Pneumococcal surface proteins as targets for next-generation vaccines: Addressing the challenges of serotype variation

Streptococcus pneumoniae is a major global pathogen causing significant morbidity and mortality, particularly among children, the elderly, and immunocompromised populations. While pneumococcal conjugate vaccines (PCVs) have successfully reduced invasive pneumococcal disease (IPD), challenges such as serotype replacement and non-encapsulated strains necessitate serotype-independent vaccine strategies. Pneumococcal surface proteins, including pneumolysin (Ply), choline-binding proteins (CBPs), and histidine triad proteins (PHTs), represent promising universal vaccine targets due to their conserved nature and roles in adhesion, immune evasion, and biofilm formation. Advances in protein engineering, such as detoxified Ply derivatives and multivalent formulations incorporating PhtD and PspA, demonstrate potential in preclinical studies. Novel technologies, including reverse vaccinology and extracellular vesicle-based platforms, further accelerate innovation. This review highlights recent progress in pneumococcal surface protein research, emphasizing their potential to address the limitations of PCVs and mitigate antibiotic-resistant pneumococcal strains, representing a transformative approach to global pneumococcal disease prevention.