#2238 In kidney transplant recipients, response to vaccination with Tozimameran is associated with T-cell activation, but not senescence or exhaustion
Authors: Stai Stamatia , Fylaktou Asimina , Christodoulou Michalis , Lioulios Georgios , Moysidou Eleni , Xochelli Aliki , Papadopoulou Anastasia , Yannaki Evangelia , Kasimatis Efstratios , Sarafidis Pantelis , Tsoulfas Georgios , Stangou Maria 
Published: May 2024

Abstract

Background and Aims
Responses to vaccinations among kidney transplant recipients (KTRs) tend to be impaired compared to those of healthy individuals, a fact that can, to some degree, be attributed to their more senescent immune system profile. However, in the current literature, few data regarding the potential effects of multiple vaccinations on these patients’ immune system aging process are available.
The aim of our research was to examine whether response to anti-SARS-CoV-2 vaccination with Tozinameran is associated with immunosenescence and immunoexhaustion in KTRs, focusing on CD4+ and CD8+ T-cell subsets. We additionally attempted to define parameters implicated in CD4+ and CD8+ differentiation process.

Method
We performed a prospective, observational study. Our sample consisted of 39 adult KTRs on stable immunosuppression, naïve to SARS-CoV-2. We evaluated them at two time points: T1 (48 hours prior to the 3rd Tozinameran dose) and T2 (3 weeks after the 3rd Tozinameran dose), by measuring: a) anti-SARS-CoV-2 neutralizing antibody (NAb) levels with chemiluminescence immunoassay (CLIA) b) viral-specific interferon gamma (IFN-γ) production with enzyme-linked immunosorbent spot (ELISpot) and concentrations of CD4+ and CD8+ subpopulations [comprising CD45RA+CCR7+ (naïve), CD45RA-CCR7+ (central memory -CM-), CD45RA-CCR7- (effector memory -EM-) and CD45RA+CCR7- (effector memory re-expressing CD45RA -EMRA-, senescent) CD4+/CD8+, CD28-expressing (CD8+) and CD28-null (CD8-, senescent) CD4+/CD8+ and CD3+PD1+ (exhausted) T-cells].
At each time point, we divided patients into responders (NAb ≥ 0.3 AU/mL and/or ELISpot ≥ 30SFC/5 × 105 PBMCs) and non-responders (NAb &lt; 0.3 AU/mL and ELISpot &lt; 30SFC/5 × 105 PBMCs). We compared the cellular subsets’ compositions and their alterations (with regards to the differentiation-senescence and the immunoexhaustion processes) between responders and non-responders. We also examined the potential association of several other parameters with the above-mentioned cellular concentrations.

Results
From T1 to T2, we observed: a) in the total number of patients: an increase in T-cell EM (TEM) CD8+ concentrations and in TCM CD4+ and TEM CD8+ percentages and a drop in naïve CD4+ and CD8+ proportions, b) in responders at T1 (RT1): an ascent of TEM CD8+ numbers and of TCM CD4+ and TEM CD8+ percentages and a reduction of naïve CD4+ proportions, c) in responders at T2 (RT2): an elevation in TEM CD8+ concentrations and in TCM CD4+ percentages and a drop in naïve CD4+ counts and proportions and in TEMRA CD4+ numbers (Figs 1 and 2).
At T2, responders compared to non-responders had higher concentrations of CD28+ CD4+ and CD8+ [756.34(368) vs. 446.57(925) and 227.15(166) vs. 131.44(121) cells/μL, p: 0.026 and 0.036 respectively] and greater percentages of CD28+CD4+ [93.8(6)% vs. 72.05(30.73)%, p: 0.05], as well as smaller proportions of CD28-CD4+ T-cells [6.1(5.5)% vs. 20.7(25)%, p: 0.04].
There was a negative association between age and naïve CD4+ and CD8+ T-cell and CD28+CD8+ concentrations at T1 (p: 0.042, 0.042 and 0.006, Spearman's ρ: −0.346, −0.345 and −0.444 respectively) and a positive correlation between exhausted T-cell (CD3+PD1+) numbers prior to the first vaccination and TEM / TEMRA CD4+ concentrations at T1 (p: 0.001 and 0.001, Spearman's ρ: 0.558 and 0.578 respectively), as well as TEMRA CD8+ counts at T2 (p: 0.037, Spearman's ρ: 0.396). There was also a positive association of eGFR value with TEMRA and CD28+ CD4+ counts at T1 (p: 0.021 and 0.014, Spearman's ρ: 0.389 and 0.402 respectively).

Conclusion
In KTRs, response to vaccination is not associated with an expansion of senescent and exhausted T-cell concentrations, but rather with a switch from naïve to differentiated-activated T-cell forms (including TEM and TCM). Age, T-cell exhaustion status at baseline and eGFR also to be correlated to the differentiation-senescence process.