Pneumococcal vaccine after hematopoietic cell transplantation: a rapid review of four-dose pneumococcal conjugate vaccine schedules.

Abstract

Hematopoietic cell transplant (HCT) recipients are at substantially elevated risk for invasive pneumococcal disease (IPD) due to prolonged immunocompromised state, yet optimal pneumococcal vaccine product selection and scheduling, including the role of higher-valency pneumococcal conjugate vaccines (PCVs), have not undergone Advisory Committee on Immunization Practices review. We conducted a rapid review to synthesize evidence on the immunogenicity and safety of four-dose PCV schedules in HCT recipients to inform future clinical guidance. Following Cochrane rapid review methods and PRISMA guidelines, we searched Medline, Embase, and Scopus (initial: November 2024; updated: March 2025) and identified 31 eligible studies. Four studies directly evaluated four-dose PCV13 or PCV15 regimens in allogeneic HCT recipients, and only one study provided a direct randomized comparison. Among studies that allowed comparison, four-dose PCV13 schedules consistently generated higher overall and serotype-specific IgG and opsonophagocytic activity responses than three-dose PCV13 followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23), while PPSV23 provided limited additional benefit when administered within 1-2 months of the final PCV13 dose. Both randomized and nonrandomized studies demonstrated robust antibody responses following the fourth PCV dose, and safety profiles were acceptable. Although adverse events were more frequent after the fourth PCV dose, serious vaccine-related events were rare and difficult to attribute given underlying comorbidities. Findings from 27 supporting studies further contextualized optimal timing and product choice, showing that later initiation (≥6 months post-HCT) was often associated with stronger and more durable immune responses, although waning immunity remained common. PCV-based regimens were consistently more immunogenic than PPSV23-only schedules. No studies evaluated PCV20 or PCV21 in HCT recipients, representing a major evidence gap despite their expanded serotype coverage. Overall, the available evidence provides evidence of immunogenicity and safety with a four-dose PCV-based schedule initiated 3-6 months post-HCT, while critical research gaps remain regarding higher-valency PCVs, mixed-product schedules, and strategies tailored to transplant type or individual immunologic risk.