Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses
Design and Characterization of a Computationally Optimized Broadly Reactive Hemagglutinin Vaccine for H1N1 Influenza Viruses
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DOI：
10.1128/jvi.03152-15
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发表时间：
2016-05-01
影响因子：
5.4
通讯作者：
Ross, Ted M.
中科院分区：
文献类型：
--
作者：
Carter, Donald M.;Darby, Christopher A.;Ross, Ted M.
开发甲型流感疫苗的挑战之一是抗原性不同的分离株的多样性。以前，一种用于H5N1流感的新型血凝素（HA）是从一种称为计算优化广义反应性抗原（COBRA）的方法中获得的。这种COBRA HA引发了针对不同进化支H5N1分离株的广泛抗体反应。我们现在报告了针对季节性和大流行性H1N1流感病毒分离株的基于cobra的疫苗的开发和特性。九种原型H1N1 COBRA HA蛋白被开发出来，并在小鼠中使用病毒样颗粒（VLP）格式进行了测试，以引发广泛反应性的功能性抗体反应，并对病毒攻击提供保护。这些候选病毒被设计用来识别过去30年分离的H1N1病毒。此外，根据过去100年间H1N1病毒的序列设计了几种COBRA候选病毒，包括现代大流行H1N1分离株。9种H1N1 COBRA HA蛋白中的4种（X1、X3、X6和P1）对17种H1N1病毒具有最广泛的血凝抑制（HAI）活性。这些疫苗被用于鸡尾酒或初级强化组合。最有效的方案是含有P1 COBRA VLP和X3或X6 COBRA VLP疫苗的疫苗，既能引起最广泛的HAI反应，又能保护小鼠免受H1N1大流行的攻击。这些小鼠很少或没有可检测到的病毒复制，与使用匹配的许可疫苗观察到的病毒复制相当。这是第一份描述基于cobra的HA疫苗战略的报告，该战略可引起针对季节性和大流行性H1N1分离株的普遍、广泛反应性和保护性反应。
One of the challenges of developing influenza A vaccines is the diversity of antigenically distinct isolates. Previously, a novel hemagglutinin (HA) for H5N1 influenza was derived from a methodology termed computationally optimized broadly reactive antigen (COBRA). This COBRA HA elicited a broad antibody response against H5N1 isolates from different clades. We now report the development and characterization of a COBRA-based vaccine for both seasonal and pandemic H1N1 influenza virus isolates. Nine prototype H1N1 COBRA HA proteins were developed and tested in mice using a virus-like particle (VLP) format for the elicitation of broadly reactive, functional antibody responses and protection against viral challenge. These candidates were designed to recognize H1N1 viruses isolated within the last 30 years. In addition, several COBRA candidates were designed based on sequences of H1N1 viruses spanning the past 100 years, including modern pandemic H1N1 isolates. Four of the 9 H1N1 COBRA HA proteins (X1, X3, X6, and P1) had the broadest hemagglutination inhibition (HAI) activity against a panel of 17 H1N1 viruses. These vaccines were used in cocktails or prime-boost combinations. The most effective regimens that both elicited the broadest HAI response and protected mice against a pandemic H1N1 challenge were vaccines that contained the P1 COBRA VLP and either the X3 or X6 COBRA VLP vaccine. These mice had little or no detectable viral replication, comparable to that observed with a matched licensed vaccine. This is the first report describing a COBRA-based HA vaccine strategy that elicits a universal, broadly reactive, protective response against seasonal and pandemic H1N1 isolates.