Scientific barriers to developing vaccines against avian influenza viruses.
Scientific barriers to developing vaccines against avian influenza viruses.
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DOI：
10.1038/nri2054
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发表时间：
2007-04
期刊：
影响因子：
--
通讯作者：
Joseph T
中科院分区：
文献类型：
--
作者：
Subbarao K;Joseph T
过去几年，禽流感病毒直接传播给人类的报告越来越多，H5N1流感病毒感染在禽类和人类中持续暴发，突显了禽流感病毒构成的大流行威胁。尽管疫苗接种是预防大流行性流感病毒引起的严重疾病和死亡的关键战略，而且尽管有针对人类流感病毒的疫苗的长期经验，但研究人员在开发成功的禽流感病毒疫苗方面面临着几个障碍。流感病毒的血凝素(HA)和神经氨酸酶(NA)糖蛋白是保护性免疫反应的主要靶点。获得许可的流感病毒疫苗旨在诱导HA特异性抗体反应，以保护宿主免受感染。然而，禽流感病毒中存在16个HA亚型和9个NA糖蛋白亚型，以及自然界中每个亚型之间的遗传和抗原多样性，为产生广泛交叉保护的疫苗提出了几个独特的挑战。在基于质粒的反向遗传学技术的基础上，正在开发针对大流行性流感的灭活病毒和减毒活病毒疫苗。基于各种其他平台的疫苗，包括活病毒载体和DNA疫苗，也在开发中，并在临床前研究中显示出希望。现有数据表明，禽流感灭活疫苗的免疫原性很差，需要高浓度的HA糖蛋白或与佐剂联合使用才能在人体内实现预期的抗体反应。禽类HA糖蛋白免疫原性差的生物学基础尚不清楚。目前尚无衡量对禽流感病毒的免疫反应，特别是细胞介导的免疫反应的分析方法，也不能很好地了解保护的免疫相关性。选择化验方法(S)评估对大流行性流感疫苗的免疫反应是评估候选疫苗的一个实际挑战。由于很难预测哪种禽流感病毒将跨越物种屏障并导致未来的大流行，因此必须建立不同亚型候选疫苗的库，并在动物模型和人类中进行评估。尽管理想的疫苗可以预防感染，但大流行性流感疫苗更现实的目标可能是预防严重疾病和死亡。禽流感病毒构成的大流行威胁突出表明需要新的安全有效的疫苗。然而，研究人员在开发这些针对禽流感病毒的疫苗时面临着几个独特的障碍。这些障碍是什么？我们如何克服它们？禽流感病毒直接传播给人类的报告越来越多，这突出表明需要采取控制战略来预防流感大流行。接种疫苗是预防大流行性流感重病和死亡的关键战略。尽管在人类流感病毒疫苗方面有长期的经验，但研究人员在开发禽流感病毒人类疫苗方面面临着几个额外的挑战。在这篇综述中，我们讨论了禽流感病毒的特征，我们对这些病毒引起的人类感染和对它们的免疫反应的认识上的差距，以及它们与人类流感病毒的区别，以及疫苗开发的现状。
The increasing number of reports of direct transmission of avian influenza viruses to humans in the past few years and the ongoing outbreak of H5N1 influenza virus infections in birds and humans highlight the pandemic threat posed by avian influenza viruses. Although vaccination is the key strategy for the prevention of severe illness and death from pandemic influenza viruses and despite the long-term experience with vaccines against human influenza viruses, researchers face several obstacles in developing successful vaccines against avian influenza viruses. The haemagglutinin (HA) and neuraminidase (NA) glycoproteins of influenza viruses are the main targets of the protective immune response. Licensed influenza virus vaccines are designed to induce HA-specific antibody responses to protect the host from infection. However, the presence of 16 subtypes of HA and 9 subtypes of NA glycoproteins among avian influenza viruses and the genetic and antigenic diversity among each subtype in nature present several unique challenges for the generation of broadly cross-protective vaccines. Inactivated virus and live attenuated virus vaccines against pandemic influenza are being developed on the basis of plasmid-based reverse-genetics technology. Vaccines based on various other platforms, including live virus vectors and DNA vaccines, are also being developed and show promise in preclinical studies. The available data indicate that inactivated avian influenza virus vaccines are poorly immunogenic and require a high concentration of HA glycoprotein or co-administration with an adjuvant to achieve the desired antibody response in humans. The biological basis for the poor immunogenicity of avian HA glycoproteins is not well understood. Assays to measure the immune response to avian influenza viruses, in particular cell-mediated immune responses, are not available and the immune correlates of protection are not well understood. The choice of assay(s) for assessment of the immune response to pandemic influenza vaccines is a practical challenge in the evaluation of candidate vaccines. As it is difficult to predict which avian influenza virus will cross the species barrier and cause a future pandemic, a library of candidate vaccines of different subtypes must be generated and evaluated in animal models and humans. Although an ideal vaccine would prevent infection, a more realistic goal for a pandemic influenza vaccine might be to prevent severe illness and death. The pandemic threat posed by avian influenza viruses highlights the need for new safe and efficient vaccines. However, several unique obstacles are faced by researchers in the development of these vaccines against avian influenza viruses. What are these obstacles and how can we overcome them? The increasing number of reports of direct transmission of avian influenza viruses to humans underscores the need for control strategies to prevent an influenza pandemic. Vaccination is the key strategy to prevent severe illness and death from pandemic influenza. Despite long-term experience with vaccines against human influenza viruses, researchers face several additional challenges in developing human vaccines against avian influenza viruses. In this Review, we discuss the features of avian influenza viruses, the gaps in our understanding of infections caused by these viruses in humans and of the immune response to them that distinguishes them from human influenza viruses, and the current status of vaccine development.
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