ISOLDA aims at the development of improved vaccines for older adults against viral diseases with highest burdens at old age, by promoting virus-specific T cell responses in vaccinees over 65 years, using modulators of T cell immunosenescence and inflammageing. It builds on leading interdisciplinary expertise and knowledge of ISOLDA partners in virology, (onco-)immunology, ageing and immunosenescence, to assess the potential of immunomodulators, including kinase inhibitors licenced for other human use, to improve vaccine-induced immune responses and safety in older adults. ISOLDA partners have shown that these compounds may indeed restore key immunosenescent signatures. They will investigate ex-vivo signatures of immunological ageing and restoring potential of selected compounds on vaccine-induced immune responses against influenza virus, using PBMC from past and on-going adult and ageing human cohorts of influenza vaccinees. Cohorts of vaccinees and/or patients for tick-borne encephalitis, Middle-East respiratory syndrome and SARS-CoV-2 are also uniquely available to ISOLDA to demonstrate broad applicability of the approach. The most promising compounds will be tested in in-vivo animal models for vaccination against these diseases. As a proof of concept, ISOLDA will aim at improving the efficacy of a licensed vaccine against a respiratory virus, up to Phase I or II clinical trial with a lead immunomodulator compound or combination of compounds added to the vaccine formulations. The choice of Phase I or Phase II study design will depend on the compound, which will be selected based on results obtained upon prior in-vitro testing and in vivo testing in animal models. Promising SMKIs and/or oleic derivatives will be combined with a licensed MF59®-adjuvanted and a non-adjuvanted seasonal influenza vaccine for a Phase I, required to establish safety for this innovative combination. Alternatively, licensed MF59® will be selected as the lead compound, and administered as licensed seasonal influenza vaccines with and without MF59® and co-administered with licensed mRNA SARS-CoV-2 S vaccine. In this case, a Phase II study will be initiated to evaluate the immunogenicity in older adults aged 65 and older. ISOLDA will further build on new generation vaccines against MERS and/or COVID-19, such as replication-competent propagation-deficient replicons and MVA-MERS S recently developed by ISOLDA partners. Taken together, ISOLDA will address call SC1-BHC-14-2019, by providing innovative solutions to reduced efficacy and safety of preventive vaccines in the increasing population of older adults, against viral infections that have the highest impact in this age group.

Hematopoietic stem cells (HSC) are an elusive cell type, whose presence can only be inferred retrospectively, from the outcome of time-consuming transplantation experiments. Since current state-of-the-art does not allow prospective HSC identification, today’s cell and gene therapy technology has been mostly optimized on surrogate progenitor cells, which differ biologically from HSC. The technological breakthrough of this proposal is to capture HSC in the ex vivo culture, achieved by a combination of innovative expansion conditions, iterative cell sorting and multiomics single cell profiling. Rapid, quantitative and qualitative in vitro HSC assessment predictive of in vivo function may become a sustainable alternative to mouse xenotransplantation experiments. Applied to a state-of-the-art toolbox of genetic engineering technologies including clinically-proven lentiviral vectors as well as established and emerging targeted genome editing approaches, our in vitro HSC readout sets new standards in terms of throughput and turnaround time, allowing to efficiently test a multitude of HSC engineering conditions and tailor the most suitable technological approach to a specific disease or therapeutic application. This new precision-based approach to ex vivo HSC gene therapy will be applied to inherited bone marrow failure syndromes and cancer as paradigmatic examples where gene therapy may be used to correct a cell-intrinsic genetic defect or turn hematopoietic progeny into therapeutic vehicles provided with novel functions. Bringing together experts in cutting-edge gene editing technologies, ex vivo HSC manipulation, assessment of HSC responses to genetic engineering and bioinformatics analysis & integration of multi-dimensional single cell data will maximize the chances of delivering safer and more effective next-generation HSC-based gene therapy products, extending the reach of gene therapy to new disease contexts and making the outcome after gene therapy more predictable.

Medical implants have revolutionised healthcare by improving quality of life through replacing missing structures, restoring function, and promoting tissue regeneration. However, implant-associated infections (IAIs) undermine these benefits, particularly in orthopaedics, otology, and odontology, leading to chronic issues and substantial healthcare costs. IAIs, exacerbated by biofilm formation and antimicrobial resistance, pose a significant public health challenge. The SHIELD doctoral network aims to advance our understanding of IAIs, from their multifactorial pathogenesis to the development of new antibacterial biomaterials, bridging the gap between basic research and practical applications. SHIELD is structured around three scientific pillars to advance IAI control strategies in orthopaedics, otology, and odontology: regenerative medicine, biomaterial science, and translational research models. These pillars drive research on therapeutic strategies, innovative biomaterials, and experimental proof-of-concept models. The network focuses on clinical studies, antimicrobial strategies for implants, and preclinical models to study IAI mechanisms. Our goal is to train 16 young researchers through an interdisciplinary and translational approach, combining basic research with preclinical and clinical testing. In collaboration with 27 partners from 11 countries, SHIELD brings together expertise from multiple disciplines to bridge the gap between research and real-world applications. By developing new antimicrobial solutions for implants and conducting bench-to-bedside research, SHIELD aims to improve infection management protocols and patient care, significantly advancing the field of infection control in medical devices.

Hospital wastewater (HWW) poses a significant environmental and health risk due to the presence of pharmaceuticals, pathogens, and other hazardous substances that are administered in healthcare institutions. Unfortunately, current urban wastewater treatment (WWT) plants are not capable of effectively removing many of the pollutants generated by hospitals. As a result, these contaminants reach and accumulate in natural water bodies, threatening ecosystems and biodiversity, and public health through the contamination of drinking water or food. In addition, public health is also menaced by HWW as it contains important amounts of antibiotic-resistant microorganisms and genes. In fact, Antimicrobial Resistance (AMR) is one of the greatest health threats of our times. While most common medicines are consumed in households, specialized drugs such as cytostatic drugs, some antibiotics, or X-ray contrast agents are mainly distributed in hospitals. Furthermore, HWW is a hotspot for the transmission of antibiotic-resistant bacteria (ARB) and antibiotic-resistant genes (ARG). To reduce the risk associated to these contaminants, it is key to remove them as close to their source as possible, and before they are discharged to the municipal water network. Despite the existence of different technologies that efficiently remove contaminants from HWW, currently, there is no single process that can be used for the comprehensive treatment of HWW regarding the elimination of a mix of pollutants to a high degree. Moreover, technology may be further developed to be more efficient, environmentally sustainable, and cost-effective for hospitals. In this context, the main objective of THERESA PCP is to launch a pre-commercial procurement process (PCP) based on the development of an environmentally sustainable on-site system to decontaminate HWW, being capable of effectively removing, among other contaminants, cytostatic drugs, X-ray contrast agents, antibiotics, ARB and ARG, from HWW.