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    Polynucleotides encoding recombinant respiratory syncytial viruses expressing immune modulatory molecules
    1.
    发明授权
    Polynucleotides encoding recombinant respiratory syncytial viruses expressing immune modulatory molecules 失效
    编码表达免疫调节分子的重组呼吸道合胞病毒的多核苷酸

    公开(公告)号：US07465794B2

    公开(公告)日：2008-12-16

    申请号：US10754895

    申请日：2004-01-08

    申请人： Peter L. Collins ,  Alexander Bukreyev ,  Brian R. Murphy ,  Stephen S. Whitehead

    发明人： Peter L. Collins ,  Alexander Bukreyev ,  Brian R. Murphy ,  Stephen S. Whitehead

    IPC分类号： C07H21/04 ,  C12P21/00 ,  A61K39/12 ,  A61K39/155

    CPC分类号： C07K14/005 ,  A61K39/00 ,  A61K48/00 ,  A61K2039/5254 ,  C07K14/54 ,  C07K2319/00 ,  C12N7/00 ,  C12N15/86 ,  C12N2760/18522 ,  C12N2760/18543 ,  C12N2760/18561 ,  C12N2840/20

    摘要： Recombinant respiratory syncytial virus (RSV) are provided which express one or more immune modulatory molecules. The recombinant virus is modified by addition or substitution of a polynucleotide sequence encoding the immune modulatory molecule, which is preferably a cytokine. Introduction of the cytokine increase, decrease, or otherwise enhances aspects of viral biology and/or host immune responses to RSV to facilitate vaccine use of the virus. Cytokines for use within the invention include but are not limited to interleukin 2 (IL-2), interleukin 4 (IL-4), interleukin 5 (IL-5), interleukin 6 (IL6), or interleukin 18 (IL-18), tumor necrosis factor (TNF) alpha, interferon gamma (IFN), and granulocyte-macrophage colony stimulating factor (GM-CSF). The polynucleotide or immune modulatory molecule is preferably added or substituted into the recombinant viral genome or antigenome, typically at an intergenic or other non-coding site, as a separate gene but may be otherwise expressed, for example as a fusion protein.

    摘要翻译： 提供重组呼吸道合胞病毒（RSV），其表达一种或多种免疫调节分子。 通过添加或取代编码免疫调节分子的多核苷酸序列来修饰重组病毒，所述多核苷酸序列优选是细胞因子。 引入细胞因子增加，减少或以其他方式增强病毒生物学和/或宿主对RSV的免疫应答的方面以促进病毒的疫苗使用。 本发明中使用的细胞因子包括但不限于白介素2（IL-2），白细胞介素4（IL-4），白介素5（IL-5），白介素6（IL6）或白细胞介素18（IL-18） ，肿瘤坏死因子（TNF）α，干扰素γ（IFN）和粒细胞巨噬细胞集落刺激因子（GM-CSF）。 多核苷酸或免疫调节分子优选地作为单独的基因加入或取代到重组病毒基因组或反向原核基因组中，通常在基因间或其他非编码位点，但可另外表达为例如融合蛋白。

    Attenuated chimeric respiratory syncytial virus
    2.
    发明授权
    Attenuated chimeric respiratory syncytial virus 有权
    减毒嵌合呼吸道合胞病毒

    公开(公告)号：US07846455B2

    公开(公告)日：2010-12-07

    申请号：US10722000

    申请日：2003-11-25

    申请人： Peter L. Collins ,  Brian R. Murphy ,  Stephen S. Whitehead

    发明人： Peter L. Collins ,  Brian R. Murphy ,  Stephen S. Whitehead

    IPC分类号： A61K39/155 ,  A61K39/12 ,  C12N7/00 ,  C12N7/01 ,  C12N7/04

    CPC分类号： C07K14/005 ,  A61K39/00 ,  A61K2039/5254 ,  C12N7/00 ,  C12N2760/18522 ,  C12N2760/18543 ,  C12N2760/18561

    摘要： Chimeric respiratory syncytial virus (RSV) and vaccine compositions thereof are produced by introducing one or more heterologous gene(s) or gene segment(s) from one RSV subgroup or strain into a recipient RSV backround of a different subgroup or strain. The resulting chimeric RSV virus or subviral particle is infectious and attenuated, preferably by introduction of selected mutations specifying attenuated phenotypes into a chimeric genome or antigenome to yield, for example, temperature sensitive (ts) and/or cold adapted (ca) vaccine strains. Alternatively, chimeric RSV and vaccine compositions thereof incorporate other mutations specifying desired structural and/or phenotypic characteristics in an infectious chimeric RSV. Such chimeric RSV incorporate desired mutations specified by insertion, deletion, substitution or rearrangement of one or more selected nucleotide sequence(s), gene(s), or gene segment(s) in a chimeric RSV clone. This provides a method for development of novel vaccines against diverse RSV strains by using a common attenuated backbone as a vector to express protective antigens of heterologous strains. The immune system of an individual is stimulated to induce protection against natural RSV infection, preferably in a multivalent manner to achieve protection against multiple RSV strains and/or subgroups.

