The impact of B‐cell reconstitution on mRNA vaccine responses in allogeneic stem cell transplant recipients

Objectives: Vaccine responses in haematopoietic stem cell transplant (alloHCT) recipients vary, with different degrees of B-cell reconstitution likely playing a key role. However, mechanistic understanding of the B-cell receptor (BCR) repertoire and its functional impact post-alloHCT remain limited. Methods: = 77), we have measured antibody titers and avidity, and performed B-cell immunophenotyping and B-cell receptor repertoire sequencing in sub-populations. Results: AlloHCT patients receiving prime-boost mRNA vaccination within 12 months post-transplant exhibited lower vaccine-specific antibody levels and memory B-cell frequencies than vaccinated healthy controls. Responses were comparable to healthy controls in patients vaccinated later than 12 months post transplant. BCR repertoire sequencing showed reduced somatic hypermutation (SHM) levels in bulk IgG+ B cells from alloHCT patients. Although some alloHCT patients showed exceptional expansion of a few IgG clones of unknown specificity, their overall B-cell repertoires remained polyclonal. Vaccine-specific B-cell clonotypes detected in patients responding to vaccination showed similar proportional expansion and SHM as in controls. The level of immature CD24hiCD38hi transitional B cells pre-vaccination was negatively correlated to the vaccine response, and can be used as a predictor of antibody titres. Conclusion: Our data indicate that mRNA vaccination can stimulate expansion of vaccine-specific B cells to affinity mature in many alloHCT recipients, though restricted by the presence of immature B-cell populations.