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    Attenuated Mycobacterium tuberculosis vaccines
    2.
    发明授权
    Attenuated Mycobacterium tuberculosis vaccines 有权
    减毒结核分枝杆菌疫苗

    公开(公告)号：US07758874B2

    公开(公告)日：2010-07-20

    申请号：US11109056

    申请日：2005-04-19

    申请人： William R. Jacobs, Jr. ,  Barry Bloom ,  Mary K. Hondalus ,  Samantha Sampson ,  Vasan Sambandamurthy

    发明人： William R. Jacobs, Jr. ,  Barry Bloom ,  Mary K. Hondalus ,  Samantha Sampson ,  Vasan Sambandamurthy

    IPC分类号： A61K39/04 ,  A61K49/00 ,  A61K39/00

    CPC分类号： C07K14/35 ,  A61K2039/51

    摘要： Non-naturally occurring mycobacteria in the Mycobacterium tuberculosis complex are provided. These mycobacteria have a deletion of an RD1 region or a region controlling production of a vitamin, and exhibit attenuated virulence in a mammal when compared to the mycobacteria without the deletion. Also provided are non-naturally occurring mycobacteria that have a deletion of a region controlling production of lysine, and mycobacteria comprising two attenuating deletions. Vaccines comprising these mycobacteria are also provided, as are methods of protecting mammals from virulent mycobacteria using the vaccines. Also provided are methods of preparing these vaccines which include the step of deleting an RD1 region or a region controlling production of a vitamin or the amino acids leucine and lysine from a mycobacterium in the M. tuberculosis complex. Embodiments of these mycobacteria, vaccines and methods, encompassing mycobacteria comprising a leucine auxotrophy and a pantothenate auxotrophy, are also provided.

    摘要翻译： 提供了结核分枝杆菌复合物中非天然存在的分枝杆菌。 与没有缺失的分枝杆菌相比，这些分枝杆菌具有RD1区域或控制维生素产生的区域的缺失，并且在哺乳动物中表现出减毒的毒力。 还提供了具有控制赖氨酸生产的区域缺失的非天然存在的分枝杆菌，以及包含两个减毒缺失的分枝杆菌。 还提供了包含这些分枝杆菌的疫苗，以及使用疫苗来保护哺乳动物免受有毒分枝杆菌的方法。 还提供了制备这些疫苗的方法，其包括在结核分枝杆菌复合物中从分枝杆菌中删除RD1区域或控制维生素或氨基酸亮氨酸和赖氨酸生产的区域的步骤。 还提供了包括亮氨酸营养缺陷型和泛酸营养缺陷型的分枝杆菌的这些分枝杆菌，疫苗和方法的实施方案。

    TM4 conditional shuttle phasmids and uses thereof
    3.
    发明授权
    TM4 conditional shuttle phasmids and uses thereof 失效
    TM4条件穿梭质粒及其用途

    公开(公告)号：US5972700A

    公开(公告)日：1999-10-26

    申请号：US938059

    申请日：1997-09-26

    申请人： William R. Jacobs, Jr. ,  Stoyan Bardarov ,  Graham F. Hatfull

    发明人： William R. Jacobs, Jr. ,  Stoyan Bardarov ,  Graham F. Hatfull

    IPC分类号： C12N15/74 ,  C12N15/63

    CPC分类号： C12N15/74

    摘要： The present invention provides a conditional shuttle phasmid constructed by inserting a cosmid into a non-essential region of the TM4 mycobacteriophage that introduces DNA of interest into mycobacteria, especially M. tuberculosis complex organisms and other slow growing mycobacteria. The present invention provides a recombinant mycobacterium which expresses a DNA of interest incorporated into its chromosome by a TM4 conditional shuttle phasmid containing the DNA of interest. The present invention further provides a mycobacterial auxotrophic mutant and a method of generating auxotrophic mutants.

