*Purpose: Varicella-zoster virus (VZV) primary infection can be prevented by using the live varicella vaccine. However, this is contraindicated after organ transplant. We investigated the non-live recombinant subunit herpes zoster vaccine (RZV) as a novel strategy to prevent primary varicella in VZV-seronegative transplant recipients.

*Methods: Adult SOT patients who were VZV-seronegative and had no history of varicella/shingles vaccine or disease were enrolled and given two doses of RZV vaccine 2-6 months apart. Blood was drawn pre-vaccination (V1), just prior to the second dose (V2) and 4 weeks after second dose (V3).Humoral immunity was evaluated by anti-gE antibodies and a positive seroresponse was defined as a baseline optical density value higher than two standard deviations above the mean. Cell-mediated immunity assays were performed after stimulating PBMCs with a VZV peptide pool. Polyfunctional cells were defined as cells producing at least two cytokines among IFNγ, TNFα, IL2 and CD40L.

*Results: Among 31 eligible VZV seronegative SOT patients screened, 23 were enrolled.Median age was 38 yrs (range 18-67) and median time since SOT was 3.8 yrs (range 0.2-22.6). Transplant types were liver (35%), lung (30%), kidney (17%) and combined (17%). Most patients (78%) were on triple immunosuppression. Median anti-gE levels significantly increased from V1 to V3 (p=0.001) and V2 to V3 (p<0.001). Three patients had baseline positive anti-gE serology. Among the remaining 20 patients, 11 (55%) had a positive seroresponse to the vaccine. There was a trend towards lower median anti-gE antibodies at V3 among thoracic transplant recipients compared to other organs (p=0.076). Median anti-gE avidity increased from V1 to V3 (0 vs. 12%;p=0.002). Polyfunctional CD4 T-cells significantly increased from V1 to V2 (median 54/10⁶ vs 104/10⁶cells; p=0.041), and from V2 to V3 (380/10⁶; p=0.002). Lung transplant recipients had lower median polyfunctional CD4 T-cells at V3 (99/10⁶) than other organ transplant recipients (540/10⁶; p=0.015). Anti-gE titers and polyfunctional CD4 T-cells at V3 were positively correlated (correlation coefficient (CC) 0.515; p=0.014). The use of prednisone and mycophenolate was associated with significantly lower anti-gE responses (p=0.046 and 0.004 respectively). Increasing doses of prednisone or mycophenolate were associated with lower polyfunctional CD4 T-cell responses at V3 (CC -0.361; p=0.09 and CC -0.593; p=0.009 respectively). There was no significant increase in polyfunctional CD8 T-cells after the vaccine.

*Conclusions: RZV was safe and elicited significant humoral and cellular responses in VZV-seronegative SOT patients. We provide the first unique data that RZV may be considered as a preventive strategy against primary varicella in transplant recipients who are VZV-naïve.

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