The study investigated how the body develops immunity against pneumococci in hematopoietic stem cell transplant patients who remain highly susceptible to pneumococcal infections despite vaccination. The researchers looked at immune responses to sequential vaccination – first with a 13-valent conjugate vaccine (PCV13) and then with a 23-valent polysaccharide vaccine (PPV23). Conjugate vaccination successfully induced the generation of pneumococcal-specific T-cells and memory cells. However, subsequent administration of the polysaccharide vaccine did not increase T-cell responses in sequentially vaccinated patients and paradoxically reduced antibody levels against the serotypes that were included in both vaccines. Nevertheless, the sequential regimen induced a strong inflammatory response characterized by increased secretion of specific cytokines. The results suggest that conjugate vaccination is necessary to activate both cellular and humoral immunity, while the polysaccharide booster primarily expands serotype coverage. The findings support a reevaluation of the need for polysaccharide boosters and optimization of pneumococcal vaccination strategies in patients at high risk of invasive disease after transplantation.