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Background: Pneumococcal conjugate vaccines (PCVs) significantly reduced pneumococcal disease burden. Nevertheless, alternative approaches for controlling more serotypes are needed. Here, the safety, tolerability, and immunogenicity of a 24-valent (1/2/3/4/5/6A/6B/7F/8/9N/9V/10A/11A/12F/14/15B/17F/18C/19A/19F/20B/22F/23F/33F) pneumococcal vaccine based on Multiple Antigen-Presenting System (MAPS) technology (Pn-MAPS24v) was assessed in toddlers., Methods: In this phase 1, blinded, dose-escalation, active-controlled multicenter study conducted in the United States (September/2020-April/2022), 12-15-month-old toddlers primed with three doses of 13-valent PCV (PCV13) were randomized 3:2 to receive a single dose of one of three Pn-MAPS24v dose levels (1 μg/2 μg/5 μg per polysaccharide) or PCV13 intramuscularly. Reactogenicity (within 7 days), treatment-emergent adverse events (TEAEs, within 180 days), serious/medically attended adverse events (SAEs/MAAEs, within 180 days), and immunogenicity (serotype-specific anti-capsular polysaccharide immunoglobulin G [IgG] and opsonophagocytic activity [OPA] responses at 30 days post-vaccination) were assessed., Results: Of 75 toddlers enrolled, 74 completed the study (Pn-MAPS24v 1 μg/2 μg/5 μg: 15/14/16, PCV13: 29). Frequencies of local (60 %/67 %/31 %) and systemic events (67 %/67 %/75 %) in the Pn-MAPS24v 1 μg/2 μg/5 μg and the PCV13 (55 %, 79 %) groups were in similar ranges. TEAEs were reported by 47 %/40 %/63 % of Pn-MAPS24v 1 μg/2 μg/5 μg recipients and 52 % of PCV13 recipients. No vaccine-related SAE was reported. At 30 days post-vaccination, for each of the 13 common serotypes, ≥93 % of participants in each group had IgG concentrations ≥0.35 μg/mL; >92 % had OPA titers ≥lower limit of quantitation (LLOQ), except for serotype 1 (79 %). For 7/11 unique serotypes (2/8/9N/11A/17F/22F/33F), at all dose levels, ≥78 % of Pn-MAPS24v recipients in each group had IgG concentrations ≥0.35 μg/mL and 80 %-100 % had OPA titers ≥LLOQ., Conclusions: In 12-15-month-old toddlers, a single dose of Pn-MAPS24v showed an acceptable safety profile, regardless of dose level; AEs were reported at similar frequencies by Pn-MAPS24v and PCV13 recipients. Pn-MAPS24v elicited IgG and OPA responses to all common and most unique serotypes. These results support further clinical evaluation in infants., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dorota Borys is an employee of GSK and holds shares from GSK. Gurunadh R Chichili, Laura L Kovanda, Vicki Santos and Ronald Smulders are employees of Astellas Pharma Global Development, Inc. Frank Malinoski, Richard Malley and Shite Sebastian were employees of Affinivax, Inc. at the time the study was designed, initiated, and/or conducted. George Siber and Richard Malley were Affinivax, Inc. board members at the time the study was designed, initiated, and/or conducted. Frank Malinoski holds stock or stock options from Affinivax, Inc. George Siber disclosed that Siber Biotechnologies LLC received consulting fees and stock ownership, as well as support for attending meetings and/or travel, from Affinivax, Inc. Richard Malley declares potential future payments and royalties as equity holder of Affinivax, Inc. and named co-inventor of MAPS technology. Richard Malley is a former employee of GSK and now a consultant of GSK. Richard Malley received consulting fees from GSK as consultant in the area of vaccines and disclosed GSK support for attending meetings and/or travel, and participation to a GSK Advisory board. Richard Malley has issued or pending patents on MAPS technology. Richard Rupp disclosed financial support from Astellas Pharma Global Development, Inc. to the University of Texas Medical Branch for the present study, and financial support from GSK and Affinivax, Inc. for participation to the Data Monitoring Committee (Affinivax, Inc.) and the Data Safety Monitoring Committee (GSK). Shite Sebastian is currently an employee of GSK. Shite Sebastian has issued and pending patents on Multivalent Pneumococcal Vaccine. All authors have no other financial or non-financial interests to declare., (Copyright © 2024 GSK. Published by Elsevier Ltd.. All rights reserved.)