Vaccines, Immunoprophylaxis, and Immunotherapy for Coronaviruses

点击翻译按钮获取中文摘要

Several animal models have been evaluated for the study of MERS-CoV. In brief, non-human primates have been utilized as infection models of MERS, with rhesus macaques displaying mild infection and marmosets more severe disease. While mice are not naturally susceptible to experimental infection with MERS-CoV, several mouse models have been generated expressing the human dipeptidyl peptidase 4 (DPP4) receptor. New Zealand white rabbits naturally display a DPP4 molecule that allows for attachment and infection by MERS-CoV and they can be experimentally infected with MERS-CoV, resulting in asymptomatic infection with mild pulmonary inflammation. Viral titers peak about three days post-inoculation. Because MERS-CoV infection in the rabbit model can be monitored by pathology and viral replication, we evaluated this model for testing a potential medical countermeasure. The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for development of medical countermeasures. Scientists at the National Cancer Institute isolated a human monoclonal antibody (hmAb) m336, from a large phage-display library from healthy humans that interacts with the receptor-binding domain of the MERS-CoV spike protein and shows exceptionally potent neutralizing activity against MERS-CoV in vitro. In collaboration with colleagues at NCI, we evaluated the efficacy of this hmAb administered as prophylaxis for MERS-CoV infection in the rabbit model. Significant reduction in viral RNA titers was demonstrated in the lungs following prophylaxis with m336 by the intravenous and intranasal routes. Within one day of infection we observed between a 40 to 9000-fold reduction in pulmonary viral RNA load, with minimal inflammation and viral antigen present. These results indicate the m336 antibody administered prior to exposure is able to prevent MERS-CoV infection and warrants further development as a medical countermeasure against MERS-CoV infection.