Cellular immunity in immunocompromised individuals: vaccines, co-infections and new therapies

In this thesis, two research conducted on two different immunocompromised population, people living with HIV and solid organ transplant recipients, will be presented and discussed. The first part of my PhD happened during the COVID-19 Pandemic. During this period there was a need to answer questions about the effects of vaccination in immunocompromised populations, specifically describing the humoral and specifically T cell response to the mRNA-BNT162b vaccine. For this reason, part of this study discusses the results about humoral and cellular immune responses after one year since the third dose of SARS-CoV-2 mRNA BNT162b2 vaccine in SOT-Rs, with a focus on the qualitative characterization of T cell response against the Omicron variant. Collectively, our data support the hypothesis that in SOT-Rs the administration of SARS-CoV-2 mRNA-based vaccine might elicit a weaker humoral and cellular immune response compared to HDs, suggesting that in SOT-Rs the third vaccine dose effect might wane during a 1-year observation period and perhaps booster doses should be considered. Moreover, in our study, the organ transplanted as well as the time elapsed since transplant affects vaccine immunogenicity after a third BNT162b2 dose in SOT-Rs, especially in antibody levels. However, T-cell-mediated response seems to be retained which is mainly important given the emergence of the Omicron sub lineages of SARS-CoV-2. The second part of this study describes the use long-acting injectable cabotegravir plus rilpivirine (CAB/RPV LA) in people with HIV (PWH). Despite effective ART, HIV infection remains a chronic condition, characterized by a persistent inflammation and immune activation. Currently, there is limited evidence comparing the role of different therapies in this context. CAB/RPV LA formulations may better bioavailability and modulate the immunoinflammatory state associated with the disease. For this reason, we provide an analysis of the dynamic changes in the lymphoid immune activation and senescence markers in PWH switching to CAB/RPV LA, compared to PWH on oral ART. Furthermore, relationship between CMV-specific immune responses and phenotypic T-cell alterations were evaluated. Our study discusses that in PWH switching to CAB/RPV LA, CD4 levels show a non significant increase over time, with a higher percentage compared to the control group, while CD8 levels remain stable. Notably, CD4 immune activation declines significantly at T48 and T72, whereas CD8 activation remains unchanged, suggesting a potential benefit in reducing immune system overactivation. Additionally, at T48, PWH switching to CAB/RPV LA exhibit a lower percentage of activated CD4 (CD38+HLA-DR+) cells compared to the control group, reinforcing the idea of a more controlled immune response. Regarding immune senescence, a general reduction over time is observed in both CD4 and CD8 compartments, with a significantly lower percentage of senescent CD8 (CD28-CD57+) cells in PWH switching to CAB/RPV LA group at T48. Furthermore, the CMV immune response remains stable, with anti-CMV antibody levels unchanged, while T-cell specific responses initially increase at T28 before returning to baseline at T48. These findings suggest that CAB/RPV LA not only maintains virological control but may also help reduce immune activation and slow immune senescence. However, CMV co-infection remains a challenge for optimizing HIV treatment. Further studies are needed to explore the long-term effects of CAB/RPV LA on immune activation and senescence to refine treatment strategies and improve patient outcomes