Immune Reconstitution and Readiness for Vaccination after Pediatric Allogeneic Bone Marrow Transplantation for Hematologic Malignancies

Introduction: Allogeneic hematopoietic cell transplantation (allo-HCT) can be a lifesaving procedure for hematologic malignancies, but conditioning regimens for allo-HCT have lasting negative consequence to the immune system including elimination of prior protection from vaccination. Re-immunization post-HCT is standard of care but there are limited data on optimal timing. Prior guidelines suggest a vaccination schedule based on time since HCT but this approach may not accurately identify an individual's immune readiness for vaccination. A protocol based on immune function measured at multiple timepoints post-HCT may better identify the optimal time to start vaccination.

We determined time to vaccine readiness for allo-HCT recipients undergoing serial immune response evaluation starting at 8 months post-HCT and compared this to the historical approach of fixed revaccination timing at 12-months post-HCT. Data for time to first vaccine receipt and immune response to vaccine administration were also collected and described. Finally, the association of patient characteristics and baseline HCT covariates likelihood of vaccination readiness at 8-months were assessed.

Methods: A cohort of patients receiving allo-HCT for a hematologic malignancy at Children's Hospital of Philadelphia from Jan 2017 to Dec 2022 was assembled. Beginning in 2018, HCT recipient readiness for vaccination was based on evidence of immune recovery starting at 8 months post-HCT. The following criteria were required to be considered vaccine ready: absolute CD3/CD4 ≥ 200, mitogens PHA ≥ 30% of normal, IgG > 400 (and ≥3 months from IVIG infusion), evidence of recovering IgA and/or IgM. Study outcomes included vaccine readiness at first immune recovery assessment at 8 months post-HCT and median time from day of HCT to day of receipt of first vaccine post-HCT. Adequate response to vaccination was defined as antibody specific IgG levels >0.1 IU/mL for tetanus and >1.3 ug/mL for at least 70% of Pneumovax serotypes measured 4 weeks after dose 3 and 4 of these immunizations, respectively. Patient characteristics and baseline HCT factors assessed for association with readiness for revaccination at 8 months included: age, sex, malignancy type, stem cell source, graft manipulation, GVHD status, and receipt of rituximab. A multivariable logistic regression model was used to estimate adjusted associations between factors of interest and vaccine readiness at 8 months. Patients that relapse, die, or are on continued immune suppression prior to initiation of immune recovery assessment at 8-months were excluded from analyses.

Results: 154 HCT recipients were identified for cohort inclusion. 69 (44.5%) were not considered in the final analysis as they either relapsed (26), required ongoing immune suppression (20), or died (23) prior to 8 months post-HCT. Of the remaining 85 patients, 36 (42%) met criteria to start revaccination at 8 months. In those ready at 8 months, median time from day of HCT to first vaccine receipt was 268 days. 34 (95%) had an adequate response to pneumococcal vaccine while 36 (100%) had an adequate response to tetanus vaccine. In adjusted regression models, factors associated with increased likelihood to not be ready for vaccination at 8 months post HCT include age <3 or >14 years old (OR 6.2, 95% CI 1.3-30.8), female (OR 13.3, 95% CI 2.6-67.4), lymphoid malignancy (OR 15.4, 95% CI 3.2-73.9), T cell depleted grafts (OR 13.8, 95% CI 1.43-132.9), receipt of rituximab prophylaxis or treatment (OR 4.75, 95% CI 1.0-22.4) and GVHD that resolves prior to 8-months (OR 2.0, 95% CI 0.4-9.6).

Conclusions: Use of an individualized immune recovery approach to guide re-immunization post-HCT can result in earlier time to vaccination relative to a fixed approach of revaccination at 12 months for a subset of patients. Importantly, assessment of immune reconstitution may reveal patients that are not ready for vaccination until after one-year post-HCT. This data will inform immune response based re-immunization protocols and equip clinicians to manage expectations about vaccine timing for patients and caregivers. Further studies are needed in this clinical arena with larger sample sizes where detecting significant associations between potential covariates and vaccine readiness may be more apparent.

Olson:Pfizer: Membership on an entity's Board of Directors or advisory committees; Akari: Research Funding; bluebird bio: Consultancy; Medexus: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Elixirgen: Membership on an entity's Board of Directors or advisory committees.