peptide, oligopeptide, polypeptide or protein. 
     
     
         34 . The beta-herpesvirus according to  claim 33 , wherein the peptide, oligopeptide, polypeptide or protein comprises at least one antigen. 
     
     
         35 . The beta-herpesvirus according to  claim 34 , wherein the antigen is an antigen selected from the group comprising viral antigens, bacterial antigens and parasite antigens. 
     
     
         36 . The beta-herpesvirus according to  claim 1 , for use in a method for the treatment of a human subject and/or for use in a method for the vaccination of a human subject. 
     
     
         37 . The beta-herpesvirus according to  claim 36 , wherein the subject is a mammal. 
     
     
         38 . The beta-herpesvirus according to  claim 36 , wherein the beta-herpesvirus is human cytomegalovirus. 
     
     
         39 . The beta-herpesvirus according to  claim 36 , wherein the subject is suffering from a disease or is at risk of suffering from a disease. 
     
     
         40 . The beta-herpesvirus according to  claim 36 , wherein the vaccination is a vaccination against a disease. 
     
     
         41 . The beta-herpesvirus according to  claim 39 , wherein the disease is a disease or condition which is associated with human cytomegalovirus infection. 
     
     
         42 . The beta-herpesvirus according to  claim 41 , wherein the disease or condition comprises congenital inclusion disease. 
     
     
         43 . The beta-herpesvirus according to  claim 36 , wherein the subject is defined as a female with the ability to reproduce. 
     
     
         44 . The beta-herpesvirus according to  claim 43 , wherein the treatment is or is suitable for or capable of preventing the transfer of a beta-herpesvirus, preferably human cytomegalovirus, from the female to a fetus and/or to an embryo carried or to be carried in the future by the female. 
     
     
         45 . The beta-herpesvirus according to  claim 43 , wherein the treatment is for or is suitable for the generation of or capable of generating an immune response in the female body or the immune response in the female body, whereby preferably such immune response confers protection to a fetus and/or to an embryo carried or to be carried in the future by the female against beta-herpesvirus, preferably human cytomegalovirus, and/or a disease or condition associated with beta-herpesvirus infection, preferably human cytomegalovirus infection. 
     
     
         46 . Use of a beta-herpesvirus according to  claim 1 , for the manufacture of a medicament. 
     
     
         47 . Use according to  claim 46 , wherein the medicament is for the treatment and/or prevention of beta-herpesvirus infection. 
     
     
         48 . Use according to  claim 46 , wherein the medicament is for the treatment and/or prevention of a disease or condition associated with beta-herpesvirus infection, preferably human cytomegalovirus infection. 
     
     
         49 . Use of a beta-herpesvirus according to  claim 1 , for the manufacture of a vaccine. 
     
     
         50 . Use according to  claim 49 , wherein the vaccine is for the treatment and/or prevention of beta-herpesvirus infection. 
     
     
         51 . Use according to  claim 50 , wherein the vaccine is for the treatment and/or prevention of a disease or condition associated with beta-herpesvirus infection, preferably human cytomegalovirus infection. 
     
     
         52 . Use according to  claim 49 , wherein the vaccine is or is suitable for the administration to a subject, whereby the subject is selected form the group comprising a pregnant female, a female of reproductive age, a donor of a transplant, a recipient of a transplant and a subject being infected with HIV or being at risk of being infected with HIV. 
     
     
         53 . Use according to  claim 52 , wherein the donor is a potential donor and/or the recipient is a potential recipient. 
     
     
         54 . A nucleic acid coding for a beta-herpesvirus according to  claim 1 . 
     
     
         55 . A vector comprising the nucleic acid according to  claim 54 . 
     
     
         56 . A vector comprising the nucleic acid according to  claim 55 , wherein the vector comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 122630 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 123668 to 233681 of the nucleotide sequence according to SEQ ID NO: 20 and wherein nucleotide 122630 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 123688 of the nucleotide sequence according to SEQ ID NO: 20. 
     
     
         57 . A vector comprising the nucleic acid according to  claim 55 , wherein the vector comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 122630 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 123668 to 233681 of the nucleotide sequence according to SEQ ID NO: 20 and a third nucleotide sequence comprising a nucleotide sequence according to SEQ ID NO: 34. 
     
     
         58 . The vector according to  claim 57 , wherein nucleotide 122630 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 1 of the nucleotide sequence according to SEQ ID NO: 34 and wherein nucleotide 252 of the nucleotide sequence according to SEQ ID NO: 34 is covalently linked to nucleotide 123668 of the nucleotide sequence according to SEQ ID NO: 20. 
     
     
         59 . A vector comprising the nucleic acid according to  claim 55 , wherein the vector comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 122630 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 123668 to 130670 of the nucleotide sequence according to SEQ ID NO: 20, a third nucleotide sequence represented by nucleotides 131243 to 233681 of the nucleotide sequence according to SEQ ID NO: 20 and wherein nucleotide 122630 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 123668 of the nucleotide sequence according to SEQ ID NO: 20 and wherein the nucleotide 130670 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to the nucleotide 131243 of the nucleotide sequence according to SEQ ID NO: 20. 
     
