Pneumococcal live attenuated vaccine: strategies, challenges and future perspectives

Pneumococcal disease remains a major global health challenge despite the availability of polysaccharide and conjugate vaccines. Although these platforms have reduced invasive disease, their limitations, such as poor immunogenicity in infants, lack of durable protection, and restricted coverage, highlight the need to explore innovative preventive strategies. Next-generation vaccines that provide comprehensive protection, sustained immunity, and cost-effectiveness are urgently required. Live attenuated vaccines (LAVs) represent a promising frontier in this effort, with recent advances focused on overcoming developmental and safety challenges. This review highlights the evolving pneumococcal vaccine landscape, with emphasis on LAV strategies. We summarize the strengths and shortcomings of current vaccines, examine recent advances in LAV development, including key aspects of attenuation, immune-protective mechanisms, and delivery approaches. LAVs demonstrate potential to induce balanced mucosal, humoral, and cellular immunity, addressing critical gaps left by existing platforms. Key challenges related to genetic stability, safety, and translational applicability are also discussed. By synthesizing established knowledge and highlighting advancements, this review underscores the promise of LAVs as next-generation candidates that can provide broader, longer-lasting protection against pneumococcal disease.