Kidney Transplant Patients Generate Varicella Zoster–Reactive T-cell and Humoral Immunity Following Protein-based Varicella Zoster Vaccination

Reactivation of latent varicella zoster virus (VZV) can lead to serious complications in immunocompromised patients such as organ transplant recipients.1,2 The clinical characteristics of herpes zoster infections can include pneumonia, cerebellar ataxia, encephalitis, and hepatitis with an overall fatality rate of 5%–10%.3,4 VZV vaccination is recommended for healthy individuals above the age of 60 and for chronically ill patients above the age of 50 y. However, data on whether VZV vaccinations induce humoral and cellular immunity in immunosuppressed transplant patients are scarce. Consequently, we characterized the humoral and cellular immunity following 2 VZV vaccinations in kidney transplant patients (KTx). In a cross-sectional study, we analyzed VZV-specific IgG and T cells in 39 immunosuppressed KTx (Tables S1 and S2, SDC, https://links.lww.com/TP/C621) vaccinated with 2 doses of a recombinant protein-based vaccine (Shingrix), containing the VZV envelope glycoprotein E as immunogenic domain. To elaborate T-cell assays for clinical utility, VZV-reactive T cells were compared in whole blood and in isolated peripheral blood mononuclear cells (PBMC) after VZV vaccine stimulation. The vaccination was well tolerated and did not influence kidney allograft function, because eGFR remained stable in all individuals in the follow-up (between 34 and 197 d after the last vaccination, median 98 d). An increased incidence of vaccination-associated rejection episodes could not be observed in our cohort (Tables S2, SDC, https://links.lww.com/TP/C621). VZV-specific IgG titers were present in all vaccinated patients (Figure 1A). In patients with prevaccination titers available, we observed an average 1.8-fold titer increase, indicating humoral responsiveness (Figure 1B). Both protocols used for the detection of VZV glycoprotein E-reactive T cells allowed the characterization of CD4+ and CD8+ T cell responses (Figure 1C–F, Figure S1, SDC, https://links.lww.com/TP/C621). In PBMC and whole blood, 67% and 59% of vaccinated KTx showed a positive VZV-reactive T-cell response (Figure 1G and H), respectively. In a substantial fraction of KTx, we even observed a 2- to 3-fold higher response than background (Figure 1G and H). Interestingly, CD8+ VZV-reactive T cells were observed in 47% and 60% of PBMC and whole blood assay, respectively (Figure 1J and K). Polyfunctional VZV-reactive CD4+ T cells—as characterized by simultaneous expression of TNF-α, IFN-γ, and IL-2—were detected in PBMC and whole blood in at least 40% of the KTx (Figure S2, SDC, https://links.lww.com/TP/C621 and Figure 1K). The amounts of VZV-reactive CD4+ and CD8+ T cells did not correlate with VZV IgG titers (Figure S3, SDC, https://links.lww.com/TP/C621).FIGURE 1.: Humoral and cellular VZV-reactive immune response in KTX after vaccination against VZV using a protein/adjuvant-based vaccine. (A) VZV-IgG titers of all vaccinated KTx (n = 30); (B) VZV-IgG titer of KTx before and after vaccination (n = 8); (C–K) VZV-glycoprotein E–reactive T-cells were analyzed by flow cytometry after an overnight stimulation of PBMC or whole blood with the VZV envelope glycoprotein E (n = 34). (C, D) CD154 and CD69 expression was used for quantification of VZV glycoprotein E-reactive CD4+ T cells in PBMC and whole blood (Figure S1, SDC, https://links.lww.com/TP/C621). (E, F) CD137 and CD69 expression was used for quantification of VZV glycoprotein E–reactive CD8+ T cells in PBMC and whole blood. (G–J) Percentage of KTx at different cut-offs (>control indicates glycoprotein E-reactive T-cell frequencies above the untreated sample; staining index [SI] > 2 and SI > 3 indicate T-cell frequencies 2 or 3 times above the untreated sample, respectively) of VZV glycoprotein E-reactive CD4+ and CD8+ T cell in whole blood and isolated PBMC. (G, H) KTX showing VZV-reactive CD4+ T cells in PBMC (G) and whole blood (H). (I, J) KTX shows VZV-reactive CD8+ T cells in PBMC (I) and whole blood (J). (K) Frequencies of KTx with trifunctional CD4+ VZV glycoprotein E-reactive T cell, which simultaneously produce IL-2, IFNγ, and TNFα. Trifunctional T cells were determined by Boolean gating of IL-2-, IFNγ-, TNFα-producing CD4+CD154+CD69+ T cell (Figure S2, SDC, https://links.lww.com/TP/C621) as previously described.6 Statistical differences were analyzed using the paired t test. KTx, kidney transplant patients; PBMC, peripheral blood mononuclear cells; VZV, varicella zoster virus.Our data are in agreement with a previously published phase 3, randomized, observer-blind, multicenter trial that reported VZV vaccination induced immunogenicity in immunosuppressed KTx lasting over 12 mo after VZV vaccination without major adverse effects.5 One limitation of our study was that vaccination side effects were only assessed at the next regular patient visit. Explicit surveys to monitor immediate side effects were not performed. Thus, the extent of side effects could be greater than reported. In summary, despite chronic immunosuppression, the majority of KTx developed humoral and T-cell responses after VZV vaccination, highlighting that this vaccination can be beneficial for KTx. Whole blood and PBMC-based protocols are suitable for quantifying the VZV-specific T- cells response.