Virology and aerosol science of IAV infection, explusion and transmission

SUMMARY – Project 1 Influenza viruses can travel between individuals via fine and coarse aerosols, droplets, and fomites, but the relative contributions of these different modalities remain unknown. Critically, each mode presents very different challenges for prevention. Animal models have provided important insights into influenza virus transmission, but critical knowledge gaps remain to understand the complexity of transmission between humans. Examination of susceptibility, shedding, and transmission in humans over the course of an infection in an experimentally controlled setting is needed to define relationships between viral shedding, the release of infectious virus into the air, and the potential for onward transmission. In Project 1 of this P01 proposal, we will apply virological and aerosol assessments to participants experimentally infected with influenza A virus in the context of an independently funded clinical trial. Importantly, we have had an opportunity to collect preliminary data from recent human challenge experiments performed at Emory University Hospital. These studies have 1) identified heterogeneity in viral shedding based on anatomical site, 2) detected infectious viruses expelled into the air by infected persons, and 3) revealed the presence of multiple genetic variants in the inoculum and within individuals, allowing us to monitor variant frequencies over time, at different anatomical locations, and during expulsion into the environment. These data will enable the identification of source populations of virus expelled into the air that could facilitate onward transmission. The proposed research will build on these successes to fulfill three Specific Aims. Aim 1 will evaluate the spatiotemporal dynamics of influenza A virus replication within humans exposed via three different routes (intranasal, aerosol, and natural exposure). We will characterize the spatial and temporal structure of viral populations replicating within challenge participants and use next generation sequencing to evaluate viral evolutionary dynamics within and between infected individuals. Aim 2 will define the characteristics and modulators of influenza A virus expulsion into the environment from infected individuals. Specifically, we will relate the size distribution of respiratory aerosol particles generated by participants to their infectivity and define features of infection and immune responses that modulate infectious aerosol production. Finally, Aim 3 will model exposure of uninfected participants to their infected counterparts to define secondary attack rates in a setting of experimental challenge with influenza A virus. Through these Aims, we will advance understanding of IAV dynamics in the human host, deliver much-needed quantitative insight into the incorporation of IAV into aerosols, and gain primary insight into transmission and the feasibility of modeling transmission in an experimental human challenge system.