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31.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。
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32.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
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。
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33.发明授权Construction and use of recombinant parainfluenza viruses expressing a chimeric glycoprotein 有权构建和使用表达嵌合糖蛋白的重组副流感病毒公开(公告)号：US07250171B1
公开(公告)日：2007-07-31
申请号：US09459062
申请日：1999-12-10
IPC分类号： A61K31/155 , C12N15/00
CPC分类号： C12N15/86 , A61K2039/5256 , C07K2319/00 , C12N2760/18643
摘要： Chimeric parainfluenza viruses (PIVs) are provided that incorporate a PIV vector genome or antigenome modified to encode a chimeric glycoprotein incorporating one or more heterologous antigenic domains, fragments, or epitopes of a second, antigenically distinct HPIV. These chimeric viruses are infectious and attenuated in humans and other mammals and are useful in vaccine formulations for eliciting an immune responses against one or more PIVs, and, optionally against respiratory syncytial virus (RSV). Also provided are isolated polynucleotide molecules and vectors incorporating a chimeric PIV genome or antigenome which includes a HPIV vector genome or antigenome combined or integrated with one or more heterologous genome segment(s) encoding one or more antigenic determinant(s) of a heterologous PIV to encode a chimeric glycoprotein. In preferred aspects of the invention, the chimeric virus is attenuated for use as a vaccine agent by additional mutations or nucleotide modifications introduced into the chimeric genome or antigenome.
摘要翻译： 提供了嵌合副流感病毒（PIV），其包含PIV载体基因组或经修饰的反义基因组，以编码掺入一个或多个异源抗原结构域，片段或第二抗原性不同HPIV表位的嵌合糖蛋白。 这些嵌合病毒在人和其他哺乳动物中是感染性和减毒性的，并且可用于引发针对一种或多种PIV的免疫应答的疫苗制剂，以及任选地抗呼吸道合胞病毒（RSV）。 还提供了分离的多核苷酸分子和掺入嵌合PIV基因组或反基因组的载体，其包括与编码异源PIV的一个或多个抗原决定簇的一个或多个异源基因组片段组合或整合的HPIV载体基因组或抗原子集， 编码嵌合糖蛋白。 在本发明的优选方面，嵌合病毒通过引入到嵌合基因组或反基因组中的附加突变或核苷酸修饰来减毒用作疫苗剂。
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34.发明授权Production of novel Newcastle disease virus strains from cDNAs and improved live attenuated Newcastle disease vaccines 有权从cDNAs生产新型新城疫病毒株，改良减毒新城疫疫苗公开(公告)号：US07244558B1
公开(公告)日：2007-07-17
申请号：US09926431
申请日：2000-05-05
申请人： Siba K. Samal , Peter L. Collins
发明人： Siba K. Samal , Peter L. Collins
CPC分类号： A61K39/17 , A61K39/00 , A61K39/12 , A61K2039/5254 , C07K14/005 , C12N7/00 , C12N15/86 , C12N2760/18122 , C12N2760/18134 , C12N2760/18143 , C12N2760/18161
摘要： The present invention concerns cDNAs for making attentuated, infectious Newcastle disease virus (NDV). Another aspect of the invention relates to methods of making the cDNAs. Another aspect of the invention is a vector containing the cDNA optionally linked to an operable promoter. Within the scope of the invention are vaccines comprising the attenuated, infectious NDV. Also disclosed are methods of making the vaccines and methods of using the vaccines to prevent or treat Newcastle disease in an avian host. The present invention also concerns the nucleotide sequences of the entire genome of NDV, the leading region, the trailing region, and the NP region, as well as proteins encoded by these nucleotide sequences.
