Preserved T-Cell Immunity Despite Impaired Humoral Responses following SARS-CoV-2 Infection and Vaccination in Children with Profound B-cell Lymphopenia

Understanding the mechanisms of vaccine-induced protection in children with humoral immunodeficiency is essential to guide prevention strategies and reduce COVID-19-related complications and mortality. Yet, comprehensive cellular, humoral and mucosal analyses are scarce in this high-risk population. We conducted a longitudinal evaluation of SARS-CoV-2 immunity at 1, 6 and 12 months after a primary series of the Pfizer-BioNTech mRNA vaccine (10 µg dose) in 27 children aged 5–11 years with primary or secondary antibody deficiencies and 48 age- and sex-matched healthy controls. Functional T-cell responses were quantified by interferon-gamma (IFN-γ) and IL-2 ELISpot, and SARS-CoV-2-specific B cells, CD4 ⁺ and CD8 ⁺ T-cell subsets were assessed using high-dimensional spectral cytometry. Systemic and mucosal antibody responses to spike (S) and receptor binding domain (RBD) were measured in serum and saliva, and neutralizing activity against ancestral and Omicron BA.5 strains variants was evaluated through microneutralization. Children with humoral immunodeficiency exhibited markedly impaired systemic antibody responses following two mRNA doses, despite SARS-CoV-2 infection, with restoration after a third vaccine dose. Those with severe B-cell lymphopenia were unable to mount neutralizing antibodies even after three doses and despite infection. Notwithstanding this profound humoral defect, they developed preserved, polyfunctional SARS-CoV-2-specific T-cell responses across multiple variants, which likely protected them from severe COVID-19. T-cell responses were higher in asymptomatic immunocompromised children, while all symptomatic infections were mild, supporting a potential contribution of cellular immunity to disease control in this population. These findings reveal a clear dissociation between humoral failure and preserved cellular immunity in B-cell–deficient children. They indicate that T-cell responses can act as alternate correlate of protection when neutralizing antibodies are absent, supporting timely vaccination in pediatric populations with profound B-cell deficiency.