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 yellow fever 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 clinical proof of concept, ISOLDA will aim at improving efficacy of current seasonal influenza vaccines up to a tiered phase I clinical trial with a lead immunomodulator compound selected from the ex vivo and in vivo studies, that will be added to current vaccine formulations. ISOLDA will further build on new generation vaccines against MERS, 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.

Lessons learned from, and intervention efforts against SARS coronavirus (CoV), MERS-CoV and other emerging viruses provide invaluable information to accelerate the coordinated response against 2019 novel (2019 -n)CoV and the rapid development and manufacture of new diagnostic, prophylactic and therapeutic intervention strategies. A -promising approach to both patient management of emerging viral infections and to better preparedness and response to emerging epidemics is the use of monoclonal antibodies. MANCO aims at contributing to the rapid international response against 2019-nCoV, through preclinical and clinical evaluation of monoclonal antibodies against 2019-nCoV. MANCO will build on and leverage outstanding results from ongoing IMI-funded project #115760 ZAPI, including recently-discovered broadly cross-reactive H2L2 monoclonal antibodies against betacoronaviruses and an established pipeline for rapid identification of specific H2L2 monoclonal antibodies against 2019-nCoV; antibodies that will be selected to proceed to GMP manufacturing in high-yield CHO cell-lines. This project furthermore builds on ZAPI consortium’s experience and expertise for the development and establishment of relevant animal models, to ensure preclinical efficacy and safety, including absence of antibody-dependent enhancement, an issue seen to occur in some immunization studies against feline and SARS CoVs. Based on the generated preclinical data, MANCO will advance one lead (prophylactic and/or therapeutic) monoclonal antibody into a Phase I clinical trial that can be completed within two years of the start of the project, by leveraging clinical expertise, infrastructure and network currently in place for ongoing CEPI-funded projects on candidate vaccines against MERS-CoV (#INID1801) and Rift Valley Fever virus (#INLA1901), and H2020-funded projects on improved vaccines targeting the elderly (ISOLDA #848166) and on universal influenza vaccines, including in LMICs (ENDFLU #874650).

ENDFLU will develop three complementary next-generation influenza vaccination strategies for the world, fueled by the unique combined expertise of Indian and European partners in rational vaccine design and development: • Create a repository of pre-pandemic GMP-compliant MVA-based vaccine seeds, each encoding an influenza hemagglutinin (HA), based on European partners demonstration of clinical safety and cross-clade immunogenicity of MVA-H5. • Optimize and select protein- and MVA-based constructs developed by Indian and European ENDFLU partners, resulting in a rationally combined vaccine formulation that induces broadly protective humoral and cell-mediated immunity against all influenza manifestations. This will be advanced in a Phase I clinical trial and Controlled Human Infection Model (CHIM) study. • Pre-clinically advance other promising protein- and MVA-based constructs toward future development beyond ENDFLU. Constructs to elicit humoral immunity build on rationally-designed and optimized conserved epitopes of influenza surface proteins, HA stem- and HA head-nanoparticles, and NA-M2e fusions either as proteins or MVA expressed. Other MVA-based constructs to elicit cell-mediated immunity will encode conserved internal protein T cell epitopes, as an artificial polyepitope. The best candidates will be selected based on biochemical, biophysical, functional and manufacturing criteria, and immunogenicity and protective efficacy in mice and ferrets. The selected protein-based construct will enter a Part A Phase I clinical trial in India assessing safety, immunogenicity and optimal dose, to be combined with the selected MVA-based construct. This protein-MVA combination will enter a Part B Phase I clinical trial in the EU, assessing safety and immunogenicity, followed by the CHIM study. A dissemination and exploitation plan, and collaboration with key scientific advocacy organizations will facilitate the adoption of ENDFLU achievements to combat influenza worldwide.

GLORIA aims to prove that the addition of chronic low dose glucocorticoids (GC) to current antirheumatic therapy is highly cost-effective and safe in elderly patients with rheumatoid arthritis (RA). RA is a frequent (affecting > 2% of the elderly population), painful and disabling chronic disease with high societal costs. RA is associated with multiple comorbidities, polypharmacy and adverse events; these problems, together with challenges in compliance (adherence) are dramatically increased in the elderly population. About 50% of patients are chronically treated with low-dose glucocorticoids (GC) in combination with other antirheumatic drugs, but without good evidence on the balance of benefit and harm. Thus, existing guidelines and information on safety and efficacy of GC are inadequate. GLORIA will address these problems by conducting a large pragmatic trial: 800 elderly (>65y) RA patients receiving standard of care will be randomized to additionally receive 5 mg prednisolone daily or placebo for 2 years. Very liberal eligibility criteria will ensure representativeness to the target population, and most data will be collected from routine clinical practice, minimizing patient and physician load, and operating costs. A novel tool will monitor compliance; it can send personalized reminders to a patient’s smart device. The efficacy of this technology will be tested in a nested trial. Compliance and other characteristics will be entered into a model that will allow personalized risk and benefit assessment in the future. Qualitative research in patients and physicians of member states will explore expectations and challenges in guideline implementation. This information and the study results will enable an update to existing guidelines and patient information, in collaboration with guideline committees and regulatory agencies. Networking conferences will improve health technology assessment in the elderly in general.