Human cytomegalovirus control in allogeneic stem cell transplant recipients in the letermovir era emerging humoral and cellular players

Allogeneic hematopoietic stem cell transplant (alloSCT) recipients frequently experience late-onset human cytomegalovirus (HCMV) reactivations following termination of letermovir prophylaxis. Letermovir prophylaxis extends the window for protective B- and T-cell reconstitution; however, our understanding of humoral responses and their contribution to HCMV immune control remains limited. Combining serological and flow cytometric analyses in 42 HCMV-seropositive alloSCT recipients, we herein provide the first comprehensive longitudinal (days 90-270 post-transplant) characterization of HCMV-specific humoral responses, natural killer (NK)-cell phenotypes, and γδ T cells in the letermovir era. HCMV controllers showed predominantly HCMV-specific IgG-driven responses, higher pre-reactivation Vδ1+ γδ T-cell frequencies, and stronger expansion of "memory-like" NK cells than patients with clinically significant CMV infection (csCMVi). In contrast, csCMVi patients showed delayed HCMV-specific IgG production, IgM-skewed responses, and stronger postreactivation expansion of memory B cells and Vδ1+ γδ T cells. Early (day 90) γδ T-cell reconstitution was associated with subsequent HCMV control. HCMV-specific IgG levels correlated only weakly with γδ T cells but showed distinct associations with "memory-like" NK-cell reconstitution in HCMV controllers, suggesting synergisms between humoral and cellular immunity. Collectively, these findings highlight a need to study anti-HCMV immune protection beyond type-1 T cells and refine risk stratification models in alloSCT patients by inclusion of novel immune markers such as γδ T-cell frequencies and phenotypes. Leveraging the extended B-cell reconstitution window created by letermovir, novel immunotherapies (e.g., therapeutic antibodies) and future vaccines might boost humoral anti-HCMV immunity and benefit from synergisms with γδ T cells and "memory-like" NK cells in improving HCMV control.