Immunogenicity and protective efficacy of a live attenuated H5N1 vaccine in nonhuman primates.
Immunogenicity and protective efficacy of a live attenuated H5N1 vaccine in nonhuman primates.
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DOI：
10.1371/journal.ppat.1000409
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发表时间：
2009-05
期刊：
影响因子：
6.7
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Fan S;Gao Y;Shinya K;Li CK;Li Y;Shi J;Jiang Y;Suo Y;Tong T;Zhong G;Song J;Zhang Y;Tian G;Guan Y;Xu XN;Bu Z;Kawaoka Y;Chen H
高致病性H5N1流感病毒在家禽和野生鸟类中的持续传播，以及耐药变种的出现和人际传播的可能性，促使人们努力研制有效的疫苗。在临床试验中，灭活的亚病毒粒子或全病毒粒子H5N1疫苗已显示出有希望的免疫原性，但它们在未引物人群中引发保护性免疫的能力仍然未知。一种含有H5N1病毒A/VN/1203/2004（进化枝1）血凝素（HA）和神经氨酸酶（NA）基因的冷适应减毒活疫苗对小鼠和雪貂体内同源和异源野生型H5N1病毒的肺复制具有保护作用。在这项研究中，我们使用反向遗传学技术生产了一种冷适应的H5N1减毒活疫苗（AH/AAca），该疫苗含有来自最近的H5N1分离物，a /安徽/2/05病毒（AH/05）（进化枝2.3）的HA和NA基因，以及冷适应流感H2N2 a /AnnArbor/6/60病毒（AAca）的主干。AH/AAca在鸡、小鼠和猴子中被减毒，并在经鼻内免疫两次的恒河猴中诱导了强大的中和抗体反应以及ha特异性CD4+ T细胞免疫反应。重要的是，接种疫苗的猕猴完全免受同源AH/05病毒或异源H5N1病毒a /bar-headed goose/Qinghai/3/05 （BHG/05; clade 2.2）的攻击。这些结果首次表明，冷适应H5N1疫苗可在非人灵长类动物模型中引发针对高致病性H5N1病毒感染的保护性免疫，并为在人体试验中进一步测试H5N1减毒活疫苗的双重免疫提供了令人信服的论据。H5N1流感病毒已在14个国家造成人类感染，致死率超过60%，并可能成为下一次大流行的源头。因此，开发针对这些病毒的有效疫苗是防备H5N1大流行的最优先事项。高剂量或佐剂可提高H5N1灭活疫苗的免疫原性；然而，常规灭活流感病毒疫苗的生产能力有限，可能严重妨碍通过疫苗接种控制H5N1流感传播的能力。在这里，我们在小鼠和非人灵长类动物身上产生并测试了一种适应冷的减毒H5N1活疫苗的功效。我们发现该疫苗在这些动物中对同源和异源H5N1病毒攻击提供了完全的保护。由于活疫苗比灭活疫苗需要更少的加工，而且不需要佐剂，因此我们的研究代表了H5N1大流行性流感疫苗开发的重大进展。
The continued spread of highly pathogenic H5N1 influenza viruses among poultry and wild birds, together with the emergence of drug-resistant variants and the possibility of human-to-human transmission, has spurred attempts to develop an effective vaccine. Inactivated subvirion or whole-virion H5N1 vaccines have shown promising immunogenicity in clinical trials, but their ability to elicit protective immunity in unprimed human populations remains unknown. A cold-adapted, live attenuated vaccine with the hemagglutinin (HA) and neuraminidase (NA) genes of an H5N1 virus A/VN/1203/2004 (clade 1) was protective against the pulmonary replication of homologous and heterologous wild-type H5N1 viruses in mice and ferrets. In this study, we used reverse genetics to produce a cold-adapted, live attenuated H5N1 vaccine (AH/AAca) that contains HA and NA genes from a recent H5N1 isolate, A/Anhui/2/05 virus (AH/05) (clade 2.3), and the backbone of the cold-adapted influenza H2N2 A/AnnArbor/6/60 virus (AAca). AH/AAca was attenuated in chickens, mice, and monkeys, and it induced robust neutralizing antibody responses as well as HA-specific CD4+ T cell immune responses in rhesus macaques immunized twice intranasally. Importantly, the vaccinated macaques were fully protected from challenge with either the homologous AH/05 virus or a heterologous H5N1 virus, A/bar-headed goose/Qinghai/3/05 (BHG/05; clade 2.2). These results demonstrate for the first time that a cold-adapted H5N1 vaccine can elicit protective immunity against highly pathogenic H5N1 virus infection in a nonhuman primate model and provide a compelling argument for further testing of double immunization with live attenuated H5N1 vaccines in human trials. H5N1 influenza viruses have caused human infections with more than 60% fatality in 14 countries and may yet be the source of the next pandemic. Therefore, the development of effective vaccines against these viruses is the highest priority for H5N1 pandemic preparedness. A high dosage or adjuvants improve the immunogenicity of H5N1 inactivated vaccines; however, limited production capacity for conventional inactivated influenza virus vaccines could severely hinder the ability to control the spread of H5N1 influenza through vaccination. Here, we generated and tested the efficacy of a cold-adapted, live attenuated H5N1 vaccine in mice and nonhuman primates. We found that the vaccine provided complete protection in these animals against homologous and heterologous H5N1 virus challenge. Since live vaccines require less processing than inactivated vaccines and do not require adjuvants, our study represents a major advance in vaccine development for H5N1 pandemic influenza.
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