The host defense, especially the adaptive immunity, is defective in the elderly, with a dramatic drop for the efficacy of vaccination with old age. Interestingly however, the innate immunity of older individuals is relatively intact, and we recently described that epigenetic and functional reprogramming of innate immune cells by certain vaccines and mild infections, termed ‘trained immunity’, induces potent heterologous protection against infections. I propose that induction of trained immunity is an important novel approach to improved vaccination in the elderly. Induction of trained immunity is regulated by the interaction between the host genome, microbiome, and the epigenetic and metabolic programs of specific populations of myeloid cells, and we need to understand how these factors are impacted by age and gender of the host. By understanding the factors that impact the response to BCG (Bacille Calmette-Guerin), the prototype vaccine that induces trained immunity, we will be able to design better vaccines for the elderly. The Key objectives of the project are: Key objective 1: To describe the innate immune cell (sub)populations, and their heterogeneity at single-cell level, responsible for mediating trained immunity in the young and elderly adults. Key objective 2: To identify the complex genetic, epigenetic, microbiome, and metabolic programs that represent the molecular and biochemical substrates of trained immunity in the myeloid cells of the elderly individuals. Key objective 3: To use systems biology to map the heterogeneity of trained immunity response determined by host (epi)genome, microbiome, and environmental factors in the elderly. Expected results: We will understand the main cellular and molecular mechanisms for the induction of trained immunity responses in vivo and the specificities of the response in the elderly. These findings will enable the design of innovative approaches to improve vaccination strategies.

The highly contagious SARS-CoV-2 virus has generated an unprecedented pandemic with global dramatic public health and socio-economic consequences need an urgent mitigation. Despite the progression of the global use of efficient vaccines, an increased transmissibility of variants of concern (VOC) is predominantly observed. The reduced sensitivity of VOCs to neutralizing response could become a serious obstacle for efficient vaccination. In the absence of approved specific antiviral therapies for vaccinated-non-responders and the scarce anti-inflammatory therapies, passive immunotherapies with polyclonal immunoglobulins could be considered a part of the solution. The main objective of EPIC-CROWN is to rapidly assess, in multicentric clinical trials (phase IIa, 16 patients and IIb, 400 patients), an EMA-authorized antiviral immunotherapy based on potent and broad equine neutralizing anti-SARS-CoV-2 polyclonal F(ab’)2 antibodies in COVID-19 patients, including VOC carriers. In order to save lives and reduce the use and costs of critical care, this therapeutic solution expect to reduce at least by 50% ICUs admissions and a highly significant mortality rate of treated patients. To optimize the indications for the treatment, potency and breath of F(ab’)2 against variants will be assessed in in vitro and in an animal model as well as prospective studies will respectively be done on immune assessment in treated patients and on mitigation of exacerbated immune responses in vivo. Fab’entech will coordinate EPIC-CROWN-2 formed by outstanding experts in different project domains that include clinical trials (HISS, Greece), virology (IMAS12, Spain), and immunopathology models and mitigation (BNITM, Germany - IRD, France). Most of them having already been working together in European projects. Importantly, EPIC-CROWN-2 will be integrated as part of both the large European trial network EU-RESPONSE and the multinational European Adaptive Platform Trial “Solid Act".

Challenges. The incidence of cardiovascular diseases (CVD) increases after infections, but causal mechanisms are not understood yet. Pneumonia, which can be acquired in the community (such as flu and COVID-19) or during hospitalization, is a leading cause of infectious diseases. The main idea of the Homi-lung project is to investigate the causal relationship between CVD progression and the immune and microbiome alterations observed after pneumonia. Objectives. During the Homi-lung project, we aim to i) define the medical and societal, and patient needs; ii) increase medical doctor’s knowledge of the physiological processes linking pneumonia and CVD; iii) enable early identification of patients at risk of CVD progression; and iv) preclinically develop new treatments. Implementation. The Homi-lung project will address this challenge by comparing CVD rates between patients cured of pneumonia and matched patients who had not developed pneumonia during a prospective 3-year follow-up. We will analyze longitudinal samples collected in these populations and develop new algorithms by artificial intelligence to associate host-microbiome interactions with CVD progression. We will also demonstrate the causal link between CVD progression and host-microbiome interactions in preclinical pneumonia models. The interdisciplinary and ambitious Homi-lung project brings together 8 partners from 5 EU countries, with expertise in pneumonia, CVD, immunology, microbiome, and artificial intelligence and is uniquely placed to reach these objectives. Impacts. The project will provide clinicians with robust evidence contributing to identifying patients at risk of CVD after pneumonia. By developing new biomarkers and preclinical validating treatments to TRL4, the project will contribute to improving patients’ recovery and reducing the burden of infections. This project, particularly timely after the COVID-19 pandemic crisis, will also increase European preparedness for the next pandemic.

The post-acute phase (PAP) of COVID-19, occurring ≥4 months after the acute phase, is associated with an increased risk for the development of non-communicable diseases (NCDs). The risk of complications in this phase does not depend on the severity of the acute phase. In the EU, more than 183 million cases of COVID-19 have been reported and up to 70% of patients suffer reduced organ function in the PAP. Our conservative estimate it that 5% of people who have suffered COVID-19 are at risk of developing NCDs of the pulmonary, cardiovascular and renal systems due to the PAP. To avoid the significant socioeconomic costs related to this burden, POINT will develop knowledge-based biomarkers for prevention and management of NCDs, a virtual twin model that offers clinical decision support, and clinical guidelines and recommendations for the entire health care value chain with special attention to vulnerable groups. We will fulfil an unmet need for knowledge and tools to minimize the risk factors of the PAP at the optimal point in time, when healthcare systems will have to redirect their focus from the acute phase of COVID-19 to the post-acute phase. The outcomes of POINT will aid the health care value chain already from an early phase of the project. Furthermore, POINT will correlate and promote knowledge on the development of NCDs in general and the risks of PAP from other infectious diseases. POINT will meet the challenges with a holistic approach from a truly interdisciplinary consortium consisting of clinical experts, molecular biologists, behavioural scientists, and computer scientists, who will take advantage of cohorts of more than 6 million Europeans, and cross-sectional biobanks from more than 6000 Europeans. Researchers will work together with standardisation experts, an end-user organization representing >120.000 physicians, as well as a dedicated partner for data management ensuring rapid absorption of the outcomes of the project by all stakeholders.

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.