A computationally designed hemagglutinin stem-binding protein provides in vivo protection from influenza in the ferret model.

Abstract

Abstract Influenza viruses cause thousands of deaths worldwide and remain a prominent public health issue. Currently, the influenza vaccine is the best tool available at protecting against infection, but the correct strains are hard to predict and the vaccines do not always work. More effective antiviral drugs are needed. Protection against influenza by broadly neutralizing antibodies targeted to a highly conserved region in the hemagglutinin (HA) stem shows great potential for immunotherapy. We have investigated the protective efficacy of an engineered protein, HB36.6, that was computationally designed to bind with high affinity to the same region in the HA stem as targeted by broadly neutralizing antibodies. Studies in the mouse model demonstrated that intranasal delivery of HB36.6 affords protection in mice lethally challenged with diverse strains of influenza, both when administered as a single dose of 6.0 mg/kg up to 48 hrs prior to challenge and significantly reduces disease when administered as a daily therapeutic after challenge. The current study was designed to evaluate HB36.6 in the ferret model, comparing prophylactic and therapeutic efficacy of this new antiviral against high dose influenza aerosol challenge. Similar to data obtained in the mouse model, results from these studies demonstrated significant reduction in viral load and clinical signs of disease in ferrets treated with HB36.6 compared to untreated controls or ferrets treated with Tamiflu. Together, these results show that binding of HB36.6 to the influenza HA stem region alone was sufficient to reduce the viral infection and disease process in vivo. These studies demonstrate a potential new class of antivirals for influenza.