Healy, Christopher M.
(2017)
Evaluation of a novel computationally designed prophylactic against pandemic influenza virus in the ferret model.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
The Influenza virus is responsible for hundreds of thousands of deaths and millions of infections worldwide each year. In spite of the annual seasonal influenza vaccine and various therapeutics that currently exist, influenza currently poses a major health hazard to the world’s population. Vaccine efficacy is diminished due to the high mutation rate commonly exhibited by negative sense RNA viruses. This complicates the decision for which strains to include in the yearly vaccine, and often results in poorly matched vaccine and circulating strains. Antivirals are available to combat influenza infection, but are also becoming less effective due to the increasing development of antiviral resistance and the limited selection. The development of improved vaccine strategies and novel antivirals are of critical importance to the public’s health and wellbeing.
Our research group has collaborated with researchers at the University of Washington in the evaluation of computationally designed influenza antiviral binder proteins. These proteins bind to the viral hemagglutinin surface protein and mimic antibodies that are naturally elicited in vivo during influenza infection, and prevent virus from binding and infecting cells by inhibiting the conformational change necessary for viral entry to host cells. Prior work evaluated viral protein binder HB36.6, demonstrating its efficacy against pandemic H1N1 in the ferret model. The present thesis was designed to evaluate an improved, smaller mini-binder that is less toxic and more soluble in the ferret model. Studies were designed to compare intranasal and intratracheal administration of mini-binder A13r33 administered 24 hours prior to aerosol challenge with pandemic H1N1 in ferrets. Our working hypothesis was that the antiviral minibinder A13r33 would result in reduced infection as measured by improved clinical outcome and lower viral loads following virus challenge. Ferrets were monitored for 7 days post infection for clinical, viral and immunological parameters. Results from these studies are presented in this thesis and provide compelling data for further evaluation of broadly protective novel therapeutics against influenza viruses.
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