摘要翻译： 本发明涉及用于制造注意感染的新城疫病毒（NDV）的cDNA。 本发明的另一方面涉及制备cDNA的方法。 本发明的另一方面是含有任选地连接到可操作的启动子的cDNA的载体。 在本发明的范围内是包含减毒，感染性NDV的疫苗。 还公开了制备疫苗的方法和使用疫苗来预防或治疗禽类宿主中的新城疫病的方法。 本发明还涉及NDV，前导区域，尾区域和NP区域的全部基因组的核苷酸序列以及由这些核苷酸序列编码的蛋白质。
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35.发明授权Production of attenuated parainfluenza virus vaccines from cloned nucleotide sequences 失效从克隆的核苷酸序列产生减毒副流感病毒疫苗公开(公告)号：US07208161B1
公开(公告)日：2007-04-24
申请号：US09083793
申请日：1998-05-22
IPC分类号： A61K39/155 , C12N7/00
CPC分类号： C07K16/1027 , A61K39/00 , A61K2039/5254 , C07K14/005 , C07K2319/00 , C12N7/00 , C12N2760/18622 , C12N2760/18643 , C12N2760/18661
摘要： Isolated polynucleotide molecules provide recombinant PIV genomes and antigenomes for production of recombinant PIV vaccines. The recombinant genome or antigenome can be expressed with a nucleoprotein (N), phosphoprotein (P), and a large (L) polymerase protein to produce isolated infectious PIV particles. The recombinant PIV genome and antigenome can be modified to produce desired changes, for example to incorporate attenuating mutations from biologically derived PIV mutants or to create chimeric PIV clones, to generate attenuated, immunogenic viruses for vaccine use.
摘要翻译： 分离的多核苷酸分子提供用于重组PIV疫苗生产的重组PIV基因组和抗原单体。 可以用核蛋白（N），磷酸化蛋白（P）和大的（L）聚合酶蛋白来表达重组基因组或反基因组以产生分离的感染性PIV颗粒。 可以修饰重组PIV基因组和反义基因组以产生所需的变化，例如从生物衍生的PIV突变体引入减毒突变或产生嵌合PIV克隆，以产生用于疫苗使用的减毒的免疫原性病毒。
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36.发明授权公开(公告)号：US07201907B1
公开(公告)日：2007-04-10
申请号：US09586479
申请日：2000-06-01
申请人： Alexander C. Schmidt , Mario H. Skiadopoulos , Peter L. Collins , Brian R. Murphy , Jane E. Bailly , Anna P. Durbin
发明人： Alexander C. Schmidt , Mario H. Skiadopoulos , Peter L. Collins , Brian R. Murphy , Jane E. Bailly , Anna P. Durbin
IPC分类号： A61K39/12 , A61K39/155
CPC分类号： C12N7/00 , A61K39/12 , A61K39/155 , A61K2039/525 , A61K2039/5254 , A61K2039/5256 , A61K2039/543 , C12N2760/18634 , C12N2760/18643 , C12N2760/18645 , C12N2760/18661 , C12N2810/6072
摘要： Chimeric human-bovine parainfluenza viruses (PIVs) are infectious and attenuated in humans and other mammals and useful individually or in combination in vaccine formulations for eliciting an anti-PIV immune response or as vectors for introducing heterologous genes into a host. Also provided are isolated polynucleotide molecules and vectors incorporating a chimeric PIV genome or antigenome which includes a partial or complete human or bovine PIV “background” genome or antigenome combined or integrated with one or more heterologous gene(s) or genome segment(s) of a different PIV. Chimeric human-bovine PIV of the invention include a partial or complete “background” PIV genome or antigenome derived from or patterned after a human or bovine PIV virus combined with one or more heterologous gene(s) or genome segment(s) of a different PIV virus to form the human-bovine chimeric PIV genome or antigenome.
摘要翻译： 嵌合人 - 牛副流感病毒（PIV）在人类和其他哺乳动物中具有感染性和减毒性，并且在疫苗制剂中单独使用或组合用于引发抗PIV免疫应答或作为将异源基因导入宿主的载体。 还提供了分离的多核苷酸分子和掺入嵌合PIV基因组或抗原组的载体，其包括部分或完整的人或牛PIV“背景”基因组或反基因组，其与一个或多个异源基因或基因组片段组合或整合， 不同的PIV。 本发明的嵌合人牛PIV包括部分或完整的“背景”PIV基因组或反义基因组，其衍生自或构图在人或牛PIV病毒与一个或多个异源基因或不同基因组的基因组片段组合 PIV病毒形成人 - 牛嵌合PIV基因组或抗原组。
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37.发明授权Respiratory syncytial virus vaccines expressing protective antigens from promoter-proximal genes 失效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：US06923971B2
公开(公告)日：2005-08-02
申请号：US09887469
申请日：2001-06-22
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 , C12N7/00 , C12N7/01 , C12Q1/70
CPC分类号： C12N7/00 , A61K39/12 , A61K39/155 , A61K2039/5254 , A61K2039/5256 , C12N2760/18521 , C12N2760/18534 , C12N2760/18543
摘要： Recombinant respiratory syncytial virus (RSV) having the position of genes shifted within the genome or antigenome of the recombinant virus are constructed by insertion, deletion or rearrangement of genes or genome segments within the recombinant genome or antigenome and are useful for eliciting an anti-RSV immune response. Shifting the position of genes in this manner provides for a selected increase or decrease in expression of the gene. In one embodiment, expression of RSV glycoproteins is 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. Additional mutations and nucleotide modifications are provided within gene position-shifted RSV to yield desired phenotypic and structural effects.