     
         60 . A vector comprising the nucleic acid according to  claim 55 , wherein the vector comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 122630 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 123668 to 130670 of the nucleotide sequence according to SEQ ID NO: 20, a third nucleotide sequence represented by nucleotides 131243 to 233681 of the nucleotide sequence according to SEQ ID NO: 20, a third nucleotide sequence comprising a nucleotide sequence according to SEQ ID NO: 34 and a fourth nucleotide sequence comprising a nucleotide sequence according to SEQ ID NO: 35. 
     
     
         61 . The vector according to  claim 60 , wherein nucleotide 122630 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 1 of the nucleotide sequence according to SEQ ID NO: 34, wherein nucleotide 252 of the nucleotide sequence according to SEQ ID NO: 34 is covalently linked to nucleotide 123668 of the nucleotide sequence according to SEQ ID NO: 20, wherein nucleotide 130670 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 1 of the nucleotide sequence according to SEQ ID NO: 35 and wherein nucleotide 67 of the nucleotide sequence according to SEQ ID NO: 35 is covalently linked to nucleotide 131243 of the nucleotide sequence according to SEQ ID NO: 20. 
     
     
         62 . A vector comprising the nucleic acid according to  claim 55 , wherein the vector comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 58442 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 59623 to 233681 of the nucleotide sequence according to SEQ ID NO: 20 and wherein nucleotide 58442 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 59623 of the nucleotide sequence according to SEQ ID NO: 20. 
     
     
         63 . A vector comprising the nucleic acid according to  claim 55 , wherein the vector comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 58442 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 59623 to 233681 of the nucleotide sequence according to SEQ ID NO: 20 and a third nucleotide sequence comprising a nucleotide sequence according to SEQ ID NO: 32. 
     
     
         64 . The vector according to  claim 63 , wherein nucleotide 58442 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 1 of the nucleotide sequence according to SEQ ID NO: 32 and wherein nucleotide 179 of the nucleotide sequence according to SEQ ID NO: 32 is covalently linked to nucleotide 59623 of the nucleotide sequence according to SEQ ID NO: 20. 
     
     
         65 . A vector comprising the nucleic acid according to  claim 55 , wherein the vector comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 62129 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 63261 to 233681 of the nucleotide sequence according to SEQ ID NO: 20 and wherein nucleotide 62129 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 63261 of the nucleotide sequence according to SEQ ID NO: 20. 
     
     
         66 . A vector comprising the nucleic acid according to  claim 55 , wherein the vector comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 62129 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 63261 to 233681 of the nucleotide sequence according to SEQ ID NO: 20 and a third nucleotide sequence comprising a nucleotide sequence according to SEQ ID NO: 33. 
     
     
         67 . The vector according to  claim 66 , wherein nucleotide 62129 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 1 of the nucleotide sequence according to SEQ ID NO: 33 and wherein nucleotide 38 of the nucleotide sequence according to SEQ ID NO: 33 is covalently linked to nucleotide 63261 of the nucleotide sequence according to SEQ ID NO: 20. 
     
     
         68 . A vector comprising the nucleic acid according to  claim 55 , wherein the vector comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 58442 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 59623 to 62129 of the nucleotide sequence according to SEQ ID NO: 20, a third nucleotide sequence represented by nucleotides 63261 to 233681 of the nucleotide sequence according to SEQ ID NO: 20 and wherein nucleotide 58442 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 59623 of the nucleotide sequence according to SEQ ID NO: 20 and wherein the nucleotide 62129 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to the nucleotide 63261 of the nucleotide sequence according to SEQ ID NO: 20. 
     
     
         69 . A vector comprising the nucleic acid according to  claim 55 , wherein the vector comprises a nucleotide sequence, wherein the nucleotide sequence comprises a first nucleic acid sequence represented by nucleotides 1 to 58442 of the nucleotide sequence according to SEQ ID NO: 20, a second nucleotide sequence represented by nucleotides 59623 to 62129 of the nucleotide sequence according to SEQ ID NO: 20, a third nucleotide sequence represented by nucleotides 63261 to 233681 of the nucleotide sequence according to SEQ ID NO: 20, a fourth nucleotide sequence comprising a nucleotide sequence according to SEQ ID NO: 32 and a fifth nucleotide sequence comprising a nucleotide sequence according to SEQ ID NO: 33. 
     
     
         70 . The vector according to  claim 69 , wherein nucleotide 58442 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 1 of the nucleotide sequence according to SEQ ID NO: 32, wherein nucleotide 179 of the nucleotide sequence according to SEQ ID NO: 32 is covalently linked to nucleotide 59623 of the nucleotide sequence according to SEQ ID NO: 20, wherein nucleotide 62129 of the nucleotide sequence according to SEQ ID NO: 20 is covalently linked to nucleotide 1 of the nucleotide sequence according to SEQ ID NO: 33 and wherein nucleotide 38 of the nucleotide sequence according to SEQ ID NO: 33 is covalently linked to nucleotide 632161 of the nucleotide sequence according to SEQ ID NO: 20.