Periodic Reporting for period 3 - ISOLDA (Improved Vaccination Strategies for Older Adults)
Periodo di rendicontazione: 2022-09-01 al 2023-10-31
Ageing is one of the main health-related challenges within the EU, and promoting healthy ageing is a key priority. Increased susceptibility to infectious diseases and their associated complications, related to altered immune responses, threatens the health of older adults. Senescence-related reduced immune function negatively affects the effectiveness of vaccination and contributes to lower protection provided by current vaccines in older adults. Identifying key factors causing poor and/or adverse responses to vaccination in older adults, and devising counter-strategies to circumvent these issues, are essential to improve vaccine-induced immune responses and achieve better vaccination-mediated protection against viral infections in this expanding vulnerable population.
Acute respiratory viral infections are recognized a leading contributor to death and disability in older adults. Among these, seasonal influenza is of major concern, as yearly-recurring epidemics cause by far the highest morbidity and mortality burdens in individuals over 65 years of age. Older adults are often also particularly vulnerable to other respiratory and emerging virus infections. Key examples are caused by viruses with high risk of emergence in Europe, such as Middle-East respiratory syndrome coronavirus (MERS-CoV) and tick-borne encephalitis virus (TBEV). Since the first half of 2020, the emerging SARS coronavirus 2 has resulted in the ongoing pandemic of COVID-19. Here also, older adults have been among the main victims of severe respiratory disease and of complications from the infection, with the highest case-fatality rate reported in this age group.
Immunological ageing is likely a major cause of the reduced potency of current vaccines as well as vaccine failure in the senior population, with two major hallmarks of human immunological ageing being “inflammageing” and T-cell immunosenescence. ISOLDA aims at the development of improved vaccines against viral infections for older adults by promoting virus-specific T cell responses in vaccinees above the age of 65 using modulators of T cell immunosenescence and inflammageing. As a proof of concept, ISOLDA will aim at improving the efficacy of current licensed seasonal influenza vaccines, up to a tiered Phase I clinical trial with a lead immunomodulator compound or combination of compounds added to the vaccine formulations. To demonstrate the broad applicability of the proposed approach, ISOLDA Phase I trial will build on pre-clinical evaluation of key signatures of immunological ageing and of the restoring potential of selected immunomodulators, targeting seasonal influenza virus, an emerging (or pandemic) respiratory virus (MERS- and/or SARS-CoV-2) and an emerging non-respiratory virus (TBEV).
Acute respiratory viral infections are recognized a leading contributor to death and disability in older adults. Among these, seasonal influenza is of major concern, as yearly-recurring epidemics cause by far the highest morbidity and mortality burdens in individuals over 65 years of age. Older adults are often also particularly vulnerable to other respiratory and emerging virus infections. Key examples are caused by viruses with high risk of emergence in Europe, such as Middle-East respiratory syndrome coronavirus (MERS-CoV) and tick-borne encephalitis virus (TBEV). Since the first half of 2020, the emerging SARS coronavirus 2 has resulted in the ongoing pandemic of COVID-19. Here also, older adults have been among the main victims of severe respiratory disease and of complications from the infection, with the highest case-fatality rate reported in this age group.
Immunological ageing is likely a major cause of the reduced potency of current vaccines as well as vaccine failure in the senior population, with two major hallmarks of human immunological ageing being “inflammageing” and T-cell immunosenescence. ISOLDA aims at the development of improved vaccines against viral infections for older adults by promoting virus-specific T cell responses in vaccinees above the age of 65 using modulators of T cell immunosenescence and inflammageing. As a proof of concept, ISOLDA will aim at improving the efficacy of current licensed seasonal influenza vaccines, up to a tiered Phase I clinical trial with a lead immunomodulator compound or combination of compounds added to the vaccine formulations. To demonstrate the broad applicability of the proposed approach, ISOLDA Phase I trial will build on pre-clinical evaluation of key signatures of immunological ageing and of the restoring potential of selected immunomodulators, targeting seasonal influenza virus, an emerging (or pandemic) respiratory virus (MERS- and/or SARS-CoV-2) and an emerging non-respiratory virus (TBEV).
ISOLDA aims at improving the effectiveness of vaccines in older adults, using influenza as a proof of concept. As the COVID-19 pandemic emerged at the start of this project, relevant activities have been conducted on SARS-CoV-2 in parallel. Cohorts have been established and characterized with regard to signs of immunosenescence. Vaccine induced immune responses have been analysed for influenza and COVID-19. For COVID-19 vaccination, the outcome of vaccination correlated with signs of immunosenescence in older adults.
Regorafinib, an inhibitor of various receptor kinases and Raf, induced cellular immune responses after two immunizations in young and naturally aged mice and antibody response after a single immunization with a non-adjuvanted influenza vaccine. Of note, the vaccine with the adjuvant MF59 was superior to unadjuvanted vaccine, especially in aged mice, administered with or without any of the SMKI. These results do not warrantee the further clinical evaluation of SMKI to enhance influenza vaccine-induced immune responses in older adults.
