Humoral and cellular immunity for TBE vaccination in allogeneic HSCT recipients

Patients undergoing allogeneic blood and marrow transplantation (HSCT) experience a prolonged period of dysfunctional immunity associated with an increased risk of bacterial and viral infections. Systematic reimmunization is necessary at appropriate time intervals following transplantation to re-establish immunity. The efficacy of vaccination following HSCT is influenced by the time elapsed since transplantation, the nature of the hematopoietic graft, the use of serial immunization, the vaccine being used, and the immune status of the patient including the presence or severity of graft-versus-host disease (GVHD) and the need for immunosuppressive drugs. Vaccination practices after HSCT remain varied and data sparse. Tick-borne encephalitis (TBE) is one of the most severe infections of the central nervous system caused by a tick-borne flavivirus and is endemic in Austria. There is no specific treatment, and prevention with the vaccine is the only intervention available. Therefore, primary vaccination against TBE is recommended for the entire Austrian population. But there are no data on the incidence of TBE and the efficacy of the TBE vaccine in HSCT patients at all. Although it can be assumed that HSCT patients have at least the similar risk for TBE as an unvaccinated immunocompetent person and a particularly high risk for severe central nervous system manifestations after TBE infection. Therefore, clinical studies on TBE vaccination in HSCT patients are urgently needed. To assess the efficacy of TBE vaccination in adult allogeneic HSCT recipients compared to an age-matched and sex-matched control group of healthy volunteers without previous TBE vaccination, a prospective open-label phase II pilot study on humoral and cellular immune responses will be performed. As primary end point the outcome of the neutralization test (NT) against TBE will be assessed in a total of 26 HSCT patients one year after HSCT and in 26 healthy volunteers, namely four weeks after the second vaccination. Therefore, the number of subjects with NT titres against TBE virus >10, assumed to be the threshold for antibody-mediated protection will be evaluated. As secondary endpoints, antibody concentrations of TBE enzyme-linked immunosorbent assay before and four weeks after the second and third vaccination and antibody concentrations of NT against TBE four weeks after primary immunization. To evaluate cellular immune responses, lymphocyte proliferations assays and cytokine detection assays will be performed. In a subgroup analysis, these secondary endpoints will be compared between healthy volunteers, HSCT patients without immunosuppressive treatment and HSCT patients receiving immunosuppressive agents. Additionally, immune reconstitution by analysis of peripheral blood lymphocyte subsets and serum immunoglobulin levels will be evaluated prior to vaccination and every twelve weeks throughout the complete study period in HSCT patients only.

In Austria tick-borne encephalitis (TBE) is the most common viral infectious disease transmitted by infected ticks. Without protection by active immunization, infection by TBE- virus can lead to severe injuries of the central nervous system or even death. Patients after bone marrow or blood stem cell transplantation who undertake outdoor activities during the tick season are at particular risk. On the one hand those patients have an increased risk for any type of infectious disease particularly in the first months after transplantation, on the other hand it is assumed that they loose their protection attained by any vaccination prior transplantation. Aim of the present pilot study performed at the Medical University of Vienna was to investigate for the first time worldwide the immune response following a basic immunization with TBE-vaccine among patients after stem cell transplantation (HSCT) compared to healthy volunteers without previous TBE-vaccination. During July 2014 and January 2018 we recruited 19 adult patients 11 to 13 months after their HSCT aged between 22 and 63 years (median age: 31 years) and 15 unvaccinated healthy adults aged between 21 and 60 years (median age: 30 years). On their own request, 2 patients left the trial nd before the 2 TBE-vaccination. 17 patients and all 15 controls received at least two doses of TBE- vaccine one month apart. To assess the immune response antibody concentrations against TBE- virus and cellular immunity were measured by different test methods prior and at different times after vaccination in patients and volunteers. We found that 15 of the 19 recruited patients (78.9%) still had neutralizing antibodies against TBE-virus with a antibody titer measured by neutralization test (NT) =1:10 (median NT-titer 1:40) one year after HSCT, whereas all unvaccinated volunteers did not have any detectable neutralizing antibodies against TBE-virus (NT-titer <1:5) prior vaccination. Equally, after stimulation with TBE- antigen at baseline, unvaccinated controls did not show any proliferation of specific immune cells, T-lymphocytes, (SI <1.3 by thymidine assay). But 10 (59%) of 17 HSCT patients presented with significant baseline TBE-specific T-cell proliferation upon incubation with TBE antigen (SI >3.0 by thymidine assay, p=0.0029) although they have not yet been re-vaccinated against TBE nd after HSCT. Four weeks after the 2 dose of TBE-vaccine, we found a statistically significantly reduced antibody response, defined by an at least 2-fold titer increase, in HSCT patients compared to healthy volunteers (35.3% titer response by NT-test and 52.9% titer by ELISA among patients versus 93.3% titer response by NT-test and ELISA among controls). Patients after HSCT showed geometric nd mean fold rises in NT-titer after 2 vaccination of 2.03 (95% confidence interval: 1.01 4.08), whereas healthy volunteers had geometric mean fold rises in NT-titer of 14.82 (95% confidence interval: 8.06 26.51) after 2nd vaccination. Interestingly, HSCT patients with titer response were only found in the group of patients who already showed a high TBE-specific T-cell proliferation (SI >10 fold by thymidine assay, p=0.0002) prior vaccination. Additionally in the multivariate regression analysis, only an increasing number of T-helper cells, a subpopulation of T-lymphocytes, at baseline was identified as independent positive predictor for a titer response after TBE- vaccination in stem cell recipients (p=0.019), whereas other classical parameters such as age, body mass index or use of drugs that suppress the immune system had no significant influence. In conclusion, the present pilot study did reveal a reduced immune response after TBE-immunization in stem cell recipients 1 year after transplantation compared to healthy volunteers. However, the majority of patients still had detectable neutralizing antibodies against TBE-virus and showed TBE-specific T-cell proliferation upon stimulation at that time. Furthermore, the presence and degree of TBE-specific baseline T-cell proliferation separates subsequent serological TBE vaccine responders from non-responders and it might be possible to postpone the TBE-immunization at least until normalisation of the T-helper cells.