FOREWARN will assess the occurrence, fate and behaviour of contaminants of emerging concern (CECs) and pathogens, and develop machine-learning methods to model their transfer and behaviour and build a decision support system (DSS) for predicting risks and propose mitigation strategies. FOREWARN will be focussed on CECs such as antibiotics and pathogens such as antibiotic-resistant bacteria (ARB), antibiotic resistance genes (ARG) and emerging viruses, such as SARS-CoV-2. The project will consider 2 types of case studies: 1) In-silico case studies will be selected from previous results, and dataset obtained in past or ongoing EU projects. Data will be used to develop the models and algorithms to feed and develop the DSS system to better understanding the sources, transport, degradation of CECs and pathogens and modelling their behaviour. 2) The adaptive DSS system will be refined and tested under real environmental conditions (6 months) to achieve TRL5 in real environment case studies.

The overall goal of the “IL-12 for HAP” proposal is to prepare an application in response to the call SC1-BHC-14-2019 ‘Stratified host-directed approaches to improve prevention, treatment and/or cure of infectious diseases’. Specifically, we propose to investigate the efficiency of recombinant human interleukin 12 for the treatment and the prevention of hospital-acquired pneumonia. Hospital-acquired pneumonia (HAP) are the most frequent cause of hospital-acquired infection, with an incidence ranging between 40 cases / 100.000 hospitalisations after major surgery and 10 cases /100 hospitalisations in intensive care units, with no significant decrease over the last decades. HAP have dramatic medical consequences notably prolonged hospitalisation and increased risk of complications for years after the infection resolution and treatment failures are still observed in 33% of patients treated for HAP. The proposal aims to improve the prevention and the treatment of HAP, which are a major concern in Europe and worldwide. HAP is moreover frequently induced by treatment-resistant pathogens, and represents the main cause of antibiotic consumption in hospitalised patients. Increasing rates of multi-drug-resistant bacteria in recent years constitute a serious threat to global public health, and threatens the effective prevention and treatment of an ever-increasing range of difficult to treat infections. By focusing on the role of host factors and immune-modulators, the “IL-12 for HAP” proposal tackles the growing challenge of antimicrobial drug resistance in hospitalised patients, and contributes to the achievement of the European One Health Action Plan against Antimicrobial Resistance. Recent progress in the understanding of the physiology of HAP has paved the way to host-target intervention. Several studies in critically ill patients considered as “immunocompetent” have revealed early and prolonged immunosuppression. The risk of HAP has been correlated with defects in immune cell function, and the involvement of critical illness-related immunosuppression in HAP is now widely accepted. These knowledge advances have yet to be translated into effective therapies and preventive measures. Bringing to the bedside new immune therapies targeting critical-illness related immunosuppression therefore represent a promising avenue to reduce both morbidity and mortality of hospital patients. We have demonstrated that the susceptibility to HAP is a consequence of low NK cells stimulation by myeloid cells, and that IL-12 treatment restores immune competence during secondary pneumonia. We have thus hypothesized that rHuIL-12 is a treatment of the critical illness-related immunosuppression, and that it can decrease the number of episodes and the severity of HAP, and finally limit the utilisation of antimicrobial therapy in hospitalised patients. The “IL-12 for HAP” project aims to i) demonstrate the proof of concept of a new host-targeted treatment with rHuIL-12 treatment to restore immune competence in hospitalised patients, thus improving both prevention and treatment of HAP and ii) and to select relevant biomarkers for patients stratifications into responders and non-responders. To reach this overall aim, the 3 workpackages of the “IL-12 for HAP” proposal are to conduct randomized clinical trials evaluating the safety and efficacy of rHuIL-12 administration to (1) prevent or (2) treat pneumonia in hospitalized patients; (3) to identify and validate biomarkers integrating host-pathogen relationships (high-throughput immunophenotyping and microbiome) to stratify patients into responders and non-responders to rHuIL-12 treatment.