Immunity in the Nose to inFLUENza: Correlates of Efficacy (INFLUENCE)

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The upper respiratory tract is the site of initial infection with respiratory viruses, such as influenza. T cells and antibodies at this mucosal site form local immune memory and are positioned to provide sterilizing immunity. Despite this known importance in preventing infections, mucosal immunity is understudied relative to its peripheral blood counterpart. This has resulted in a weak understanding of the contribution of mucosal immunity to preventing viral infection, and those factors that could be enhanced in next-generation influenza vaccines. This proposal aims to address two major technological limitations that have hindered our understanding of mucosal immunity. Firstly, studies have suffered from a lack of well validated and consistently applied tools for sampling the respiratory mucosa. Nasosorption is a minimally invasive, well tolerated, sampling tool that yields highly reproducible data on the abundance of protein mediators in the human nose. Here, nasosorption will be employed to collect respiratory secretions from healthy control volunteers and analyzed alongside biobanked samples arising from human infection challenge studies of influenza. This first aim seeks to demonstrate the utility of nasosorption as a human nasal sampling tool that can bring a greater level of consistency to future immunology and vaccine efficacy studies. Secondly, studies have suffered from an inability to determine the functional activity of mucosal antibodies. This inability has arisen from the focus of research on systemic immunity, where antibody titres are higher than in mucosal secretions. Existing technologies such as haemagglutination inhibition, neutralization, and antibody-mediated cytotoxicity assays are therefore either insufficiently sensitive or not optimized for use with mucosal samples. To address this technology gap, this proposal aims to develop the use of pseudovirus neutralization and FcγR-dimer binding assays to study the activity of mucosal antibodies against influenza. These technologies are ideally suited to mucosal samples as they have greater sensitivity than classical approaches and can be readily modified to study new antigens as viruses evolve and vaccines emerge. Utilizing samples from human infection challenge studies with wild-type (H1N1) influenza and vaccine-virus (LAIV) samples enables the testing of these technologies in a tightly controlled setting and analysis of the homo- and hetero- subtypic immune responses resulting from infection/vaccination. Finally, the robustness of the developed technologies will be tested to enable widespread dissemination of the techniques, enabling the understanding of mucosal immunity in future studies of influenza vaccines.