Biological challenges and technological opportunities for respiratory syncytial virus vaccine development.
Biological challenges and technological opportunities for respiratory syncytial virus vaccine development.
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DOI：
10.1111/j.1600-065x.2010.00972.x
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发表时间：
2011-01
影响因子：
8.7
通讯作者：
Graham BS
中科院分区：
文献类型：
--
作者：
Graham BS
呼吸道合胞病毒(RSV)是导致呼吸道疾病的重要原因，导致婴儿住院率高，儿童和成人发病率高，老年人死亡率高。疫苗开发的主要障碍包括RSV感染的早期年龄、RSV逃避天然免疫的能力、RSV诱导的适应性免疫未能防止再感染、RSV疫苗增强型疾病的病史以及缺乏完全允许人类RSV感染的动物模型。这些生物学挑战、安全问题和实际问题大大延长了RSV疫苗的开发进程。与其他困难的病毒疫苗靶标相比，一个巨大的优势是被动给予中和单抗可以保护婴儿免受严重的RSV疾病的影响。因此，疫苗开发的免疫学目标是诱导有效的中和抗体以防止感染，并避免诱导与疾病增强相关的T细胞反应模式。减毒活RSV和复制能力强的嵌合病毒正在进行高级临床试验。基于基因的策略，可以利用复制缺陷载体控制RSV特异性T细胞反应的特异性和表型特性，并可能提高对自然感染的免疫力，正在通过临床前试验取得进展。RSV包膜糖蛋白与中和抗体形成的复合体的原子级结构信息正在指导新疫苗抗原的设计，这种抗原可能能够在不诱导RSV特异性T细胞反应的情况下诱导RSV特异性抗体反应。这些新技术可能会使疫苗的开发能够预防婴儿中RSV介导的疾病，并在宿主中建立新的免疫学范式，以实现对再次感染的更持久的保护。
Respiratory syncytial virus (RSV) is an important cause of respiratory disease causing high rates of hospitalizations in infants, significant morbidity in children and adults, and excess mortality in the elderly. Major barriers to vaccine development include early age of RSV infection, capacity of RSV to evade innate immunity, failure of RSV-induced adaptive immunity to prevent reinfection, history of RSV vaccine-enhanced disease, and lack of an animal model fully permissive to human RSV infection. These biological challenges, safety concerns, and practical issues have significantly prolonged the RSV vaccine development process. One great advantage compared to other difficult viral vaccine targets is that passively administered neutralizing monoclonal antibody is known to protect infants from severe RSV disease. Therefore, the immunological goals for vaccine development are to induce effective neutralizing antibody to prevent infection and to avoid inducing T-cell response patterns associated with enhanced disease. Live-attenuated RSV and replication-competent chimeric viruses are in advanced clinical trials. Gene-based strategies, which can control the specificity and phenotypic properties of RSV-specific T-cell responses utilizing replication-defective vectors and which may improve on immunity from natural infection, are progressing through preclinical testing. Atomic level structural information on RSV envelope glycoproteins in complex with neutralizing antibodies is guiding design of new vaccine antigens that may be able to elicit RSV-specific antibody responses without induction of RSV-specific T-cell responses. These new technologies may allow development of vaccines that can protect against RSV-mediated disease in infants and establish a new immunological paradigm in the host to achieve more durable protection against reinfection.