摘要翻译： 具有在重组病毒的基因组或反向原核基因内移位的基因位置的重组呼吸道合胞病毒（RSV）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，缺失或重排而构建，并且可用于引发抗RSV 免疫反应。 以这种方式转移基因的位置提供了基因表达的选择性增加或减少。 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糖蛋白的表达。 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。 在基因位置偏移RSV中提供了额外的突变和核苷酸修饰，以产生所需的表型和结构效应。
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38.发明授权Production of attenuated respiratory syncytial virus vaccines involving modification of M2 ORF2 有权涉及M2 ORF2修饰的减毒呼吸道合胞病毒疫苗的生产公开(公告)号：US06713066B1
公开(公告)日：2004-03-30
申请号：US09611829
申请日：2000-07-07
IPC分类号： A61K3912
CPC分类号： C07K14/005 , A61K39/00 , A61K2039/5254 , C12N7/00 , C12N2760/18522 , C12N2760/18543 , C12N2760/18561
摘要： Recombinant respiratory syncytial virus (RSV) are provided in which expression of the second translational open reading frame encoded by the M2 gene (M2ORF2) is reduced or ablated to yield novel RSV vaccine candidates. Expression of M2 ORF2 is reduced or ablated by modifying a recombinant RSV genome or antigenome to incorporate a frame shift mutation, or one or more stop codons in M2 ORF2. Alternatively, M2 ORF2 is deleted in whole or in part to render the M2-2 protein partially or entirely non-functional or to disrupt its expression altogether. M2 ORF2 deletion and knock out mutants possess highly desirable phenotypic characteristics for vaccine development. These changes specify one or more desired phenotypic changes in the resulting virus or subviral particle. Vaccine candidates are generated that show a change in mRNA transcription, genomic or antigenomic RNA replication, viral growth characteristics, viral antigen expression, viral plaque size, and/or a change in cytopathogenicity. In addition, M2-2 knock out or deletion virus exhibits increased levels of synthesis of viral proteins in cell culture, providing an enriched source of viral antigen or protein for purification and use as a noninfectious subunit vaccine.
摘要翻译： 提供了重组呼吸道合胞病毒（RSV），其中由M2基因（M2ORF2）编码的第二翻译开放阅读框的表达被减少或消融以产生新的RSV疫苗候选物。 M2 ORF2的表达通过修饰重组RSV基因组或抗原组合来结合帧移位突变或M2 ORF2中的一个或多个终止密码子来减少或消除。 或者，M2 ORF2全部或部分缺失，以使M2-2蛋白部分或完全不起作用或完全破坏其表达。 M2 ORF2缺失和敲除突变体对于疫苗开发具有非常需要的表型特征。 这些变化指定所得病毒或亚病毒颗粒中的一种或多种期望的表型变化。 产生疫苗候选物，其显示mRNA转录，基因组或反基因组RNA复制，病毒生长特征，病毒抗原表达，病毒斑块大小和/或细胞致病性变化的变化。 此外，M2-2敲除或缺失病毒在细胞培养物中表现出增加的病毒蛋白质合成水平，提供用于纯化和用作非感染性亚单位疫苗的病毒抗原或蛋白质的丰富来源。
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公开(公告)号：US20130052718A1
公开(公告)日：2013-02-28
申请号：US13501447
申请日：2006-01-10
CPC分类号： C07K14/005 , A61K2039/5254 , A61K2039/5256 , C12N7/00 , C12N15/86 , C12N2760/18722 , C12N2760/18743 , C12N2760/18761
摘要： The invention provides self replicating infectious recombinant paramyxoviruses. The recombinant paramyxovirus preferably have one or more attenuating mutations. In some embodiments, the recombinant paramyxovirus has a separate variant polynucleotide encoding a P protein and a separate monocistronic polynucleotide encoding a V protein. In some embodiments, recombinant paramyxovirus have at least one temperature sensitive mutation and one non-temperature sensitive mutation. Also provided are compositions and methods for using the recombinant paramyxoviruses as described herein.
