Preservation and Transfer of Hepatitis B Virus Immunity after Non-Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation in Adult Sickle Cell Disease Patients (Protect Study).

Sickle cell disease (SCD) is an inherited hemoglobinopathy, characterized by
chronic hemolytic anemia and microvascular occlusions leading to pain attacks
and progressive deterioration of organ function. As a result, SCD patients have
a significantly reduced life expectancy. Allogeneic hematopoietic stem cell
transplantation (HSCT) is currently the only available curative treatment for
SCD. Recently, a mild non-myeloablative conditioning regimen for HSCT with
alemtuzumab (1mg/kg) and low dose (3Gy) total body irradiation (TBI) has been
developed for adult SCD patients with a matched sibling donor (MSD) and been
implemented in the Netherlands since 2018. The post-transplant setting of SCD
patients treated with the alemtuzumab/TBI regimen differs greatly from that in
other transplantation regimens usually used as treatment for malignant
hematological diseases. Because of its mild character, the conditioning regimen
typically results in mixed chimerism. In most patients, stable T-cell donor
chimerism of around 50% is achieved. Thus, approximately half of the adaptive
immunity is still patient-derived. However, whether these patients preserve
their immune response after the transplantation, is not known.
Another promising development is the improvement of HSCT conditioning regimens
for adult SCD patients with an haploidentical related donor. At the Amsterdam
UMC, haploidentical HSCT has been implemented in 2020 using antithymocyte
globulin, fludarabine, cyclophosphamide, thiotepa and low-dose (2Gy) TBI as
conditioning regimen and post-transplantation cyclophosphamide (PTCy) as in
vivo T-cell depletion. Besides improved engraftment rates, this conditioning
regimen is also associated with a reasonably swift immune reconstitution.
Unlike the conditioning with alemtuzumab/TBI in MSD HSCT, the above-mentioned
conditioning for haploidentical HSCT results in full donor chimerism. Patients
losing their immune response due to HSCT might benefit from the transfer of
protective immunity from the stem cell donor. Two previous studies have
demonstrated the adoption of immunity against hepatitis B virus (HBV) by
transplant recipients. However, transplant recipients are also at high risk of
gradual disappearance of protective antibodies. In contrast to our study
patient population, these studies were conducted in heavily pretreated patients
with malignant hematological diseases undergoing mostly myeloablative
conditioning regimens.
Currently, it is common practice to revaccinate all patients post-transplant
according to the revaccination schedules used for other allogeneic HSCT
recipients. However, revaccinating might not be necessary in SCD patients
undergoing non-myeloablative HSCT, as they might either preserve their immunity
(mixed chimerism after alemtuzumab/TBI conditioning) or benefit from transfer
of immunity (haploidentical HSCT)).
We hypothesize, that patients ending with mixed mononuclear chimerism after
HSCT will preserve their immune response to vaccinations administered prior to
the transplantation and will therefore not need to be revaccinated.
Furthermore, we hypothesize, that SCD patients after haploidentical HSCT can
benefit from adoptive transfer of immunity from their donors.
To test the first hypothesis, we will vaccinate patients undergoing the
alemtuzumab/TBI HSCT with a hepatitis B virus (HBV) vaccine before the
transplant. To test the second hypothesis, we will vaccinate haploidentical and
matched sibling donors prior to stem cell donation against HBV. Neither the
recipient nor the donor may previously have been immunized against HBV in all
cohorts. Post-transplantation, we will be able to evaluate whether SCD patients
preserve their pre-transplant immune response in the post-transplantation
period. Furthermore, we will determine whether donors transfer their immunity
to HSCT recipients with SCD disease.

Primarily, to investigate whether recipient immunity is preserved and how fast
it reconstitutes after non-myeloablative MSD HSCT resulting in mixed chimerism
in adult SCD patients. Secondly, to investigate whether donor immunity is
transferred to SCD patients after non-myeloablative haploidentical and MSD
HSCT.

Prospective observational cohort study. Six SCD patients with a MSD and six SCD
patients with a haploidentical donor will be vaccinated with recombinant HBV
vaccine before allogeneic HSCT and followed until 2 years post-transplantation
(cohort 1a and cohort 1b, respectively). Six HBV naive SCD patients not
undergoing allogeneic HSCT will be vaccinated as controls (cohort 2). Six
haploidentical donors and six matched sibling donors of unvaccinated receivers
will be vaccinated against HBV before stem cell donation (cohort 3a and 3b,
respectively). All vaccinated patients and the receivers of stem cells of
vaccinated donors will receive a booster vaccination at 12 months
post-transplantation.

Providing evidence that recipient immunity is preserved or transferred after
HSCT is the first step to safely omitting revaccinations in this patient
population. This would free patients from multiple visits to the hospital,
injections, potential side effects and also save costs. Conducting this study
will help gain valuable knowledge about the extent to which patients preserve
their immune response following non-myeloablative allogeneic HSCT. Preserved
immunity means a decreased risk of infectious complications after HSCT. We will
use a recombinant HBV vaccine because of its potential to induce high levels of
seroprotective antibodies. The HBV vaccine is safe and effective. Therefore,
we expect the risk for patients and donors to be low. The potential gain of
information from the study outweighs the potential discomfort that a patient or
donor might experience. Furthermore, most current guidelines advise vaccination
against HBV in the post allogeneic HSCT setting, which will not be necessary
for the study patients if anti-hepatitis B surface antigen antibody (anti-HBs)
response is preserved or adopted from the donor.