Conjugated pneumococcal vaccination yields broadly functional, mucosal-directed responses detectable up to at least 42 months in older adults.

Streptococcus pneumoniae is a causative agent of severe pneumonia, particularly in at-risk populations. To characterize immune responses elicited by the 13-valent pneumococcal conjugate (PCV13) or 23-valent pneumococcal polysaccharide (PPSV23) vaccines, we deeply profiled antibody responses against select serotypes (Pn1, Pn3, Pn6A, Pn6B, Pn7F, Pn19A, Pn19F, and Pn23F) at 1, 12, and 42 months post-vaccination in vaccine-naive adults aged 60-64 years. At 1 month post-vaccination, recipients of PCV13 had higher IgG, IgA, and antibody-dependent complement deposition (ADCD) levels than PPSV23 recipients, particularly against serotype Pn6A. At 12 months post-vaccination, PCV13 induced IgA and IgG-ADCD networks against S. pneumoniae Pn1, Pn6A, Pn6B, and Pn7F, while only serotype Pn6A was targeted by both mechanisms in PPSV23 recipients. At 42 months post-vaccination, recipients of PCV13 retained IgA and IgG-ADCD networks against multiple S. pneumoniae serotypes. A durable IgA- and ADCD-primed response in PCV13 recipients points to a strong, multifunctional humoral response by this vaccine platform.