摘要翻译： 本发明提供了自我复制的感染性重组副粘病毒。 重组副粘病毒优选具有一个或多个减毒突变。 在一些实施方案中，重组副粘病毒具有编码P蛋白的单独变体多核苷酸和编码V蛋白的分离的单顺反子多核苷酸。 在一些实施方案中，重组副粘病毒具有至少一个温度敏感突变和一个非温度敏感突变。 还提供了使用如本文所述的重组副粘病毒的组合物和方法。
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40.发明申请RECOMBINANT HUMAN PARAINFLUENZA TYPE 1 VIRUSES (HPIV1s) CONTAINING MUTATIONS IN OR DELETION OF THE C PROTEIN ARE ATTENUATED IN AFRICAN GREEN MONKEYS AND IN CILIATED HUMAN AIRWAY EPITHELIAL CELLS AND ARE POTENTIAL VACCINE CANDIDATES FOR HPIV1 审中-公开包含非蛋白绿色猴子和CILIA人类航空上皮细胞中C蛋白质突变或残留的重组人类亚型流感病毒1型病毒（HPIV1）和HPIV1潜在的候选药物候选物公开(公告)号：US20110189232A1
公开(公告)日：2011-08-04
申请号：US13001710
申请日：2009-07-01
CPC分类号： C12N7/00 , A61K39/12 , A61K39/155 , A61K2039/5254 , A61K2039/543 , C12N2760/18634 , C12N2760/18661
摘要： Two recently characterized live attenuated HPIV1 vaccine candidates, rHPIV1-CR84G/Δ170HNT553ALY942A and rHPIV1-CR84G/Δ170HN-T553ALΔ1710-11, which contain temperature sensitive (ts) attenuating (att) and non-ts att mutations, were evaluated in a Human Airway Epithelium (HAE) model culture system and in vivo in African Green monkeys (AGM). The vaccine candidates were highly restricted in growth in HAE at permissive (32° C.) and restrictive (37° C.) temperatures. The viruses grew slightly better at 37° C. than at 32° C., and rHPIV1-CR84G/Δ170HNT553A-LY942A was less attenuated than rHPIV1-CR84G/Δ170HNT553ALΔ1710-11. The level of replication in HAE correlated with that observed in African Green monkeys, suggesting that the HAE model is useful as a tool for pre-clinical evaluation of HPIV1 vaccines. A live attenuated HPIV1 vaccine candidate having a normal P/C gene structure of overlapping P and C open reading frames, but does not express any functional C protein, is found to highly attenuated in AGMs, and provides a significant immune response in AGMs.
摘要翻译： 两个最近出现的活的减毒HPIV1疫苗候选物，rHPIV1-CR84G /＆Dgr; 170HNT553ALY942A和rHPIV1-CR84G /＆Dgr; 170HN-T553AL＆Dgr; 1710-11，其含有温度敏感（ts）减毒（att）和非ts att突变 在人类气道上皮（HAE）模型培养系统和非洲绿猴（AGM）体内评估。 疫苗候选物在允许（32℃）和限制性（37℃）温度下HAE的生长受到高度限制。 病毒在37℃比在32℃生长稍微好一些，而rHPIV1-CR84G / Dgr; 170HNT553A-LY942A比rHPIV1-CR84G / Dgr; 170HNT553AL＆Dgr; 1710-11弱得多。 HAE中的复制水平与非洲绿猴中观察到的水平相关，表明HAE模型可用作HPIV1疫苗临床前评估的工具。 被发现在AGM中高度减毒的具有重叠P和C开放阅读框但不表达任何功能性C蛋白的正常P / C基因结构的活的减毒的HPIV1疫苗候选物在AGM中提供显着的免疫应答。
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