    摘要翻译： 嵌合呼吸道合胞病毒（RSV）及其疫苗组合物通过将一个或多个异源基因或基因区段从一个RSV亚组或菌株引入不同亚组或菌株的受体RSV背景中而产生。 所得到的嵌合RSV病毒或亚病毒颗粒是感染性和减毒性的，优选通过将指定减毒表型的选定突变引入到嵌合基因组或反基因组中以产生例如温度敏感（ts）和/或冷适应（ca）疫苗株。 或者，嵌合RSV及其疫苗组合物掺入在感染性嵌合RSV中指定所需结构和/或表型特征的其它突变。 这种嵌合RSV包含通过嵌合RSV克隆中的一个或多个选定的核苷酸序列，基因或基因片段的插入，缺失，取代或重排而指定的所需突变。 这提供了通过使用共同的减毒骨架作为表达异源株的保护性抗原的载体来开发针对不同RSV菌株的新型疫苗的方法。 刺激个体的免疫系统以诱导针对天然RSV感染的保护，优选以多价方式实现针对多个RSV菌株和/或亚组的保护。

    Respiratory syncytial virus vaccines expressing protective antigens from promoter-proximal genes
    4.
    发明授权
    Respiratory syncytial virus vaccines expressing protective antigens from promoter-proximal genes 有权
    呼吸道合胞病毒疫苗从启动子近端基因表达保护性抗原

    公开(公告)号：US07662397B2

    公开(公告)日：2010-02-16

    申请号：US11054343

    申请日：2005-02-08

    申请人： Christine D. Krempl ,  Peter L. Collins ,  Brian R. Murphy ,  Ursula Buchholz ,  Stephen S. Whitehead

    发明人： Christine D. Krempl ,  Peter L. Collins ,  Brian R. Murphy ,  Ursula Buchholz ,  Stephen S. Whitehead

    IPC分类号： A61K39/155 ,  A61K39/12

    CPC分类号： C07K14/005 ,  A61K39/12 ,  A61K39/155 ,  A61K2039/5254 ,  A61K2039/5256 ,  A61K2039/543 ,  C12N7/00 ,  C12N15/86 ,  C12N2760/18522 ,  C12N2760/18534 ,  C12N2760/18543 ,  C12N2760/18561 ,  C12N2760/18622

    摘要： Recombinant respiratory syncytial virus (RSV) having the position of genes shifted within the genome or antigenome of the recombinant virus are infectious and attenuated in humans and other mammals. Gene shifted RSV are constructed by insertion, deletion or rearrangement of genes or genome segments within the recombinant genome or antigenome and are useful in vaccine formulations for eliciting an anti-RSV immune response. Also provided are isolated polynucleotide molecules and vectors incorporating a recombinant RSV genome or antigenome wherein a gene or gene segment is shifted to a more promoter-proximal or promoter-distal position within the genome or antigenome compared to a wild type position of the gene in the RSV gene map. Shifting the position of genes in this manner provides for a selected increase or decrease in expression of the gene, depending on the nature and degree of the positional shift.

    摘要翻译： 重组呼吸道合胞病毒（RSV）具有在重组病毒的基因组或反向基因组内移位的基因位置，在人和其他哺乳动物中具有传染性和减毒性。 通过在重组基因组或反向原核基因组内的基因或基因组片段的插入，缺失或重排构建基因转移的RSV，并且可用于引发抗RSV免疫应答的疫苗制剂中。 还提供了分离的多核苷酸分子和掺入重组RSV基因组或反基因组的载体，其中与基因组或基因片段中的基因的野生型位置相比，基因或基因片段转移到基因组或反基因组内的更多启动子近端或启动子远端位置 RSV基因图。 以这种方式移动基因的位置提供基因的选择性增加或降低，这取决于位置偏移的性质和程度。

