Half a century of pneumococcal vaccination in sickle cell disease: Are we winning the battle or losing immunity?

Despite marked reductions in the rate of invasive pneumococcal disease (IPD) due to widespread use of penicillin prophylaxis and vaccination, individuals with sickle cell disease (SCD) remain at disproportionately high risk of pneumococcal infections. Pneumococcal conjugate vaccines (PCVs) have demonstrated improved immunogenicity over time by inducing T cell-dependent memory responses and have contributed significantly to reducing vaccine-type IPD in this population. However, persistent disease burden from non-vaccine serotypes and suboptimal antibody durability underscores the need for broader serotype coverage and a tailored immunization schedule. Until recently, the 23-valent pneumococcal polysaccharide vaccine (PPSV23) was recommended for individuals with SCD to expand serotype protection. However, numerous studies indicate that PPSV23 has limited effectiveness in immunocompromised populations, including SCD, and may induce hyporesponsiveness when administered repeatedly or when inappropriately sequenced with PCVs. The approval of higher-valency conjugate vaccines (e.g., PCV20 and PCV21) offers promise for expanding serotype coverage while minimizing reliance on PPSV23. Nonetheless, real-world data on immunogenicity, durability, and clinical efficacy in SCD remain sparse. This review examines the intricate immunological interactions between PCVs and PPSV23 in the context of SCD, with a focus on vaccine-induced hyporesponsiveness, serotype replacement, and the evolving epidemiology of pneumococcal disease. It highlights the need for optimized evidence-based vaccination strategies and longitudinal monitoring among patients with SCD. A precision vaccination approach tailored to the unique immunological deficits of individuals with SCD will be essential to ensure sustained and comprehensive protection against pneumococcal disease.