biostudies-literatureUnknown136(3)Li KTraditional polysaccharide vaccines are constrained by streptococcus pneumoniae diversity. We propose a protein-based pneumococcal vaccine (PBPV) - formulated with conserved surface proteins P3296, P5668, PRx1, and pneumolysin (Ply) - that could potentially offer superior immune breadth independent of capsular polysaccharide serotypes. Here, we evaluated the multifunctional antibody responses induced by PBPV, including immunogenicity, Ply neutralization, opsonophagocytic activity (OPA), and such nonopsonic functions as NK cell activation (ADNKA), antibody-dependent cellular phagocytosis, and neutrophil phagocytosis (ADNP) in a cohort of 50- to 69-year-olds. While PBPV showed shorter-lasting immune responses, including reduced Ply-neutralizing capacity, it provided broader cross-serotype prThe Journal of clinical investigatione196261https://www.ebi.ac.uk/biostudies/studies/S-EPMC12867161biostudies-literatureA protein-based pneumococcal vaccine elicits broad immunity associated with multifunctional antibody responses in humans.PMC12867161Yang JWei BJin SGou JLi KZhou XWang JYang XZhai XZhang YSui XWang YSu XWang ZZhu TfalseA protein-based pneumococcal vaccine elicits broad immunity associated with multifunctional antibody responses in humans.Traditional polysaccharide vaccines are constrained by streptococcus pneumoniae diversity. We propose a protein-based pneumococcal vaccine (PBPV) - formulated with conserved surface proteins P3296, P5668, PRx1, and pneumolysin (Ply) - that could potentially offer superior immune breadth independent of capsular polysaccharide serotypes. Here, we evaluated the multifunctional antibody responses induced by PBPV, including immunogenicity, Ply neutralization, opsonophagocytic activity (OPA), and such nonopsonic functions as NK cell activation (ADNKA), antibody-dependent cellular phagocytosis, and neutrophil phagocytosis (ADNP) in a cohort of 50- to 69-year-olds. While PBPV showed shorter-lasting immune responses, including reduced Ply-neutralizing capacity, it provided broader cross-serotype pr2026-01-01T00:00:00Z2026 Feb2026-07-15T13:13:18.065Z2026-07-05T03:08:12.495ZS-EPMC128671614162316710.1172/JCI196261