Long-Term Varicella Zoster Virus Immunity in Paediatric Liver Transplant Patients Can Be Achieved by Booster Vaccinations-A Single-Centre, Retrospective, Observational Analysis

Abstract

Varicella is one of the most common vaccine-preventable infections after paediatric solid organ transplantation; thus, vaccination offers simple and cheap protection. However, children with liver disease often progress to liver transplantation (LT) before they reach the recommended vaccination age. As a live vaccine, varicella zoster virus (VZV) vaccination after transplantation is controversial; however, many case series demonstrate that vaccination may be safe and effective in paediatric liver transplant recipients. Only limited data exists describing long-term vaccination response in such immunocompromised patients. We investigated retrospectively vaccination response in paediatric patients before and after transplantation and describe long-term immunity over ten years, including the influence of booster-vaccinations. In this retrospective, single-centre study, 458 LT recipients were analysed between September 2004 and June 2021. Of these, 53 were re-transplantations. Patients with no available vaccination records and with a history of post-transplant lymphoproliferative disease, after hematopoietic stem cell transplantation and clinical chickenpox were excluded from this analysis (n = 198). In total, data on 207 children with a median annual follow-up of 6.2 years was available: 95 patients (45.9%) were unvaccinated prior to LT. Compared to healthy children, the response to vaccination, measured by seroconversion, is weaker in children with liver disease: almost 70% after one vaccination and 93% after two vaccinations. One year after transplantation, the mean titres and the number of children with protective antibody levels (VZV IgG ≥ 50 IU/L) decreased from 77.5% to 41.3%. Neither diagnosis, gender, nor age were predictors of vaccination response. Booster-vaccination was recommended for children after seroreversion using annual titre measurements and led to a significant increase in mean titre and number of protected children. Response to vaccination shows no difference from monotherapy with a calcineurin inhibitor to intensified immunosuppression by adding prednisolone or mycophenolate mofetil. Children with liver disease show weaker seroconversion rates to VZV vaccination compared to healthy children. Therefore, VZV-naïve children should receive basic immunization with two vaccine doses as well as those vaccinated only once before transplantation. An average of 2-3 vaccine doses are required in order to achieve a long-term seroconversion and protective antibody levels in 95% of children.

Keywords: VZV; chickenpox; chronic liver disease; immunization; immunosuppression; paediatric liver transplantation; vaccination; varicella.

Figure 1

(A) VZV-specific antibodies before and 1 year after paediatric liver transplantation, depending on number of VZV vaccinations prior to transplantation. The y-axis is scaled logarithmically. Data is shown as mean ± standard deviation. The dashed line marks the threshold for serological protection. All groups show a decrease in mean titre after transplantation, regardless of the number of vaccine doses. However, as the bar plots in (B) show, patients with protective VZV antibodies after 1 vaccination are more than 60%, and after 2 vaccinations, more than 85% are still serologically protected. Significant data is marked as follows: * <0.05, ** <0.01, *** <0.001.

Figure 2

VZV-specific antibody responses following VZV-vaccination in VZV-naïve paediatric liver transplant recipients immunized for the first time 1 year after transplantation. Titre levels over 4 years, following (A) one dose after 1 year, (B) one dose after 1 and 2 years, and (C) two doses after 1 year. The y-axis is scaled logarithmically. Data is shown as mean ± standard deviation. The dashed line marks the threshold of serological protective titres.

Figure 3

(A) VZV-specific antibody course in paediatric liver transplant recipients over ten years after transplantation. The y-axis is scaled logarithmically. Data is shown as mean ± standard deviation. The dashed line marks the threshold for serological protection. The titre dropped significantly up to the first annual check but increased over the next few years with the possibility of vaccination, even if this increase was only significant at the second and third annual check. This also affected the numbers of patients with protective VZV titres, as shown in the bar plots in (B). The brown graph shows the average number of VZV vaccinations per patient. This was stable from the seventh annual check-up on, when around 95% of all patients were serologically protected, which required an average of 2.3 vaccinations per patient. Significant data is marked as follows: ** <0.01, *** <0.001.

Figure 4

VZV-specific antibody course in paediatric liver transplant recipients over ten years after transplantation dependent on normal (monotherapy with ciclosporin A or tacrolimus) or intensified (monotherapy supplemented by prednisolone or mycophenolate mofetil) immunosuppression (IS). At the first annual follow-up after transplantation, the titres dropped significantly in both groups, and children with intensified immunosuppression also had a significantly lower titre compared with those with normal immunosuppression. At the second annual check-up, titres increased again and did not show any further difference. The y-axis is scaled logarithmically. Data is shown as mean ± standard deviation. The dashed line marks the threshold for serological protection. Significant data is marked as follows: * <0.05, ** <0.01, *** <0.001.