    Production of attenuated respiratory syncytial virus vaccines from cloned nucleotide sequences
    6.
    发明授权
    Production of attenuated respiratory syncytial virus vaccines from cloned nucleotide sequences 有权
    从克隆的核苷酸序列产生减毒呼吸道合胞病毒疫苗

    公开(公告)号：US07709007B2

    公开(公告)日：2010-05-04

    申请号：US10934003

    申请日：2004-09-02

    申请人： Brian R. Murphy ,  Peter L. Collins ,  Stephen S. Whitehead ,  Alexander A. Bukreyev ,  Katalin Juhasz ,  Michael N. Teng

    发明人： Brian R. Murphy ,  Peter L. Collins ,  Stephen S. Whitehead ,  Alexander A. Bukreyev ,  Katalin Juhasz ,  Michael N. Teng

    IPC分类号： A61K39/155

    CPC分类号： C07K14/005 ,  A61K39/00 ,  C12N7/00 ,  C12N2760/18522 ,  C12N2760/18561

    摘要： Attenuated respiratory syncytial virus (RSV) and vaccine compositions thereof are produced by introducing specific mutations associated with attenuating phenotypes into wild-type or RSV which is incompletely attenuated by cold-passage or introduction of mutations which produce virus having a temperature sensitive (ts) or cold adapted (ca) phenotype. Alternatively, recombinant RSV and vaccine compositions thereof incorporate attenuating and other mutations specifying desired structural and or phenotypic characteristics in an infectious RSV. Recombinant RSV incorporate desired mutations specified by insertion, deletion, substitution or rearrangement of a selected nucleotide sequence, gene, or gene segment in an infectious RSV clone. The immune system of an individual is stimulated to induce protection against natural RSV infection, or multivalently against infection by RSV and another pathogen, such as PIV, by administration of attenuated, biologically derived or recombinant RSV.

    摘要翻译： 减毒的呼吸道合胞病毒（RSV）及其疫苗组合物通过将与将减毒表型相关的特异性突变引入野生型或RSV，通过冷通道或引入产生具有温度敏感性（ts）或 冷适应（ca）表型。 或者，重组RSV及其疫苗组合物结合了在感染性RSV中指定所需结构和/或表型特征的减毒和其它突变。 重组RSV包含通过在感染性RSV克隆中选择的核苷酸序列，基因或基因片段的插入，缺失，取代或重排而指定的所需突变。 通过施用减毒的，生物衍生的或重组的RSV，刺激个体的免疫系统以诱导针对天然RSV感染的保护，或多重抗RSV和另一种病原体如PIV的感染。

    Production of attenuated chimeric respiratory syncytial virus vaccines from cloned nucleotide sequences
    7.
    发明授权
    Production of attenuated chimeric respiratory syncytial virus vaccines from cloned nucleotide sequences 有权
    从克隆的核苷酸序列产生减毒的嵌合呼吸道合胞病毒疫苗

    公开(公告)号：US06689367B1

    公开(公告)日：2004-02-10

    申请号：US09291894

    申请日：1999-04-13

    申请人： Peter L. Collins ,  Brian R. Murphy ,  Stephen S. Whitehead

    发明人： Peter L. Collins ,  Brian R. Murphy ,  Stephen S. Whitehead

    IPC分类号： A61K39155

    CPC分类号： C07K14/005 ,  A61K39/00 ,  A61K2039/525 ,  C12N7/00 ,  C12N15/86 ,  C12N2760/18521 ,  C12N2760/18522 ,  C12N2760/18543 ,  C12N2760/18561

    摘要： Chimeric respiratory syncytial virus (RSV) and vaccine compositions thereof are produced by introducing one or more heterologous gene(s) or gene segment(s) from one RSV subgroup or strain into a recipient RSV backround of a different subgroup or strain. The resulting chimeric RSV virus or subviral particle is infectious and attenuated, preferably by introduction of selected mutations specifying attenuated phenotypes into a chimeric genome or antigenome to yield, for example, temperature sensitive (ts) and/or cold adapted (ca) vaccine strains. Alternatively, chimeric RSV and vaccine compositions thereof incorporate other mutations specifying desired structural and/or phenotypic characteristics in an infectious chimeric RSV. Such chimeric RSV incorporate desired mutations specified by insertion, deletion, substitution or rearrangement of one or more selected nucleotide sequence(s), gene(s), or gene segment(s) in a chimeric RSV clone. This provides a method for development of novel vaccines against diverse RSV strains by using a common attenuated backbone as a vector to express protective antigens of heterologous strains. The immune system of an individual is stimulated to induce protection against natural RSV infection, preferably in a multivalent manner to achieve protection against multiple RSV strains and/or subgroups.

