A Computationally Optimized Hemagglutinin Virus-Like Particle Vaccine Elicits Broadly Reactive Antibodies that Protect Nonhuman Primates from H5N1 Infection
A Computationally Optimized Hemagglutinin Virus-Like Particle Vaccine Elicits Broadly Reactive Antibodies that Protect Nonhuman Primates from H5N1 Infection
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DOI：
10.1093/infdis/jis232
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发表时间：
2012-05-15
影响因子：
6.4
通讯作者：
Ross, Ted M.
中科院分区：
文献类型：
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作者：
Giles, Brendan M.;Crevar, Corey J.;Ross, Ted M.
高致病性 H5N1 禽流感病毒继续通过水禽传播，造成人类致命感染。疫苗可以预防与大流行性流感分离株相关的发病率和死亡率。预测可能从 10 个不同的 H5N1 进化枝中出现的特定分离株对于疫苗设计来说是一个巨大的挑战。在这项研究中，我们基于一种新方法、计算优化的广泛反应性抗原 (COBRA) 生成了合成血凝素 (HA)，该方法使用了专门针对 H5N1 进化枝 2 人类分离株的序列的全球测序和监测工作。接种 COBRA 进化枝 2 HA 的食蟹猴与接种进化枝 2.2 HA VLP 的非人灵长类动物相比，H5N1 病毒样颗粒 (VLP) 具有血凝抑制抗体滴度，可识别来自不同进化枝的更多代表性分离株。此外，所有接种疫苗的动物均免受 A/大天鹅/蒙古/244/2005 (WS/05) clade 2.2 攻击，在鼻腔或气管冲洗液中未检测到病毒。然而，与接受 WS/05 VLP 疫苗的非人灵长类动物相比，接种 COBRA VLP 疫苗的非人灵长类动物减少了肺部炎症和病理影响。COBRA clade 2 HA H5N1 VLP 引发针对来自不同分支的多种 H5N1 分离株的广泛体液免疫。此外，COBRA VLP疫苗比同源疫苗更能有效对抗高致病性禽流感病毒。
Highly pathogenic H5N1 avian influenza viruses continue to spread via waterfowl, causing lethal infections in humans. Vaccines can prevent the morbidity and mortality associated with pandemic influenza isolates. Predicting the specific isolate that may emerge from the 10 different H5N1 clades is a tremendous challenge for vaccine design.In this study, we generated a synthetic hemagglutinin (HA) on the basis of a new method, computationally optimized broadly reactive antigen (COBRA), which uses worldwide sequencing and surveillance efforts that are specifically focused on sequences from H5N1 clade 2 human isolates.Cynomolgus macaques vaccinated with COBRA clade 2 HA H5N1 virus-like particles (VLPs) had hemagglutination-inhibition antibody titers that recognized a broader number of representative isolates from divergent clades as compared to nonhuman primates vaccinated with clade 2.2 HA VLPs. Furthermore, all vaccinated animals were protected from A/Whooper Swan/Mongolia/244/2005 (WS/05) clade 2.2 challenge, with no virus detected in the nasal or tracheal washes. However, COBRA VLP-vaccinated nonhuman primates had reduced lung inflammation and pathologic effects as compared to those that received WS/05 VLP vaccines.The COBRA clade 2 HA H5N1 VLP elicits broad humoral immunity against multiple H5N1 isolates from different clades. In addition, the COBRA VLP vaccine is more effective than a homologous vaccine against a highly pathogenic avian influenza virus challenge.