The recombinant adjuvant zoster vaccine induces similar immune responses in ruxolitinib-treated patients with myelofibrosis and polycythemia vera

Abstract Introduction: Patients with myeloproliferative neoplasms (MPN) such as myelofibrosis (MF) or polycythemia vera (PV) who are receiving the JAK inhibitor (JAKi) ruxolitinib are at high risk of developing herpes zoster, with reported incidence rates approximately tenfold higher than in MPN patients not on JAK inhibition. Assessing the efficacy of the recombinant adjuvanted herpes zoster vaccine Shingrix® in this population is crucial, as it is the currently recommended option for zoster prevention. Our objective was to evaluate the humoral and cellular immune response after two doses of Shingrix® in patients with MF and PV treated with ruxolitinib. Methods: Participants with MPN were recruited for this study (n=14): MF (n=7) and PV (n=7). Blood samples were collected at baseline, a median of 4.5 months after the first vaccine dose (IQR 3.5-5.4), and 3.2 months after the second dose (IQR 3.1-4.7). Humoral immunity was assessed by measuring total B-cell counts and subset distribution by flow cytometry, along with the expression of activating markers BAFF, APRIL, and BCMA. IgG levels specific to varicella-zoster virus (VZV) glycoprotein E (gE) were quantified by CLIA. Cellular immunity was evaluated by analyzing total CD4+ and CD8+ T cell counts, their Th and Tc subset distribution, respectively, and the production of IFNg, granzyme B (GZB), and perforin in response to gE peptides, using flow cytometry. Results: 1) The median age of participants was 65 years for MF and 67 years for PV; 71.4% of the MF group and 42.9% of the PV group were male. Median time since diagnosis was 10 years (IQR 3.4–20.7). Median duration on ruxolitinib was 2 years (IQR 1.6–4.2) for MF and 4 years (IQR 1.3–7.5) for PV. 2) Humoral immunity: All participants had detectable anti-VZV IgG at baseline, with significant increases after the first dose (2.2-fold, p=0.0018 for MF; 2.4-fold, p=0.0015 for PV), which were sustained following the second dose. No significant changes were observed in total B-cell counts, B-cell subset distribution or activation marker expression between groups. 3) Cellular immunity: No changes were found in total CD8+ T-cell counts or Tc subset distribution. However, CD8+ Tc1 cells from PV participants produced significantly more IL-2 in response to gE peptides than those from MF patients. No significant changes were observed in IFNγ, GZB, or perforin production by CD8+ or CD4+ T cells, nor in Th subset distribution. Notably, PV participants showed a marked decrease in CD4+ naïve T-cell levels over the 6-month follow-up (3.6-fold; p=0.0233).Conclusions: Despite the limited sample size, our findings suggest that ruxolitinib does not significantly impair the immunogenicity of the recombinant zoster vaccine Shingrix® in people with MPN, as all participants developed a robust and sustained anti-VZV IgG response, with no major differences between MF and PV patients. Cellular immunity also appeared preserved; however, the decrease in CD4+ naïve T cells in PV patients, together with their enhanced IL-2 response by Tc1 cells, may reflect a compensatory mechanism. Although we did not assess the neutralizing capacity of the antibodies, and clinical follow-up is needed to evaluate real-world protection against zoster, these preliminary results support current vaccination recommendations for MPN patients on JAK inhibition. Future studies will include healthy controls and MPN patients without JAKi receiving Shingrix® to better contextualize the immune responses observed. Larger prospective trials are necessary to confirm these findings and refine vaccination strategies in this vulnerable population. This work was supported by the Strategic Action in Health 2024 of the Instituto de Salud Carlos III (Spain) (PI24/00861)