Systems analysis of immunity to pneumococcal vaccination in preterm and full term infants

Abstract Background Preterm infants mount lower humoral responses to the 13-valent pneumococcal conjugate vaccine (PCV13) than full-term infants; however, the long-term impact of prematurity on vaccine-induced protection remains unclear. This study investigates the innate and adaptive immune responses to a 3+1 PCV13 schedule in preterm versus full-term infants using transcriptomic profiling and B-cell immunophenotyping. Methods Thirty-eight infants (19 preterm,19 full-term) received PCV13 at 2,4,6, and 12 months. Polysaccharide (PS)1- and PS9V-specific memory B cells (MBCs) were enumerated and phenotyped by flow cytometry, while PS-specific IgG concentrations were measured by ELISA before and after the third and booster doses. RNA sequencing was performed before and 3 days after the third dose. Results Primary PCV13 immunization induced a markedly broader transcriptional response in preterm than in full-term infants (267 differentially expressed genes vs. 29 in full-term), dominated by pro-inflammatory signatures. Preterm infants exhibited higher frequencies of total and PS-specific extra-germinal center(GC) MBCs but lower switched MBCs following primary immunization; these differences largely converged post-booster. PS-specific IgG titers remained lower in preterm infants both after primary and booster doses. PS-specific switched MBCs post-primary were positively correlated with antibody titers post-booster. The broad upregulation of pro-inflammatory genes in preterm infants was negatively correlated with their PS-specific antibody titers. Conclusions PCV13 immunization elicits distinct immunological profiles in preterm vs full-term infants, marked by skewed B-cell differentiation and broader pro-inflammatory transcriptional activity. Booster immunization largely harmonized MBC composition across gestational groups, while early GC-derived MBC populations emerged as candidate correlated of durable vaccine-induced immunity.