Recent pandemics showed Europe how serious health threats can be to society. Proactive approaches are needed to ensure that medical countermeasures are available during pandemics. PROACT EU-Response’s overarching objective is to prepare Europe for future pandemics by strengthening upon existing networks of experts and civil society focused on clinical therapeutic platform trials within hospital inpatient settings across Europe. In case of an outbreak, this network will provide capacity to pivot rapidly to implement large, multi-country platform trials studying therapeutics and diagnostic-tool performance. Underpinned by strong community involvement and further strengthened by the inclusion of social and implementation scientists, PROACT EU-Response centres on six objectives: expand a solid network of clinical centres across Europe that will implement a clinical trial assessing a syndromic approach for respiratory viral infections; strengthen a laboratory network to identify pathogens and biomarkers of disease monitoring for routine surveillance; support a network of methodologists and trialists who will ensure the trials’ logistical and methodological aspects; initiate a network of professionals to work on preparedness tools to ensure a smooth pivot from inter-pandemic to the pandemic period in case of an outbreak; build a network of social science researchers who will provide nuanced understanding of the social contexts; and establish a community group to work on activities that will empower patients and citizens in Europe regarding their own health and educate them about science and health issues. By bringing together scientists, social science researchers, and civil society members, PROACT EU-Response will benefit the entire European population and beyond through decreased mortality and morbidity associated with emerging diseases, lower societal economic costs of morbidity, strengthened research and innovation expertise, human capacities, and know-how for combatting communicable diseases.

The consequences of SARS-CoV-2 exposure range from a lack of infection to lethal COVID-19. This immense inter-individual clinical variability is the key scientific and medical enigma in the field. While age and certain co-morbidities are known to influence disease outcome, these parameters do not explain all variation. In addition, there are other SARS-CoV-2 phenotypes of clinical importance: multisystem inflammatory syndrome in children and adults (MIS-C/A), and longCOVID. An important breakthrough to unravel the pathogenesis of COVID-19 came from our two Science papers that were recognized by Nature among the top 10 discoveries of 2020. We found that about 4% of patients with critical COVID-19 pneumonia had inborn errors of immunity (IEI) that impair TLR3- and IRF7-dependent type I interferon (IFN) immunity and at least 10% of the patients carried pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs. These findings pave the way for further studies of COVID-19 pneumonia and other SARS-CoV-2 infection phenotypes and form the basis of the present research proposal, UNDINE, which follows a "bed side to bench" and "bench to bed side" approach, with the following objectivies i) to decipher the genetic and immunological basis of the various SARS-CoV-2 disease manifestations, to identify individuals at increased risk of critical COVID-19, post-infectious immunological complications, and vaccine failure iii) to develop ready-to-use diagnostic tests for large-scale detection of auto-Abs to type I IFNs and propose novel preventive and therapeutic approaches, based on the pathogenesis of SARS-CoV-2 infection for translation into personalised medicine. To achieve these goals, our project will coordinate a European multidisciplinary and translational research effort relying on a strong and synergistic combination of assets, including unique cohorts from 11 EU countries and state-of-the art human genetic, immunological and virological expertises and technologies.

The management of febrile patients is one of the most common and important problems facing healthcare providers. Distinction between bacterial infections and trivial viral infection on clinical grounds is unreliable, and as a result innumerable patients worldwide undergo hospitalization, invasive investigation and are treated with antibiotics for presumed bacterial infection when, in fact, they are suffering from self-resolving viral infection. We aim to improve diagnosis and management of febrile patients, by application of sophisticated phenotypic, transcriptomic (genomic, proteomic) and bioinformatic approaches to well characterised large-scale, multi-national patient cohorts already recruited with EU funding. We will identify, and validate promising new discriminators of bacterial and viral infection including transcriptomic and clinical phenotypic markers. The most accurate markers distinguishing bacterial and viral infection will be evaluated in prospective cohorts of patients reflecting the different health care settings across European countries. By linking sophisticated new genomic and proteomic approaches to careful clinical phenotyping, and building on pilot data from our previous studies we will develop a comprehensive management plan for febrile patients which can be rolled out in healthcare systems across Europe.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, and is characterized by a high mortality of up to 30-40%. Treatment of sepsis was revolutionized by two steps that significantly decreased mortality: antibiotics and the intensive care units. It has been hoped that a third revolution, immunotherapy, would further improve outcome of sepsis, but this hope did not materialize. This was due to the incompletely understood pathophysiology, and the heterogeneity of the immune status in different sepsis patients. We propose that while both overinflammation and immunoparalysis are important, they are present in individual sepsis patients.The mission of the present project is to design and perform a proof-of-concept clinical trial of personalized immunotherapy in sepsis, and within this clinical trial, to develop a next-generation theranostics platform for the design of future personalized immunotherapy trials in sepsis. This theranostics platform would be based on an integrated, multidimensional systems biology analysis of omics-based datasets, to identify biomarkers, clinical endotypes, and therapeutic targets for precision medicine approaches. In order to achieve the mission proposed, several complementary aims will be pursued: Aim 1: To design and perform a large personalized immunotherapy trial in sepsis patients, that can provide a clinical answer towards the usefulness of currently employed immunotherapies for sepsis. Aim 2: To chart host genome, epigenome, transcriptome, metabolome and microbiome in at least 180 sepsis patients enrolled in Aim 1 over a defined time course. Aim 3: To use a theranostics approach based on the data provided by Aim 2 to design novel personalized immunotherapeutic strategies. Aim 4: To integrate the clinical and psychological aspects involved when introducing novel immunotherapies for infections in the health care systems of European countries, building bridges with the patient community.

Antimicrobial resistance (AMR) is of great public health concern, causing numerous losses of lives worldwide and threatening to reverse many of the considerable strides modern medicine has made over the last century. There is a need to stratify antibiotic and alternative treatments in terms of the actual benefit for the patient, improving patient outcome and limit the impact on AMR. High quality, effective and appropriate diagnostic tests to steer appropriate use of antibiotics are available. However, implementation of these tests into daily healthcare practice is hampered due to lack of insight in the medical, technological and health economical value and limited knowledge about psychosocial, ethical, regulatory and organisational barriers to their implementation into clinical practice. VALUE-Dx will define and understand these value indicators and barriers to adoption of diagnostics of Community-Acquired Acute Respiratory Tract Infections (CA-ARTI) in order to develop and improve health economic models to generate insight in the whole value of diagnostics and develop policy and regulatory recommendations. In addition, efficient clinical algorithms and user requirement specifications of tests will be developed fuelling the medical and technological value of CA-ARTI diagnostics. The value of diagnostics will be tested and demonstrated in a unique pan-European clinical and laboratory research infrastructure allowing for innovative adaptive trial designs to evaluate novel CA-ARTI diagnostics. Close and continuous interaction with the VALUE-Dx multi-stakeholder platform provides for optimal alignment of VALUE-Dx activities with stakeholder opinions, expert knowledge and interests. A variety of dissemination and advocacy measures will promote wide-spread adoption of clinical and cost-effective innovative diagnostics to achieve more personalized, evidence-based antibiotic prescription in order to transform clinical practice, improve patient outcomes and combat AMR.