Polysaccharide conjugate vaccines: From historical milestones to future strategies

Capsular polysaccharides (CPSs) of encapsulated bacterial pathogens, such as Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, serve as potent antigens for eliciting protective immunity against invasive infections. Polysaccharide and protein-polysaccharide conjugate vaccines have significantly reduced the global burden of diseases caused by these pathogens through direct immune protection and herd immunity. While traditional polysaccharide vaccines induce T cell-independent responses, conjugate vaccines-comprising CPSs linked to carrier proteins, drive robust T cell-dependent immunity, offering enhanced and durable protection. This review examines the evolution of polysaccharide-based vaccines, focusing on antigen design, carrier protein selection, and conjugation strategies, while addressing current challenges and future prospects. Key hurdles include the expansion of vaccine valency to broaden coverage against non-vaccine serotypes to lower the risk of serotype replacement, managing manufacturing and quality control complexities in multivalent formulations, and mitigating interference between carrier proteins and CPSs during T cell activation. Emerging strategies propose leveraging bacterial surface immunogenic proteins as novel carriers, which could streamline vaccine valency, amplify antibody-mediated protection, and circumvent existing limitations. Such innovations hold promise for advancing next-generation conjugate vaccines, optimizing efficacy while addressing the dynamic challenges of bacterial pathogenicity and vaccine development.