Outcome of Repeated Vaccination to Hepatitis B Virus in Patients Failing to Respond to Vaccination Following Allogeneic Hematopoietic Stem Cell Transplantation (HSCT): If at First You Don't Succeed, Try Try Again

Background: Recipient immunity is compromised after HSCT, obligating patients (pts) to take prophylactic antimicrobial and antiviral agents and to be reimmunized to viral and bacterial pathogens. Hepatitis B virus (HBV) infection is a major public health problem, with about 30% of the world population having serological evidence of current or past HBV infection. HBV vaccination post-HSCT is imperative in these pts, as most lose protective HBV surface antibodies (anti-HBs) following conditioning, placing them at high risk for HBV reactivation. Guidelines recommend delaying vaccination (including HBV) for 6-12 months following transplantation to allow for cellular and humoral immune recovery. Even with delaying vaccination, immunosuppression, graft-versus-host disease (GVHD), and delayed immune reconstitution hinder the effectiveness of vaccines. The efficacy of HBV vaccination is not well defined in pts on immunosuppressive therapy (IST) and/or in those with GVHD. Further, little data exists on the efficacy of HBV revaccination in pts failing to respond to the 1^st vaccination series. We studied factors impacting the success of vaccination in pts undergoing one to four HBV vaccination series after HSCT.

Methods: This single-center, retrospective study evaluated the effectiveness of HBV vaccine in HSCT pts by assessing protective antibody generation after vaccination. Fifty-two pts (25 female, 27 male) who received at least one 3-dose HBV vaccination series post-HSCT and who had evaluable post-vaccine anti-HBs titers were included in the analysis. Pts with negative or indeterminate anti-HBs titers following the first vaccine series were eligible to receive one or more additional series of HBV vaccinations. All pts were treated with cyclophosphamide and fludarabine based conditioning (± anti-thymocyte globulin) and received GVHD prophylaxis with either cyclosporine/tacrolimus with or without mycophenolate mofetil. The vaccine response rate over a series of vaccinations was estimated by Kaplan-Meier methods. The development of response after the first vaccination was correlated with patient baseline and post-HSCT factors including pretransplant HBV titers, vaccination time post-transplant, use of rituximab and IST and absolute lymphocyte count (ALC), CD4, and CD8 cell counts and history of acute or chronic GVHD.

Results: The studied cohort included 52 HSCT pts with a median age of 22 years (range 7-62) and a variety of diagnoses (38 aplastic anemia, 6 myelodysplastic syndrome and 8 hematological malignancies). Thirty-five pts underwent HSCT from an HLA-matched donor and 17 pts received a combined haploidentical and umbilical cord blood transplant. The median time to first HBV vaccination was 12 months (8-37) post-HSCT. Following the 1^st vaccination series; 19, 4 and 2 pts received a 2nd, 3rd and 4th vaccination series. The estimated cumulative anti-HBs response rates were 51.9%, 82.3%, 91.1% and 100% for the four vaccination series, respectively (Figure). A logistic regression analysis revealed: a) Pts who achieved a response after the initial vaccination series had higher CD4 counts compared to those who failed to mount a response (median CD4 count 450 vs. 300/μL, P= 0.024, Figure); b) Pts without a history of acute GVHD (n=23) were significantly more likely to respond to the 1^st vaccination series compared to those with acute GVHD (n=29) (response: 69.6% vs 37.9%, P= 0.029). Other factors included in this analysis were not found to be correlated with the anti-HBs response after the initial vaccination series.

Conclusions: Multiple rounds of HBV vaccination may be required before a protective antibody response is achieved. After the first vaccination series, only 51.9% of pts achieved a response, with lower pre-vaccination CD4 counts and a prior history of acute GVHD being negatively associated with vaccine success. Remarkably, with continued vaccination attempts (up to four vaccination series), all evaluable pts ultimately developed a protective anti-HBs response.

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