    摘要翻译： 本发明提供了一种通过将粘粒插入到TM4分枝杆菌噬菌体的非必需区域中构建的条件穿梭质粒，其将感兴趣的DNA引入分枝杆菌，特别是结核分枝杆菌复合生物体和其他缓慢生长的分枝杆菌。 本发明提供了一种重组分枝杆菌，其通过含有感兴趣的DNA的TM4条件穿梭载体表达感兴趣的DNA并入其染色体中。 本发明还提供了分枝杆菌营养缺陷突变体和产生营养缺陷突变体的方法。

    Mycobacterial mutants inducing IL-12
    4.
    发明授权
    Mycobacterial mutants inducing IL-12 有权
    分枝杆菌突变体诱导IL-12

    公开(公告)号：US08591918B2

    公开(公告)日：2013-11-26

    申请号：US12450193

    申请日：2008-03-10

    申请人： William R. Jacobs, Jr. ,  Kari Sweeney ,  Dee Dao ,  Steven A. Porcelli ,  John Chan ,  Tsungda Hsu

    发明人： William R. Jacobs, Jr. ,  Kari Sweeney ,  Dee Dao ,  Steven A. Porcelli ,  John Chan ,  Tsungda Hsu

    IPC分类号： A61K39/04 ,  A61K49/00 ,  A01N63/00

    CPC分类号： C07K14/35

    摘要： Provided are mycobacteria deleted in at least a portion of a region 3 ESAT-6-like gene cluster. Also provided are mycobacteria comprising a mutation in an roc-1 gene. Additionally, vaccines comprising these mycobacteria are provided. Further provided are methods of making a recombinant mycobacterium, methods of inducing an immune response in a mammal, methods of inhibiting IL-12 production in a mammal, and methods of stimulating IL-12 production in a mammal. Vaccine adjuvants are also provided, as are methods of inducing immunity to a target antigen in a mammal.

    摘要翻译： 提供在区域3 ESAT-6样基因簇的至少一部分中缺失分枝杆菌。 还提供了包含roc-1基因突变的分枝杆菌。 另外，提供了包含这些分枝杆菌的疫苗。 进一步提供了制备重组分枝杆菌的方法，在哺乳动物中诱导免疫应答的方法，抑制哺乳动物中IL-12产生的抑制方法，以及刺激哺乳动物中IL-12产生的方法。 还提供疫苗佐剂，以及在哺乳动物中诱导免疫目标抗原的方法。

    Mycobacterial isocitrate lyase gene and uses thereof
    5.
    发明授权
    Mycobacterial isocitrate lyase gene and uses thereof 失效
    分枝杆菌异柠檬酸裂解酶基因及其用途

    公开(公告)号：US06733761B2

    公开(公告)日：2004-05-11

    申请号：US10029715

    申请日：2001-12-20

    申请人： John D. McKinney ,  William R. Jacobs, Jr.

    发明人： John D. McKinney ,  William R. Jacobs, Jr.

    IPC分类号： A61K3904

    CPC分类号： C12N9/88

    摘要： The present invention provides a purified and isolated nucleic acid encoding mycobacterial isocitrate lyase, as well as mutated forms of the nucleic acid. Further provided are purified and isolated isocitrate lyase proteins and mutated isocitrate lyase proteins. Additionally, the present invention provides vectors which comprises nucleic acid sequences encoding mycobacterial isocitrate lyase and mutated forms of this nucleic acid, as well as host cells containing these vectors. Also provided is a mycobacterium containing one or more mutations in its isocitrate lyase gene. Further provided by the present invention are agents that inhibit the activity or expression of a mycobacterial lyase protein, a method of identifying these, and a method of producing them. Finally, the present invention also provides a method of identifying genes required for persistence of mycobacteria.

    摘要翻译： 本发明提供了编码分枝杆菌异柠檬酸裂解酶的纯化和分离的核酸，以及核酸的突变形式。 还提供纯化和分离的异柠檬酸裂合酶蛋白和突变的异柠檬酸裂合酶蛋白。 另外，本发明提供了包含编码分枝杆菌异柠檬酸裂合酶和突变形式的核酸的核酸序列以及含有这些载体的宿主细胞的载体。 还提供了在其异柠檬酸裂合酶基因中含有一个或多个突变的分枝杆菌。 本发明进一步提供的是抑制分枝杆菌裂解酶蛋白的活性或表达的试剂，鉴定这些的方法及其制备方法。 最后，本发明还提供了鉴定分枝杆菌持久性所需的基因的方法。

    Recombinant mycobacteria
    6.
    发明授权
    Recombinant mycobacteria 失效
    重组分枝杆菌

    公开(公告)号：US06372478B1

    公开(公告)日：2002-04-16

    申请号：US09314207

    申请日：1999-05-19

    申请人： Barry R. Bloom ,  Ronald W. Davis ,  William R. Jacobs, Jr. ,  Richard A. Young ,  Robert N. Husson