    摘要翻译： 嵌合呼吸道合胞病毒（RSV）及其疫苗组合物通过将一个或多个异源基因或基因区段从一个RSV亚组或菌株引入不同亚组或菌株的受体RSV背景中而产生。 所得到的嵌合RSV病毒或亚病毒颗粒是感染性和减毒性的，优选通过将指定减毒表型的选定突变引入到嵌合基因组或反基因组中以产生例如温度敏感（ts）和/或冷适应（ca）疫苗株。 或者，嵌合RSV及其疫苗组合物掺入在感染性嵌合RSV中指定所需结构和/或表型特征的其它突变。 这种嵌合RSV包含通过嵌合RSV克隆中的一个或多个选定的核苷酸序列，基因或基因片段的插入，缺失，取代或重排而指定的所需突变。 这提供了通过使用共同的减毒骨架作为表达异源株的保护性抗原的载体来开发针对不同RSV菌株的新型疫苗的方法。 刺激个体的免疫系统以诱导针对天然RSV感染的保护，优选以多价方式实现针对多个RSV菌株和/或亚组的保护。

    Production of attenuated, human-bovine chimeric respiratory syncytial viruses for use in immunogenic compositions
    9.
    发明授权
    Production of attenuated, human-bovine chimeric respiratory syncytial viruses for use in immunogenic compositions 失效
    用于免疫原性组合物的减毒的人 - 牛嵌合呼吸道合胞病毒的生产

    公开(公告)号：US07820182B2

    公开(公告)日：2010-10-26

    申请号：US10704116

    申请日：2003-11-07

    申请人： Ursula Buchholz ,  Peter L. Collins ,  Brian R. Murphy ,  Stephen S. Whitehead ,  Christine D. Krempl

    发明人： Ursula Buchholz ,  Peter L. Collins ,  Brian R. Murphy ,  Stephen S. Whitehead ,  Christine D. Krempl

    IPC分类号： A61K39/155 ,  A61K39/12

    CPC分类号： C12N15/86 ,  A61K39/00 ,  A61K39/12 ,  A61K39/155 ,  A61K2039/5254 ,  A61K2039/5256 ,  A61K2039/543 ,  A61K2039/544 ,  C07K14/005 ,  C07K2319/00 ,  C12N7/00 ,  C12N2760/18521 ,  C12N2760/18522 ,  C12N2760/18534 ,  C12N2760/18543 ,  C12N2760/18561 ,  C12N2840/203

    摘要： Chimeric human-bovine respiratory syncytial virus (RSV) are infectious and attenuated in humans and other mammals and useful in immunogenic compositions for eliciting an anti-RSV immune response. Also provided are isolated polynucleotide molecules and vectors incorporating a chimeric RSV genome or antigenome which includes a partial or complete human or bovine RSV “background” genome or antigenome combined or integrated with one or more heterologous gene(s) or genome segment(s) of a different RSV strain. Chimeric human-bovine RSV of the invention include a partial or complete “background” RSV genome or antigenome derived from or patterned after a human or bovine RSV strain or subgroup virus combined with one or more heterologous gene(s) or genome segment(s) of a different RSV strain or subgroup virus to form the human-bovine chimeric RSV genome or antigenome. In preferred aspects of the invention, chimeric RSV incorporate a partial or complete bovine RSV background genome or antigenome combined with one or more heterologous gene(s) or genome segment(s) from a human RSV. Genes of interest include any of the NS1, NS2, N, P, M, SH, M2(ORF1), M2(ORF2), L, F or G genes or a genome segment including a protein or portion thereof. A variety of additional mutations and nucleotide modifications are provided within the human-bovine chimeric RSV of the invention to yield desired phenotypic and structural effects.

