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.