    发明人： Barry R. Bloom ,  Ronald W. Davis ,  William R. Jacobs, Jr. ,  Richard A. Young ,  Robert N. Husson

    IPC分类号： C12N120

    CPC分类号： A61K39/04 ,  A61K39/00 ,  C07K14/005 ,  C07K14/35 ,  C12N15/74 ,  C12N15/87 ,  C12N2795/10022 ,  C12R1/32 ,  Y02A50/412 ,  Y02A50/476

    摘要： Recombinant mycobacterial vaccine vehicles capable of expressing DNA of interest which encodes at least one protein antigen for at least one pathogen against which an immune response is desired and which can be incorporated into the mycobacteria or stably integrated into the mycobacterial genome. The vaccine vehicles are useful for administration to mammalian hosts for purposes of immunization. A recombinant vector which replicates in E. coli but not in mycobacteria is also disclosed. The recombinant vector includes 1) a mycobacterial gene or portions thereof, necessary for recombination with homologous sequences in the genome of mycobacteria transformed with the recombinant plasmid; 2) all or a portion of a gene which encodes a polypeptide or protein whose expression is desired in mycobacteria transformed with the recombinant plasmid; 3) DNA sequences necessary for replication and selection in E coli; and 4) DNA sequences necessary for selection in mycobacteria (e.g., drug resistance). The present invention also relates to two types of recombinant vectors useful in introducing DNA of interest into mycobacteria, where it is expressed. One type of vector is a recombinant phasmid capable of replicating as a plasmid in E. coli and of lysogenizing a mycobacterial host. The other type of vector is a recombinant plasmid which can be introduced into mycobacteria, where it is stably maintained extrachromosomally.

    摘要翻译： 能够表达目的的DNA的重组分枝杆菌疫苗载体，其编码针对至少一种需要免疫应答的至少一种病原体的至少一种蛋白质抗原并且可以并入分枝杆菌中或稳定整合到分枝杆菌基因组中。 疫苗载体用于哺乳动物宿主用于免疫的目的。 还公开了在大肠杆菌中但不在分枝杆菌中复制的重组载体。 重组载体包括1）与用重组质粒转化的分枝杆菌基因组中与同源序列重组所必需的分枝杆菌基因或其部分; 2）编码在用重组质粒转化的分枝杆菌中表达所需的多肽或蛋白质的基因的全部或部分; 3）在大肠杆菌中复制和选择所需的DNA序列; 和4）在分枝杆菌中选择所需的DNA序列（例如耐药性）。 本发明还涉及可用于将感兴趣的DNA引入分枝杆菌的两种类型的重组载体，其中它被表达。 一种载体是能够在大肠杆菌中作为质粒复制并使分枝杆菌宿主溶解的重组噬菌粒。 另一种载体是可以引入分枝杆菌的重组质粒，其在染色体外稳定地保持。

    Mycobacteriophages and uses thereof
    7.
    发明授权
    Mycobacteriophages and uses thereof 失效
    分枝杆菌噬菌体及其用途

    公开(公告)号：US5968733A

    公开(公告)日：1999-10-19

    申请号：US14560

    申请日：1998-01-28

    申请人： Barry R. Bloom ,  Ronald W. Davis ,  William R. Jacobs, Jr. ,  Richard A. Young ,  Robert N. Husson

    发明人： Barry R. Bloom ,  Ronald W. Davis ,  William R. Jacobs, Jr. ,  Richard A. Young ,  Robert N. Husson

    IPC分类号： G01N33/53 ,  A61K39/00 ,  A61K39/04 ,  A61K39/39 ,  A61P31/04 ,  A61P31/06 ,  A61P31/08 ,  A61P31/12 ,  A61P31/16 ,  A61P31/18 ,  A61P31/22 ,  A61P37/04 ,  A61P39/02 ,  C07K14/01 ,  C07K14/35 ,  C12N1/21 ,  C12N15/09 ,  C12N15/74 ,  C12N15/87 ,  C12P21/02 ,  C12R1/19 ,  C12R1/32 ,  C12R1/325 ,  C12R1/33 ,  C12R1/34 ,  G01N33/50 ,  C12Q1/70 ,  C07H21/04

