The development and characterization of H5 influenza virus vaccines derived from a 2003 human isolate
The development and characterization of H5 influenza virus vaccines derived from a 2003 human isolate
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DOI：
10.1016/j.vaccine.2005.07.005
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发表时间：
2006-04-24
期刊：
影响因子：
5.5
通讯作者：
Kawaoka, Y
中科院分区：
文献类型：
--
作者：
Horimoto, T;Ayato, T;Kawaoka, Y
高致病性H5N1甲型流感病毒构成的大流行威胁导致了对疫苗的迫切需求，以预防H5病毒感染。由于致病病毒在鸡蛋中生长不良，其毒力对疫苗生产商构成生物危害，通过反向遗传学产生的无毒病毒已成为疫苗生产的首选基础。在这里，我们研究了潜在的H5疫苗候选的两个关键特征：血凝素(HA)裂解位点序列及其为降低毒力而进行的修饰，以及背景病毒的选择以提供高生长速度。我们生产的重组病毒(6：2重配)具有一系列修改的无毒型HA和神经氨酸酶基因，这两种基因都来自H5N1人分离株。这些重组病毒的其他基因来自已知在鸡蛋中生长良好的供体病毒株：人株A/波多黎各/8/34(PR8)或禽株。所有的重组病毒都在鸡蛋中生长良好，在雏鸡中是无毒的，并保护动物免受野生型病毒的感染。然而，其中一种具有禽类病毒背景的重组病毒获得了HA裂解位点序列的突变，这赋予了该病毒毒力潜力。此外，具有禽类病毒背景的候选疫苗比具有人类病毒背景的候选疫苗的毒力更强。我们的结论是，具有PR8背景的6：2重组病毒比具有禽类病毒背景的重组病毒更适合于疫苗开发，并且必须修改HA裂解位点序列，以最大限度地减少疫苗病毒转化为强毒形式的可能性。(C)2006爱思唯尔有限公司。保留所有权利。
The pandemic threat posed by highly pathogenic H5N1 influenza A viruses has created ail Urgent need for vaccines to protect against H5 virus infection. Because pathogenic viruses grow poorly in chicken eggs and their virulence poses a biohazard to vaccine producers, avirulent viruses produced by reverse genetics have become the preferred basis for vaccine production. Here, we investigated two key characteristics of potential H5 vaccine candidates: the hemaggutinin (HA) cleavage site sequence and its modification to attenuate virulence and the choice of background virus to provide a high-growth rate. We produced recombinant (6:2 reassortant) viruses that possessed a series of modified avirulent-type HA and neuraminidase genes, both of which were derived from an H5N1 human isolate. The other genes of these recombinant viruses were derived from donor virus strains known to grow well in eggs: the human strain A/Puerto Rico/8/34 (PR8) or an avian strain. All of the recombinant viruses grew well in eggs, were avirulent in chicks, and protected animals against infection with a wild-type virus. However, one of the recombinant viruses with an avian virus background acquired a Mutation in the HA cleavage site sequence that conferred virulence potential to this virus. Moreover, vaccine candidates with the avian virus background were more virulent than those with the human virus background. We conclude that 6:2 recombinant viruses with a PR8 background are more suitable than those with an avian virus background for vaccine development and that the HA cleavage site sequence must be modified to minimize the potential for a vaccine virus to convert to a virulent form. (c) 2006 Elsevier Ltd. All rights reserved.