A permissive humanized animal model for SARS-CoV-2 infection has been established and can be used to evaluate immunogenicity and protective efficacy of vaccines with or without immunomodulatory compounds. Immunogenicity and protective efficacy of SARS-CoV-2 virus-like particles (VLP) containing RNA replicon was confirmed in humanized transgenic K18-hACE2 mice. Interestingly, IgA antibodies binding the S protein RBD were detected in bronchoalveolar lavages, providing the proof of concept for the induction of a mucosal immune response that promotes sterilizing immunity. Improved versions of RNA replicons with increased rescue efficiency and stability have been engineered by CSIC by deleting different sets of viral genes. Recombinant SARS-CoV-2 viruses encoding precursors of immunomodulatory miRNAs-138, 181a, 155 and 223 were efficiently rescued in different cell lines and their genomic stability throughout cell passages was confirmed. The expression of the precursor RNAs and processing of the mature miRNAs was confirmed, providing the proof of principle of the delivery of immunomodulatory miRNAs by SARS-CoV-2 genomes. In a second stage, miRNAs will be inserted into the improved final version of replication-competent propagation-deficient RNA replicons developed as vaccine candidates.
Regorafinib, an inhibitor of various receptor kinases and Raf, induced cellular immune responses after two immunizations in young and naturally aged mice and antibody response after a single immunization with a non-adjuvanted influenza vaccine. Of note, the vaccine with the adjuvant MF59 was superior to unadjuvanted vaccine, especially in aged mice, administered with or without any of the SMKI. These results do not warrantee the further clinical evaluation of SMKI to enhance influenza vaccine-induced immune responses in older adults.
A permissive humanized animal model for SARS-CoV-2 infection has been established and can be used to evaluate immunogenicity and protective efficacy of vaccines with or without immunomodulatory compounds. Immunogenicity and protective efficacy of SARS-CoV-2 virus-like particles (VLP) containing RNA replicon was confirmed in humanized transgenic K18-hACE2 mice. Interestingly, IgA antibodies binding the S protein RBD were detected in bronchoalveolar lavages, providing the proof of concept for the induction of a mucosal immune response that promotes sterilizing immunity. Improved versions of RNA replicons with increased rescue efficiency and stability have been engineered by CSIC by deleting different sets of viral genes. Recombinant SARS-CoV-2 viruses encoding precursors of immunomodulatory miRNAs-138, 181a, 155 and 223 were efficiently rescued in different cell lines and their genomic stability throughout cell passages was confirmed. The expression of the precursor RNAs and processing of the mature miRNAs was confirmed, providing the proof of principle of the delivery of immunomodulatory miRNAs by SARS-CoV-2 genomes. In a second stage, miRNAs will be inserted into the improved final version of replication-competent propagation-deficient RNA replicons developed as vaccine candidates.
ISOLDA builds on cutting-edge approaches and leading interdisciplinary expertise and knowledge of the consortium in virology, (onco-) immunology, ageing and immunosenescence, from the use of in vitro and in vivo systems to the conduct of a Phase I clinical trial. The expected results of the project are improved vaccine candidates against influenza in older adults clinically ready for advanced clinical trials, as well as pre-clinical concepts for improved vaccine candidates against COVID-19, MERS and/or TBE in older adults. ISOLDA will contribute to and strengthen Europe’s excellence in research and development.
By the end of the first reporting period, ISOLDA already has pushed progress beyond the state-of-the-art, with the rapid development of a relevant aged model for COVID-19, and the early identification of promising SMKIs against immunosenescence. One candidate proved to be a strong immunostimulatory agent potentially beneficial against other human pathologies beyond infectious diseases, such as cancer. Other tested compounds demonstrated stimulatory activities beyond T cells, towards the activation and differentiation of myeloid dendritic cells. An experimental setup to test effects of SMKIs on influenza A virus T-cell clones was refined and established.
ISOLDA will increase Europe’s capacity to control infectious diseases and reduce the burden of major infectious diseases, such as influenza, COVID-19, MERS and TBE, by contributing to better and tailor-made control strategies for these infections in an expanding section of the population. It will enrich product development pipelines with novel, potentially more effective preventive measures for infectious diseases as well as validated ageing biomarkers with potential for rapid uptake into clinical practice and enhanced innovation capacity. ISOLDA’s approach and results are expected to have strong benefits for society beyond the viral targets of ISOLDA, opening among other benefits, new avenues for the improvement of healthy ageing.
By the end of the first reporting period, ISOLDA already has pushed progress beyond the state-of-the-art, with the rapid development of a relevant aged model for COVID-19, and the early identification of promising SMKIs against immunosenescence. One candidate proved to be a strong immunostimulatory agent potentially beneficial against other human pathologies beyond infectious diseases, such as cancer. Other tested compounds demonstrated stimulatory activities beyond T cells, towards the activation and differentiation of myeloid dendritic cells. An experimental setup to test effects of SMKIs on influenza A virus T-cell clones was refined and established.
ISOLDA will increase Europe’s capacity to control infectious diseases and reduce the burden of major infectious diseases, such as influenza, COVID-19, MERS and TBE, by contributing to better and tailor-made control strategies for these infections in an expanding section of the population. It will enrich product development pipelines with novel, potentially more effective preventive measures for infectious diseases as well as validated ageing biomarkers with potential for rapid uptake into clinical practice and enhanced innovation capacity. ISOLDA’s approach and results are expected to have strong benefits for society beyond the viral targets of ISOLDA, opening among other benefits, new avenues for the improvement of healthy ageing.