ZPY-CpG-Ch, a broad coverage vaccine against Streptococcus pneumoniae.

Existing licensed pneumococcal vaccines, including Prevnar-13 and its higher-valency successors, have played a major role in reducing invasive pneumococcal disease worldwide. However, their effectiveness is increasingly threatened by the rise of multidrug-resistant strains and the shift in circulating serotypes toward those not targeted by current vaccines-a trend known as serotype replacement. These evolving challenges underscore the urgent need for next-generation vaccines with broader, serotype-independent protection-long considered the holy grail of pneumococcal vaccine development. Here, we report the discovery and preclinical evaluation of ZPY-CpG-Ch, a broad-coverage protein-based pneumococcal vaccine formulation. We assessed the protective efficacy and immunogenicity of ZPY-CpG-Ch in translational murine models, using both adult and neonatal mice, and tested various adjuvants, protein combinations, and doses, followed by challenge experiments with both vaccine- and non-vaccine-covered serotypes. Prevnar-13 was included as a benchmark. While Prevnar-13® demonstrated robust efficacy, our results show that ZPY-CpG-Ch achieves greater cross-serotype protection. We attribute this enhanced efficacy primarily to TH17 (T helper 7)-biased immune responses. Together, these findings highlight the promise of genome-guided, protein-based vaccines in overcoming the limitations of current serotype-based approaches and represent a meaningful step toward a truly universal pneumococcal vaccine.