Periodic Reporting for period 4 - ISOLDA (Improved Vaccination Strategies for Older Adults)
Reporting period: 2023-11-01 to 2025-06-30
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.
ISOLDA aimed 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).
To achieve this, ISOLDA specifically addressed the following four key objectives:
1) Characterization of age-related immunosenescence and exhaustion key factors and signatures of infection- and vaccine-induced immune responses in available cohorts of older adults infected with, and/or vaccinated against influenza, MERS/COVID-19 and TBE.
2) Development of vaccine formulations with kinase inhibitors and inflammageing modulators that effectively overcome T cell senescence while limiting unproductive inflammation ex vivo.
3) Evaluation of selected modulators of immunosenescence and inflammageing for their ability to enhance vaccine efficacy in vivo in relevant (immunosenescence) animal models of influenza virus, and MERS-CoV/SARS-CoV-2 infection.
4) Clinical trial of a selected (combinations of) modulator of immunosenescence and inflammageing in healthy volunteers vaccinated with licensed respiratory virus vaccines.
In conclusion of the action, immunosenescence negatively impact both infection and vaccination outcomes; while kinase inhibitors did not prove efficient to restore immune responses to vaccination in older adults, adjuvanted vaccines remain advantageous.
ISOLDA aimed 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).
To achieve this, ISOLDA specifically addressed the following four key objectives:
1) Characterization of age-related immunosenescence and exhaustion key factors and signatures of infection- and vaccine-induced immune responses in available cohorts of older adults infected with, and/or vaccinated against influenza, MERS/COVID-19 and TBE.
2) Development of vaccine formulations with kinase inhibitors and inflammageing modulators that effectively overcome T cell senescence while limiting unproductive inflammation ex vivo.
3) Evaluation of selected modulators of immunosenescence and inflammageing for their ability to enhance vaccine efficacy in vivo in relevant (immunosenescence) animal models of influenza virus, and MERS-CoV/SARS-CoV-2 infection.
4) Clinical trial of a selected (combinations of) modulator of immunosenescence and inflammageing in healthy volunteers vaccinated with licensed respiratory virus vaccines.
In conclusion of the action, immunosenescence negatively impact both infection and vaccination outcomes; while kinase inhibitors did not prove efficient to restore immune responses to vaccination in older adults, adjuvanted vaccines remain advantageous.
Objective #1: Immunosenescent signatures and T cell immunophenotypes were characterized in different cohorts. Using Influenza/age cohort samples, age related changes in immune cells were identified. These differences were also observed in the SARS-CoV-2 cohort and the signs of immunosenescence observed in older adults were found to correlate with a poor outcome of COVID-19 mRNA vaccination. These changes included reduced frequency of naïve T cells and increased frequency of immunosenescent cells.
Objective #2: The ISOLDA partners selected Axitinib, Sorafenib and BIRB796/oleuropein combination as candidates. BIRB stimulates T cells from healthy donors and expands flu-specific central memory T cells. Oleuropein strongly potentiates differentiation of activated conventional dendritic cells and monocytes, which in turns improves antigen presentation to T cells. Lastly, the effect of MF59-adjuvanted influenza vaccine on immunogenicity of SARS-CoV-2 mRNA vaccine was assessed in vitro and up-regulated CD209 expression on monocytes potentially marking their differentiation into dendritic cells, but elucidating the biological significance of these changes requires further investigation.
Objective #3: the vaccine with the adjuvant MF59 was superior to unadjuvanted vaccine, administered with or without any of the SMKI, incl. in aged mice. The limited effect of the SMKI precluded their further evaluation in a clinical trial. A permissive avatar humanized mouse model for SARS-CoV-2 was established by BNITM team by transplanting PBMCs from human donors into recipient NSG-A2-KDnull mice. Recombinant SARS-CoV-2 viruses encoding precursors of immunomodulatory miRNAs-138, 181a, 155 and 223 were engineered and significantly decreased the proportion of PD1 positive CD4+ T cells in aged mice. Since PD1 is a marker of T cell exhaustion, these results suggest that the expression of immunomodulatory miRNAs promotes T cell activation.
Objective #4: A Phase-II, single-centre, randomized, single-blind, clinical trial was conducted to assess the immunogenicity of co-administration of licensed vaccines against COVID-19 and FLU with or without MF59 adjuvant, or the COVID-19 vaccine alone, in adults aged 65 years and over. The results from this trial indicate that an MF-59 adjuvanted FLU vaccine or an unadjuvanted FLU vaccine, co-administered ipsilaterally with a Comirnaty COVID-19 vaccine, does not result in clinically meaningful differences in the humoral or cellular immune response.
The project resulted in a total of 66 peer-reviewed publications and 6 doctoral theses, and 5 patents.
Objective #2: The ISOLDA partners selected Axitinib, Sorafenib and BIRB796/oleuropein combination as candidates. BIRB stimulates T cells from healthy donors and expands flu-specific central memory T cells. Oleuropein strongly potentiates differentiation of activated conventional dendritic cells and monocytes, which in turns improves antigen presentation to T cells. Lastly, the effect of MF59-adjuvanted influenza vaccine on immunogenicity of SARS-CoV-2 mRNA vaccine was assessed in vitro and up-regulated CD209 expression on monocytes potentially marking their differentiation into dendritic cells, but elucidating the biological significance of these changes requires further investigation.
Objective #3: the vaccine with the adjuvant MF59 was superior to unadjuvanted vaccine, administered with or without any of the SMKI, incl. in aged mice. The limited effect of the SMKI precluded their further evaluation in a clinical trial. A permissive avatar humanized mouse model for SARS-CoV-2 was established by BNITM team by transplanting PBMCs from human donors into recipient NSG-A2-KDnull mice. Recombinant SARS-CoV-2 viruses encoding precursors of immunomodulatory miRNAs-138, 181a, 155 and 223 were engineered and significantly decreased the proportion of PD1 positive CD4+ T cells in aged mice. Since PD1 is a marker of T cell exhaustion, these results suggest that the expression of immunomodulatory miRNAs promotes T cell activation.
Objective #4: A Phase-II, single-centre, randomized, single-blind, clinical trial was conducted to assess the immunogenicity of co-administration of licensed vaccines against COVID-19 and FLU with or without MF59 adjuvant, or the COVID-19 vaccine alone, in adults aged 65 years and over. The results from this trial indicate that an MF-59 adjuvanted FLU vaccine or an unadjuvanted FLU vaccine, co-administered ipsilaterally with a Comirnaty COVID-19 vaccine, does not result in clinically meaningful differences in the humoral or cellular immune response.
The project resulted in a total of 66 peer-reviewed publications and 6 doctoral theses, and 5 patents.
ISOLDA demonstrated that oleuropein mobilizes “dormant” CD4 and CD8 T cells specific for SARS-CoV-2 antigens. A key scientific advancement was the successful proof of concept for the in vivo expression of immunomodulatory miRNAs from the SARS-CoV-2 genome in the lungs of aged mice. The trial was exploratory in nature and warrantees further clinical evaluation. Specifically, larger scale trials should be deployed, where contralateral co-administration (in the same arm and lymph node) is compared against ipsilateral co-administration, and/or (MF-59 adjuvanted) FLU vaccines without co-administration are compared against co-administration strategies (specifically regarding local reactogenicity), to help guide future vaccination strategies and national implementation recommendations.