公开(公告)号：US20120294879A1

公开(公告)日：2012-11-22

申请号：US13501339

申请日：2010-10-13

申请人： J. Thomas August ,  Paul ThiamJoo Tan ,  Tin Wee Tan ,  Mohammad Asif Khan

发明人： J. Thomas August ,  Paul ThiamJoo Tan ,  Tin Wee Tan ,  Mohammad Asif Khan

IPC分类号： A61K39/145 ,  C12N15/33 ,  C12N15/85 ,  C12N15/86 ,  C07K14/11 ,  C12P21/02 ,  C07K7/06 ,  A61P31/16 ,  C07K19/00 ,  C07K7/08 ,  C12N15/62 ,  C12N5/10

CPC分类号： A61K39/145 ,  A61K39/12 ,  A61K2039/5154 ,  A61K2039/5156 ,  A61K2039/70 ,  C07K14/005 ,  C07K2319/00 ,  C12N2760/16122 ,  C12N2760/16134

摘要： Pandemic A(H1N1) continues its global spread, and vaccine production is a serious problem. Protection by current vaccines is limited by the mutational differences that rapidly accumulate in the circulating strains, especially in the virus surface proteins. New vaccine strategies are focusing at conserved regions of the viral internal proteins to produce T cell epitope-based vaccines. T cell responses have been shown to reduce morbidity and promote recovery in mouse models of influenza challenge. We previously reported 54 highly conserved sequences of NP, M1 and the polymerases of all human H1N1, H3N2, H1N2, and H5N1, and avian subtypes over the past 30 years. Sixty-three T cell epitopes elicited responses in HLA transgenic mice (A2, A24, B7, DR2, DR3 and DR4). These epitopes were compared to the 2007-2009 human H1N1 sequences to identify conserved and variant residues. Seventeen T cell epitopes of PB1, PB2, and M1 were selected as vaccine targets by analysis of sequence conservation and variability, functional avidity, non-identity to human peptides, clustered localization, and promiscuity to multiple HLA alleles. The vaccines composed of these epitopes, being highly conserved and temporally stable, would be useful for any avian or human influenza A virus.

摘要翻译： 大流行A（H1N1）继续全球蔓延，疫苗生产是一个严重的问题。 目前疫苗的保护受到循环菌株尤其是病毒表面蛋白质快速积累的突变差异的限制。 新的疫苗策略着重于病毒内部蛋白质的保守区域，以产生基于T细胞表位的疫苗。 已经显示T细胞应答降低发病率并促进小鼠流感病毒模型的恢复。 以前报道过去30年来，54种高度保守的NP，M1和所有人类H1N1，H3N2，H1N2和H5N1以及禽亚型的聚合酶序列。 六十三个T细胞表位在HLA转基因小鼠（A2，A24，B7，DR2，DR3和DR4）中引发反应。 将这些表位与2007-2009年人类H1N1序列进行比较，以鉴定保守和变异残基。 通过分析序列保守性和可变性，功能亲合力，与人肽的非同一性，聚类定位和对多个HLA等位基因的混杂，选择PB1，PB2和M1的17个T细胞表位作为疫苗靶。 由这些表位组成的高度保守和时间稳定的疫苗对于任何禽类或人类甲型流感病毒都是有用的。