During the first 18 months, CLARITY achieved all major planned milestones and made substantial scientific and operational progress. Analysis of human genetic data from the Estonian Biobank led to the identification of approximately 100 protein-coding variants reaching genome-wide significance, predominantly in genes involved in immune and epithelial functions. These findings provide a strong foundation for understanding genetic susceptibility to respiratory disease. Towards identifying and characterizing high risk RSV strains, all preparatory activities for the clinical studies were successfully completed, including ethical approvals. Two complementary studies were initiated: one focusing on young asthma patients with a history of severe RSV infection in infancy and available respiratory samples, and a second aiming to identify RSV strains with an increased capacity to promote asthma development through epidemiological analysis of seasonal RSV variants and long-term outcomes.Experimental studies investigating the role of RSV G and F proteins in bronchiolitis severity and asthma development are progressing as planned. A major early achievement was the generation of a comprehensive, high-quality RSV ORFeome comprising 213 expression-ready open reading frames representing 42 RSV clades. This unique resource enables systematic mapping of RSV–host protein interaction networks and represents a key milestone for downstream functional and systems-level analyses.Towards integration of all generated data, eKorts focused on establishing essential strategies and methodologies needed for later high-throughput analyses. Towards functional studies, major advances were made in setting up functional assays in Utrecht, to study RSV-induced changes in primary nasal organoid cultures. Organoid systems have been successfully established and optimised, and the development of transfection and co-culture strategies is well advanced. Following careful evaluation, organoid-based validation was selected as the primary strategy for testing candidate compounds. This decision ensures feasibility within the project timeframe while maintaining scientific rigor. All major activities remain on track. The next phase of the project will build directly on the foundations that are now established. The project will advance from preparatory and discovery phases into large-scale functional analyses, integration of genetic, virological, and clinical data, to progress towards organoid-based validation of key findings. These eKorts will accelerate the identification of RSV-related mechanisms underlying bronchiolitis severity and asthma development, supporting the translation of project results toward clinically relevant interventions.
