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Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic: ORCHESTRA

Periodic Reporting for period 2 - ORCHESTRA (Connecting European Cohorts to Increase Common and Effective Response to SARS-CoV-2 Pandemic: ORCHESTRA)

Berichtszeitraum: 2022-06-01 bis 2023-11-30

The COVID-19 pandemic created an urgent demand for evidence-based innovative and rapid solutions to advance the knowledge on the control of the SARS-CoV-2 pandemic, to provide optimized treatment for COVID-19 patients and to inform on longer-term consequences of COVID-19 on health and well-being of individuals. Moreover, the roll out of widespread vaccination campaigns, the emergence of viral variants, and the introduction of preventive and therapeutic options have underlined the importance of creating a research infrastructure capable of adapting to the evolving epidemiological scenario and flexible enough to capture and adjust to the constantly emerging evidence (therapeutic response, clinical outcomes, vaccine response, onset of long-term sequelae, social and economic consequences).

The overall objective of the ORCHESTRA project, therefore, is the creation of a new pan-European cohort (general population, COVID-19 patients, fragile individuals, and healthcare workers) applying homogenous data collection, data sharing and sampling protocols, to provide evidence-based recommendations on the control and management of the SARS-CoV-2 pandemic and to contribute to preparedness in case of future public health threats.
The project builds upon existing and new large-scale population-based cohorts in Europe (France, Germany, Spain, Italy, Belgium, Romania, Netherlands, Luxemburg, and Slovakia) and non-European countries (India, Perú, Ecuador, Colombia, Venezuela, Argentina, Brazil, Congo, and Gabon) and involves also fragile individuals (children, transplanted, oncological, HIV infected, and those with Parkinson or rheumatologic disease), and healthcare workers. ORCHESTRA includes more than 80 cohorts (WP2: COVID-19 and post-COVID-19 syndrome, WP3: population based, WP4: fragile population, WP5: healthcare workers) that prospectively enrolled more than 500 000 individuals. The COVID-19 WP2 includes also a unique prospective cohort of fragile outpatients enrolled at early treatment of COVID-19 with monoclonal antibodies. The ORCHESTRA retrospective cohorts include 2 350 000 subjects’ data.

To support data sharing and implementation of standards among different European cohorts, a federated learning infrastructure has been developed in accordance with the General Data Protection Regulation (GDPR). The project proceeds with its work of fostering common semantics by establishing standardised variables’ definitions which now reached 3 730 variables in total. Major results of the studies run within the ORCHESTRA cohorts, which substantially added to the existing evidence on the topics, include identification of clinical phenotypes and preventive factors of post-COVID-19 syndrome in adults, children, and pregnant women, assessment of immune response and its drivers after multiple vaccine doses in different fragile populations, in population-based cohorts and in healthcare workers, socio-economic consequences of COVID-19 in fragile subjects and low- and medium-income countries, preventive factors of breakthrough infections, and advanced analysis of impact of respiratory and intestinal microbe on severity of COVID-19.

As a distinctive characteristic of the ORCHESTRA project, the cohorts continued to evolve with collaborative agreements being forged with new, external cohorts. Collaboration with other EU projects has also intensified thanks to the leadership of ORCHESTRA in the Cohort Coordination Board which currently comprises 12 EU projects and 2 national cohorts. Collaboration takes place at multiple levels including exchange of deliverables to foster greater consistency across projects, sharing of methodological approaches of benefit to all EU projects (e.g. data harmonisation) and networking activities where ORCHESTRA has used its wide platform of 26 partners and extensive cohorts to support the dissemination activities of other EU projects. The dissemination of the results of the ORCHESTRA project targeted scientific community with more than 90 publications in peer-reviewed journal and the public with videos, podcast, and newspapers interviews.
The innovation of the ORCHESTRA project lies in the development of a common language for different cohorts and populations in Europe, which has simplified enormously the opportunities to develop the evidence needed for Public Health interventions and clinical recommendations.

Among major results, using machine learning techniques, the project prospectively identified, for the first time to the best of our knowledge, four distinct clinical phenotypes (respiratory, chronic fatigue-like, neurosensorial, and chronic pain) in the post-COVID-19 syndrome (PCS) with different determinants and impact on quality of life and described severe PCS. The data has contributed to the understanding and management of PCS and has provided substantial information to drive the selection of high-risk population for the development of the PCS to be enrolled in clinical trials assessing new treatments.

The project also highlighted how early therapy with monoclonal antibodies significantly reduced crude mortality, hospitalisation, and the risk of development of PCS. Microbiological and immunological analyses showed however that these treatments lead to an increased mutation rate of SARS-CoV-2, highlighting a new and specific side effect of this class of drug of relevance for patients and at the level of public health policies.

The fragile cohort of ORCHESTRA includes different patients’ populations longitudinally followed since the first dose of vaccine administration till 18 months. By demonstrating the heterogeneity of the humoral response after mRNA vaccines among different fragile patients, the results have been valuable to support public health decisions in terms of booster dosages and for recommendations regarding monitoring immunisation status in vulnerable patients.

Population-based ORCHESTRA cohorts provided estimates of risk factors and indicators of COVID-19 infection, intra-household transmission, viral spread, prevention measures, geographic factors (including small area social deprivation and pollution exposure), socio-demographic factors, and medical history through precise estimations of seroprevalence, to improve epidemiological models of diffusion of epidemic diseases, together with estimates of number of contacts and risk of transmission.

Detailed characterisation of the serological response of HCW following SARS-CoV-2 vaccination has been performed to an extent not attained in previous studies. The analysis showed that the risk of breakthrough infection after vaccine booster dosage is significantly reduced by the number of previous infections, heterologous vaccination, and older age. Time elapsed from vaccine booster dose affects breakthrough infection severity.

The cohort studies have been extended to cover the follow-up of included patients to 24-month from SARS-CoV-2 infection diagnosis, to proceed further with the collection of clinical and epidemiological data and biobanking to increase the accuracy of the already developed new definition of PCS, and to produce new evidence for severe PCS and related immunological, virological, and genetic predisposing factors.
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