Influenza continues to cause a significant burden of disease globally and in the United States. In the United States alone, it's estimated that in the 2017-2018 season there were 959,000 hospitalizations related to influenza illness, and 79,400 deaths. Worldwide, the World Health Organization (WHO) estimates that annual influenza epidemics cause 3-5 million cases of severe disease, with 290,000-650,000 of these severe cases resulting in death. Although annual influenza immunizations are recommended and antivirals are available, both have several limitations. The efficacy of the seasonal influenza vaccine is compromised by several factors: antigenic changes over time (requiring a strain-specific match each year), slow manufacturing processing, vaccine strain egg-adapted changes, short duration of protection, lack of cross-reactivity, and poor immunogenicity in certain populations (e.g. the elderly). Antiviral agents such as neuraminidase inhibitors are most effective if administered early in the disease course, and even then, have only a modest impact upon the duration of clinical symptoms. Furthermore, data are inconclusive regarding the ability of neuraminidase inhibitors to reduce the risk of complications, such as hospitalizations or progression to pneumonia. Data are needed to better understand correlates of immune protection that could be afforded by influenza vaccination and to test new therapeutics. As such, influenza challenge models can be informative.

Human challenge models have several benefits to traditional models (e.g. animal models) that can advance scientific understanding of influenza infection, the efficacy of influenza vaccination, and the benefits of influenza therapy. Ultimately, discoveries from the influenza challenge model could decrease the morbidity and mortality associated with influenza. Animal models do not directly translate well in predicting baseline human influenza immunity and subsequent immunological responses. Human challenge studies have been successfully conducted historically and offer significant advantages. The human challenge model is efficient (relatively few subjects are required to power a study), immunological responses of humans can be studied directly, and the exact timing of infection is known so that specific time points and measurements are precisely determined, which is especially useful when testing new vaccinations or therapeutics. Human challenge studies for influenza are a particularly attractive modality for the development of a universal influenza vaccine. As outlined by the National Institute of Allergy and Infectious Diseases (NIAID) strategic plan, a universal flu vaccine would be at least 75% effective, maintain protection for at least one year, protect against group I (e.g., H1, H5) and II (e.g., H3, H7) influenza A virus strains, and be effective for all age groups. The strategic plan also states that a human challenge model could offer unique benefits to better understand the concept of imprinting, determine correlates of protection against influenza, and evaluate different universal influenza vaccine candidates.

The goal of this study is to conduct a human challenge study to validate the influenza challenge model at Emory University and better understand influenza pathogenesis, immunity, transmission and evolution. Up to forty healthy subjects will be challenged using a previously validated influenza challenge model with influenza A H3N2 strain (A/Perth/16/2009 H3N2). Participants will take part in the study for 5 months. Enrolled participants will be admitted to Emory University Hospital during which time they will receive the influenza virus in the form of a spray in the nose or breathing in influenza virus through a device followed by an 8-day inpatient stay for observation, or by being exposed to participants already infected with the flu virus followed by a 9 to 12-day hospital stay. Follow-up outpatient visits will take place at the Hope Clinic of the Emory Vaccine Center.