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.
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