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Pneumococcal protein vaccines have attracted considerable attention owing to their favorable immunogenicity and antigen conservation, and have demonstrated protective potential against non-serotype-dependent infections. Mice immunized with a trivalent vaccine targeting protein PepN, PepO, and SPD_1609 elicited a robust humoral immune response, as well as Th1, Th2, and Th17 cellular immune responses. The antiserum derived from the trivalent vaccine significantly inhibited <jats:italic>Streptococcus pneumoniae<\/jats:italic> adhesion to A549 cells, reduced pneumococcal colonization in the nasopharynx, and improved lung tissue damage and inflammatory responses compared to the monovalent or bivalent vaccine group. In terms of <jats:italic>in vivo<\/jats:italic> protection, the trivalent vaccine significantly increased the survival rate of infected mice. The findings suggest that the trivalent vaccine targeting PepN, PepO, and SPD_1609 is a promising multivalent vaccine candidate against <jats:italic>Streptococcus pneumoniae<\/jats:italic>.<\/jats:p>","DOI":"10.3389\/fcimb.2025.1563661","type":"journal-article","created":{"date-parts":[[2025,6,27]],"date-time":"2025-06-27T05:32:05Z","timestamp":1751002325000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Intranasal trivalent candidate vaccine elicits broad humoral and cellular immunity against pneumococcal pneumonia"],"prefix":"10.3389","volume":"15","author":[{"given":"Fangyu","family":"Ren","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luyun","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shilu","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changjin","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xianlian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiqi","family":"Linghu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huaqin","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyu","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuanqin","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xun","family":"Min","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,6,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2022.105734","article-title":"The role of bacterial ATP-binding cassette (ABC) transporters in pathogenesis and virulence: Therapeutic and vaccine potential","volume":"171","author":"Akhtar","year":"2022","journal-title":"Microb. 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