The ORCHESTRA project provides an innovative approach to learn from the SARS-CoV-2 health crisis and derive recommendations for increasing preparedness for future outbreaks. The main outcome of the project is the creation of a new pan-European cohort built on existing and new large-scale population cohorts in European and non-European countries. Data analysis through a federated learning technique supported by advanced modelling capabilities will allow the integration of epidemiological, clinical, microbiological and genotypic aspects of population-based cohorts with environment and socio-economic features. The ORCHESTRA cohort will include SARS-CoV-2 infected and non-infected individuals of all ages and conditions and thereby enabling a retrospective evaluation of risk factors for the disease acquisition and progression of the disease and prospective follow-up aimed at exploring long term consequences and analysis of vaccination response. To better address these research questions, the ORCHESTRA-cohort will include adequately sampled representatives of general populations, COVID-19 patients and special ‘at risk’ populations of fragile individuals and health-care workers. The project aims also to evaluate how the acquisition of SARS-CoV-2 variants impacts on the severity of disease. ORCHESTRA will specifically assess the immunity function status in vaccinated and not vaccinated health care workers, including assessment in-between the first and the second dosages of any available vaccine and explore differences in level and durability of antibody immune responses and frequency of breakthrough infections (symptomatic and asymptomatic) in fragile population (e.g oncological, transplanted, hematological, HIV-infected and suffering from Parkison disease). The understanding of the evoked immune response by population, variants and type of vaccine are key to better understand how vaccines againstSARS-CoV-2 variants can prevent transmission and severe SARS-CoV-2 infections, why certain variants may be able to escape vaccines, and whether refresher boosters at regular intervals could change any of these outcomes. The participation of non-European and Low-Medium Income Countries and a Global COVID-19 Guidance group of major stakeholders and investigators from successful clinical trials addressing therapeutic approaches to COVID-19, ensures inclusion of all expertise needed and translation of recommendations to different social and economic settings. The project will significantly impact on the responsiveness to SARS-CoV-2 and can be used as a model for responsiveness for new public health threats.