Abstract
BackgroundThe urgent medical need for innovative approaches to control influenza is emphasized by the widespread resistance of circulating subtype H1N1 viruses to the leading antiviral drug oseltamivir, the pandemic threat posed by the occurrences of human infections with highly pathogenic avian H5N1 viruses, and indeed the evolving swine-origin H1N1 influenza pandemic. A recently discovered class of human monoclonal antibodies with the ability to neutralize a broad spectrum of influenza viruses (including H1, H2, H5, H6 and H9 subtypes) has the potential to prevent and treat influenza in humans. Here we report the latest efficacy data for a representative antibody of this novel class.Methodology/Principal FindingsWe evaluated the prophylactic and therapeutic efficacy of the human monoclonal antibody CR6261 against lethal challenge with the highly pathogenic avian H5N1 virus in ferrets, the optimal model of human influenza infection. Survival rates, clinically relevant disease signs such as changes in body weight and temperature, virus replication in lungs and upper respiratory tract, as well as macro- and microscopic pathology were investigated. Prophylactic administration of 30 and 10 mg/kg CR6261 prior to viral challenge completely prevented mortality, weight loss and reduced the amount of infectious virus in the lungs by more than 99.9%, abolished shedding of virus in pharyngeal secretions and largely prevented H5N1-induced lung pathology. When administered therapeutically 1 day after challenge, 30 mg/kg CR6261 prevented death in all animals and blunted disease, as evidenced by decreased weight loss and temperature rise, reduced lung viral loads and shedding, and less lung damage.Conclusions/SignificanceThese data demonstrate the prophylactic and therapeutic efficacy of this new class of human monoclonal antibodies in a highly stringent and clinically relevant animal model of influenza and justify clinical development of this approach as intervention for both seasonal and pandemic influenza.
Highlights
A novel class of human monoclonal antibodies against influenza has been recently discovered [1]
CR6261 represents a new class of human monoclonal antibodies that exhibits immediate and potent efficacy for the prevention or treatment of influenza in a clinically relevant model for severe disease
The results presented here confirm previously reported data demonstrating the prophylactic and therapeutic efficacy of CR6261 in mice challenged with H5N1 influenza viruses
Summary
A novel class of human monoclonal antibodies against influenza has been recently discovered [1]. Due to the high conservation of their recognition site, this class of antibodies has shown the ability to neutralize a broad spectrum of influenza subtypes, including H1, H2, H5, H6 and H9 [1], and can be expected to neutralize viruses from subtypes H4, H8, H11–H14 and H16, as well as their future antigenic drift variants [2]. One of these antibodies, CR6261, was investigated in mice and shown to be protective when given before and after lethal challenges with H1N1 and H5N1 virus, suggesting that it has potential as the first-ever broad-spectrum monoclonal antibody for prophylaxis and treatment of influenza virus infections [1]. We report the latest efficacy data for a representative antibody of this novel class
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