Vaccines, Immunoprophylaxis, and Immunotherapy for SARS

严重急性呼吸道综合征（SARS）是一种由新发现的SARS冠状病毒（SARS-CoV）引起的严重呼吸道疾病。该病于2002年底在中国南部出现，并于2003年初蔓延到亚洲的几个国家以及欧洲和北美。该综合征的特征是发热，寒战或寒战，头痛和非特异性症状，如不适和肌痛，其次是咳嗽和呼吸困难。与SARS相关的严重发病率和死亡率使得必须开发和评估预防和治疗该疾病的有效手段，特别是因为尚不清楚该病毒是否会像其他呼吸道病毒病原体一样重新出现并表现出季节性循环模式，或者它是否会独立地重新引入人群。可以根据适用于其他病原体的原则制定预防和治疗策略，但评估这些策略的有效性需要动物模型。 我们研究了SARS-CoV在小鼠和非人灵长类动物中的复制。经鼻内给予1 e5 50%组织培养感染剂量（TCID 50）后，SARS-CoV在BALB/c小鼠的呼吸道中复制到高滴度（每克肺和鼻甲组织分别为1 e7和1 e6 TCID 50）。根据给药剂量的不同，在第1天或第2天无疾病的情况下观察到峰值复制，病毒在一周内被清除。小鼠产生血清中和抗体应答，并在初次感染后28天免受再次感染。免疫血清的被动转移保护未处理小鼠在鼻内攻击后免受呼吸道中的病毒复制。因此，抗体，单独作用，可以防止SARS冠状病毒在小鼠肺中的复制，这对于疫苗，免疫疗法和免疫预防方案的开发是一个令人鼓舞的观察结果。 SARS-CoV还通过鼻内和肠道途径以1 e6 TCID 50的剂量给予恒河猴和非洲绿色猴。在无疾病的情况下观察到病毒复制;猴的上呼吸道和下呼吸道中的复制水平在恒河猴中较低（峰值1e2.7和1e1.5 TCID 50/ml），在非洲绿色猴中中等（峰值1e3.5和1 e4 TCID 50/ml），病毒在10天内被清除。在两组中均观察到血清中和抗体升高4倍（平均滴度1：25和1：81）。 总之，SARS-CoV在BALB/c小鼠和非洲绿色猴的呼吸道中复制到允许评估疫苗、免疫和抗病毒药物治疗策略的有效性的水平。我们在小鼠模型中的观察结果表明，原发性感染可以防止再次感染，而抗体本身可以防止病毒复制，这表明诱导中和抗体的疫苗和免疫预防策略或免疫治疗可能对SARS有效。

Severe Acute Respiratory Syndrome (SARS) is a severe respiratory illness caused by a newly identified virus named SARS coronavirus (SARS-CoV). The disease emerged in southern China in late 2002 and spread to several countries within Asia and to Europe and North America in early 2003. The syndrome is characterized by fever, chills or rigors, headache and non-specific symptoms such as malaise and myalgias, followed by cough, and dyspnea. The severe morbidity and mortality associated with SARS make it imperative that effective means to prevent and treat the disease be developed and evaluated, especially since it is not known whether the virus will reappear and exhibit a seasonal pattern of circulation like other respiratory virus pathogens or whether it will be independently reintroduced into the human population. Prevention and treatment strategies can be developed based on principles that apply to other pathogens but evaluation of the efficacy of these strategies requires animal models. We have studied the replication of SARS-CoV in mice and non-human primates. Following intranasal administration of 1e5 50% tissue culture infectious doses (TCID50), SARS-CoV replicated to high titer in the respiratory tract of BALB/c mice (1e7 and 1e6 TCID50 per gram of lung and nasal turbinate tissue, respectively). Peak replication was seen in the absence of disease on days 1 or 2, depending on the dose administered, and the virus was cleared within a week. Mice developed a serum neutralizing antibody response and were protected from re-infection 28 days following primary infection. Passive transfer of immune serum protected naive mice from virus replication in the respiratory tract following intranasal challenge. Thus antibodies, acting alone, can prevent replication of the SARS coronavirus in the lungs of mice, an encouraging observation for the development of vaccines, immunotherapy and immunoprophylaxis regimens. SARS-CoV was also administered to rhesus and African Green monkeys at a dose of 1e6 TCID50 via the intranasal and intratracheal routes. Virus replication was seen in the absence of disease; the level of replication in the upper and lower respiratory tract of the monkeys was low in rhesus (peaks 1e2.7 and 1e1.5 TCID50/ml) and modest in African Green monkeys (peaks 1e3.5 and 1e4 TCID50/ml), respectively and the virus was cleared within 10 days. Four-fold rises in serum neutralizing antibody were seen in both groups (mean titers 1:25 and 1:81). In summary, SARS-CoV replicates in the respiratory tract of BALB/c mice and African Green monkeys to levels that will permit an evaluation of the efficacy of vaccines, immunotherapeutic and antiviral drug treatment strategies. Our observations in the mouse model, that primary infection provides protection from re-infection and that antibody alone can protect against viral replication, suggest that vaccines that induce neutralizing antibodies and strategies for immunoprophylaxis or, perhaps, immunotherapy are likely to be effective in SARS.