Human monoclonal antibody as prophylaxis for SARS coronavirus infection in ferrets

Abstract

SARS coronavirus continues to cause sporadic cases of severe acute respiratory syndrome (SARS) in China. No active or passive immunoprophylaxis for disease induced by SARS coronavirus is available. We investigated prophylaxis of SARS coronavirus infection with a neutralising human monoclonal antibody in ferrets, which can be readily infected with the virus. Prophylactic administration of the monoclonal antibody at 10 mg/kg reduced replication of SARS coronavirus in the lungs of infected ferrets by 3.3 logs (95% CI 2.6-4.0 logs; p<0.001), completely prevented the development of SARS coronavirus-induced macroscopic lung pathology (p=0.013), and abolished shedding of virus in pharyngeal secretions. The data generated in this animal model show that administration of a human monoclonal antibody might offer a feasible and effective prophylaxis for the control of human SARS coronavirus infection.

Figure 1

Binding of CR3014 monoclonal antibody to viral peplomers of SARS coronavirus (A, B) and to HEK293T cells expressing glycoprotein spike of SARS coronavirus (C), and in vitro neutralisation of SARS coronavirus strain HK-39849 (D) Incubation with CR3014 led to a dense gold-label of the outer peplomer region of SARS coronavirus strain Frankfurt 1 (A), whereas a control human IgG1 monoclonal antibody did not induce any label (B). Bar indicates 100 nm. (C) Filled histogram=glycoprotein spike of SARS coronavirus, strain Frankfurt 1. Open histogram=control plasmid.

Figure 2

SARS coronavirus replication in lung tissue (A), shedding of SARS coronavirus in pharyngeal secretions (B), and macroscopic lung pathology (C,D) in ferrets (A) SARS coronavirus titres in lung homogenates on day 4 after challenge shown as TCID₅₀/mL. Horizontal bars indicate mean values. Dotted line shows lower detection limit of assay.(B) SARS coronavirus excretion measured by RT-PCR in pharyngeal swabs expressed as SARS coronavirus equivalents (eq), which equal TCID₅₀. One animal in the CR3014 group, indicated by open circles, shed virus. (C) All CR3014-treated ferrets were free from macroscopic lung pathology, whereas all control ferrets showed multifocal lesions. (D) Left formalin-fixed lung (inflated with formalin by intrabronchial intubation)of a control ferret, with multifocal lesions (asterisks).