    CPC分类号： A61K39/04 ,  C07K14/005 ,  C07K14/35 ,  C12N15/74 ,  C12N15/87 ,  C12R1/32 ,  A61K39/00 ,  C12N2795/10022

    摘要： Recombinant mycobacterial vaccine vehicles capable of expressing DNA of interest which encodes at least one protein antigen for at least one pathogen against which an immune response is desired and which can be incorporated into the mycobacteria or stably integrated into the mycobacterial genome. The vaccine vehicles are useful for administration to mammalian hosts for purposes of immunization. A recombinant vector which replicates in E. coli but not in mycobacteria is also disclosed. The recombinant vector includes 1) a mycobacterial gene or portions thereof, necessary for recombination with homologous sequences in the genome of mycobacteria transformed with the recombinant plasmid; 2) all or a portion of a gene which encodes a polypeptide or protein whose expression is desired in mycobacteria transformed with the recombinant plasmid; 3) DNA sequences necessary for replication and selection in E. coli; and 4) DNA sequences necessary for selection in mycobacteria (e.g., drug resistance). The present invention also relates to two types of recombinant vectors useful in introducing DNA of interest into mycobacteria, where it is expressed. One type of vector is a recombinant phasmid capable of replicating as a plasmid in E. coli and of lysogenizing a mycobacterial host. The other type of vector is a recombinant plasmid which can be introduced into mycobacteria, where it is stably maintained extrachromosomally.

    摘要翻译： 能够表达目的的DNA的重组分枝杆菌疫苗载体，其编码针对至少一种需要免疫应答的至少一种病原体的至少一种蛋白质抗原并且可以并入分枝杆菌中或稳定整合到分枝杆菌基因组中。 疫苗载体用于哺乳动物宿主用于免疫的目的。 还公开了在大肠杆菌中但不在分枝杆菌中复制的重组载体。 重组载体包括1）与用重组质粒转化的分枝杆菌基因组中与同源序列重组所必需的分枝杆菌基因或其部分; 2）编码在用重组质粒转化的分枝杆菌中表达所需的多肽或蛋白质的基因的全部或部分; 3）在大肠杆菌中复制和选择所需的DNA序列; 和4）在分枝杆菌中选择所需的DNA序列（例如耐药性）。 本发明还涉及可用于将感兴趣的DNA引入分枝杆菌的两种类型的重组载体，其中它被表达。 一种载体是能够在大肠杆菌中作为质粒复制并使分枝杆菌宿主溶解的重组噬菌粒。 另一种载体是可以引入分枝杆菌的重组质粒，其在染色体外稳定地保持。

    Dim mutants of mycobacteria and use thereof
    9.
    发明授权
    Dim mutants of mycobacteria and use thereof 有权
    分枝杆菌的突变体及其用途

    公开(公告)号：US06290966B1

    公开(公告)日：2001-09-18

    申请号：US09350326

    申请日：1999-07-09

    申请人： Jeffery S. Cox ,  William R. Jacobs, Jr.

    发明人： Jeffery S. Cox ,  William R. Jacobs, Jr.

    IPC分类号： A61K3902

    CPC分类号： C12R1/32 ,  A61K2039/52 ,  C07K14/35

    摘要： Disclosed are novel recombinant mutant strains of mycobacteria that are deficient for the synthesis or transport of dimycoserosalphthiocerol (“DIM”). The present invention also provides a method of producing a recombinant mutant mycobacterium that is deficient for the synthesis or transport of DIM, comprising mutating a nucleic acid responsible for the synthesis or transport of dimycoserosalphthiocerol, including a nucleic acid comprising the promoter for the pps operon, fadD28 or mmpL7. The present invention also provides a vaccine comprising a DIM mutant mycobacterium of the present invention, as well as a method for the treatment or prevention of tuberculosis in a subject using the vaccine.

    摘要翻译： 公开了分子细菌的新型重组突变菌株，其用于合成或转运二环神经节硫辛（“DIM”）。 本发明还提供了一种制备DIM的合成或转运缺陷的重组突变型分枝杆菌的方法，包括突变负责合成或转运二环神经节硫蛋白的核酸，包括包含用于pps操纵子的启动子的核酸， fadD28或mmpL7。 本发明还提供了包含本发明的DIM突变型分枝杆菌的疫苗，以及使用疫苗治疗或预防受试者的结核病的方法。