    摘要翻译： 嵌合人 - 牛呼吸道合胞病毒（RSV）在人和其他哺乳动物中具有感染性和减毒性，并且可用于引发抗RSV免疫应答的免疫原性组合物。 还提供了分离的多核苷酸分子和掺入嵌合RSV基因组或抗原组的载体，其包括部分或完整的人或牛RSV“背景”基因组或与一个或多个异源基因或基因组片段 不同的RSV菌株。 本发明的嵌合人类牛RSV包括部分或完整的“背景”RSV基因组或在与一个或多个异源基因或基因组片段组合的人或牛RSV病毒株或亚组病毒之后衍生或构图的部分或完整的“背景” 的不同RSV株或亚组病毒形成人 - 牛嵌合RSV基因组或抗原组。 在本发明的优选方面，嵌合RSV包含与来自人RSV的一个或多个异源基因或基因组片段组合的部分或完整的牛RSV背景基因组或反义基因组。 感兴趣的基因包括任何NS1，NS2，N，P，M，SH，M2（ORF1），M2（ORF2），L，F或G基因或包含蛋白质或其部分的基因组片段。 在本发明的人 - 牛嵌合RSV内提供了多种额外的突变和核苷酸修饰，以产生所需的表型和结构效果。

    Respiratory syncytial virus vaccines expressing protective antigens from promotor-proximal genes
    10.
    发明授权
    Respiratory syncytial virus vaccines expressing protective antigens from promotor-proximal genes 有权
    呼吸道合胞病毒疫苗从启动子近端基因表达保护性抗原

    公开(公告)号：US07744902B2

    公开(公告)日：2010-06-29

    申请号：US11033055

    申请日：2005-01-10

    申请人： Christine D. Krempl ,  Peter L. Collins ,  Brian R. Murphy ,  Ursula Buchholz ,  Stephen S. Whitehead

    发明人： Christine D. Krempl ,  Peter L. Collins ,  Brian R. Murphy ,  Ursula Buchholz ,  Stephen S. Whitehead

    IPC分类号： A61K39/155

    CPC分类号： C07K14/005 ,  A61K39/00 ,  A61K2039/5254 ,  A61K2039/5256 ,  A61K2039/543 ,  A61K2039/545 ,  C07H21/02 ,  C07K2319/00 ,  C12N7/00 ,  C12N15/86 ,  C12N2760/18522 ,  C12N2760/18543 ,  C12N2760/18561 ,  C12N2760/18562

    摘要： Recombinant respiratory syncytial virus (RSV) having the position of genes shifted within the genome or antigenome of the recombinant virus are infectious and attenuated in humans and other mammals. Gene shifted RSV are constructed by insertion, deletion or rearrangement of genes or genome segments within the recombinant genome or antigenome and are useful in vaccine formulations for eliciting an anti-RSV immune response. Also provided are isolated polynucleotide molecules and vectors incorporating a recombinant RSV genome or antigenome wherein a gene or gene segment is shifted to a more promoter-proximal or promoter-distal position within the genome or antigenome compared to a wild type position of the gene in the RSV gene map. Shifting the position of genes in this manner provides for a selected increase or decrease in expression of the gene, depending on the nature and degree of the positional shift. In one embodiment, RSV glycoproteins are upregulated by shifting one or more glycoprotein-encoding genes to a more promoter-proximal position. Genes of interest for manipulation to create gene position-shifted RSV include any of the NS1, NS2, N, P, M, SH, M2(ORF1), M2(ORF2), L, F or G genes or a genome segment that may be part of a gene or extragenic. A variety of additional mutations and nucleotide modifications are provided within the gene position-shifted RSV of the invention to yield desired phenotypic and structural effects.

    摘要翻译： 重组呼吸道合胞病毒（RSV）具有在重组病毒的基因组或反向基因组内移动的基因位置，在人和其他哺乳动物中具有传染性和减毒性。 通过在重组基因组或反向原核基因组内的基因或基因组片段的插入，缺失或重排构建基因转移的RSV，并且可用于引发抗RSV免疫应答的疫苗制剂中。 还提供了分离的多核苷酸分子和掺入重组RSV基因组或反基因组的载体，其中与基因组或基因片段中的基因的野生型位置相比，基因或基因片段转移到基因组或反基因组内的更多启动子近端或启动子远端位置 RSV基因图。 以这种方式移动基因的位置提供基因的选择性增加或降低，这取决于位置偏移的性质和程度。 在一个实施方案中，通过将一个或多个编码糖蛋白的基因移位到更多的启动子近端位置来上调RSV糖蛋白。 用于产生基因位置偏移RSV的操作感兴趣的基因包括NS1，NS2，N，P，M，SH，M2（ORF1），M2（ORF2），L，F或G基因中的任何一个或可能 成为基因的一部分或非原生质体。 在本发明的基因位置偏移的RSV中提供了多种另外的突变和核苷酸修饰，以产生所需的表型和结构效应。