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We propose a protein-based pneumococcal vaccine (PBPV) \u2014 formulated with conserved surface proteins P3296, P5668, PRx1, and pneumolysin (Ply) \u2014 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 protection than 23-valent pneumococcal polysaccharide vaccine. Correlation analysis identified distinct PspA-specific IgG subclass roles: P3296-IgG1 correlated with OPA, and IgG3 correlated with ADNKA\/ADNP; P5668-IgG2 correlated with ADNKA\/ADNP, and IgG3 correlated with OPA; and PRx1-IgG2 correlated with OPA, and IgG3 correlated with ADNKA. Critically, while no efficacy data have yet confirmed the protective effect of PBPV, its targeting of conserved proteins rather than capsular polysaccharides enables simplified manufacturing and expanded coverage, positioning it as a promising alternative to traditional multipolysaccharide vaccines.<\/jats:p>","DOI":"10.1172\/jci196261","type":"journal-article","created":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T19:01:17Z","timestamp":1769972477000},"source":"Crossref","is-referenced-by-count":1,"title":["A protein-based pneumococcal vaccine elicits broad immunity associated with multifunctional antibody responses in humans"],"prefix":"10.1172","volume":"136","author":[{"given":"Kaiyi","family":"Li","sequence":"first","affiliation":[{"name":"State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 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