Effects of Sirolimus treatment on patients with ß-Thalassemia: Lymphocyte immunophenotype and biological activity of memory CD4+ and CD8+ T cells.

Inhibitors of the mammalian target of rapamycin (mTOR) have been proposed to improve vaccine responses, especially in the elderly. Accordingly, testing mTOR inhibitors (such as Sirolimus) and other geroprotective drugs might be considered a key strategy to improve overall health resilience of aged populations. In this respect, Sirolimus (also known as rapamycin) is of great interest, in consideration of the fact that it is extensively used in routine therapy and in clinical studies for the treatment of several diseases. Recently, Sirolimus has been considered in laboratory and clinical studies aimed to find novel protocols for the therapy of hemoglobinopathies (e.g. ß-Thalassemia). The objective of the present study was to analyse the activity of CD4+ and CD8+ T cells in ß-Thalassemia patients treated with Sirolimus, taking advantages from the availability of cellular samples of the NCT03877809 clinical trial. The approach was to verify IFN-γ releases following stimulation of peripheral blood mononuclear cells (PBMCs) to stimulatory CEF and CEFTA peptide pools, stimulatory for CD4+ and CD8+ T cells, respectively. The main results of the present study are that treatment of ß-Thalassemia patients with Sirolimus has a positive impact on the biological activity and number of memory CD4+ and CD8+ T cells releasing IFN-γ following stimulation with antigenic stimuli present in immunological memory. These data are to our knowledge novel and in our opinion of interest, in consideration of the fact that ß-Thalassemia patients are considered prone to immune deficiency.

Age differentially impacts adaptive immune responses induced by adenoviral versus mRNA vaccines against COVID-19.

Adenoviral and mRNA vaccines encoding the viral spike (S) protein have been deployed globally to contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Older individuals are particularly vulnerable to severe infection, probably reflecting age-related changes in the immune system, which can also compromise vaccine efficacy. It is nonetheless unclear to what extent different vaccine platforms are impacted by immunosenescence. Here, we evaluated S protein-specific immune responses elicited by vaccination with two doses of BNT162b2 or ChAdOx1-S and subsequently boosted with a single dose of BNT162b2 or mRNA-1273, comparing age-stratified participants with no evidence of previous infection with SARS-CoV-2. We found that aging profoundly compromised S protein-specific IgG titers and further limited S protein-specific CD4+ and CD8+ T cell immunity as a probable function of progressive erosion of the naive lymphocyte pool in individuals vaccinated initially with BNT162b2. Our results demonstrate that primary vaccination with ChAdOx1-S and subsequent boosting with BNT162b2 or mRNA-1273 promotes sustained immunological memory in older adults and potentially confers optimal protection against coronavirus disease 2019.

Ageing Curtails the Diversity and Functionality of Nascent CD8+ T Cell Responses against SARS-CoV-2.

Age-related changes in the immune system are thought to underlie the vulnerability of elderly individuals to emerging viral diseases, such as coronavirus disease 2019 (COVID-19). In this study, we used a fully validated in vitro approach to determine how age impacts the generation of de novo CD8+ T cell responses against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19. Our data revealed a generalized deficit in the ability of elderly individuals to prime the differentiation of naïve precursors into effector CD8+ T cells defined by the expression of interferon (IFN)-γ and the transcription factor T-bet. As a consequence, there was an age-related decline in the diversity of newly generated CD8+ T cell responses targeting a range of typically immunodominant epitopes derived from SARS-CoV-2, accompanied by an overall reduction in the expression frequency of IFN-γ. These findings have potential implications for the development of new strategies to protect the elderly against COVID-19.

Development of an Oral IgA Response against SARS-CoV-2 Following Immunization with Different COVID-19 Vaccines.

The mucosal immune response is recognized to be important in the early control of infection sustained by viruses with mucosal tissues as the primary site of entry and replication, such as SARS-CoV-2. Mucosal IgA has been consistently reported in the mouth and eye of SARS-CoV-2 infected subjects, where it correlated inversely with COVID-19 symptom severity. Yet, there is still scarce information on the comparative ability of the diverse SARS-CoV-2 vaccines to induce local IgA responses at the virus entry site. Thus, the aim of this study was to assess the presence of anti-SARS-CoV-2 IgA in the saliva of 95 subjects vaccinated with a booster dose and different combinations of vaccines, including mRNA-1273 (Moderna), BNT162b2 (Pfizer-BioNTech), and Vaxzevria (AstraZeneca). The results showed the presence of a mucosal response in 93.7% of vaccinated subjects, with a mean IgA titer of 351.5 ± 31.77 U/mL, strongly correlating with the serum anti-SARS-CoV-2 IgG titer (p < 0.0001). No statistically significant differences emerged between the vaccine types, although the salivary IgA titer appeared slightly higher after receiving a booster dose of the mRNA-1273 vaccine (Moderna) following two doses of BNT162b2 (Pfizer-BioNTech), compared to the other vaccine combinations. These data confirm what was previously reported at the eye level and suggest that monitoring salivary IgA may be a useful tool for driving forward vaccine design and surveillance strategies, potentially leading to novel routes of vaccine administration and boosting.

Impaired Priming of SARS-CoV-2-Specific Naive CD8+ T Cells in Older Subjects.

Advanced age is associated with severe symptoms and death upon SARS-CoV-2 infection. Virus-specific CD8+ T-cell responses have shown to be protective toward critical COVID-19 manifestations, suggesting that suboptimal cellular immunity may contribute to the age-pattern of the disease. The induction of a CD8+ T-cell response against an emerging pathogen like SARS-CoV-2 relies on the activation of naive T cells. To investigate whether the primary CD8+ T-cell response against this virus is defective in advanced age, we used an in vitro approach to prime SARS-CoV-2-specific naive CD8+ T cells from healthy, unexposed donors of different age groups. Compared to younger adults, older individuals display a poor SARS-CoV-2-specific T-cell priming capacity in terms of both magnitude and quality of the response. In addition, older subjects recognize a lower number of epitopes. Our results implicate that immune aging is associated with altered primary SARS-CoV-2-specific CD8+ T-cell responses.