Background: Individuals who receive allogeneic hematopoietic cell transplant (allo-HCT) are immunocompromised and at high risk of pneumococcal infections, especially in the months following transplant. This study evaluated the safety and immunogenicity of V114 (VAXNEUVANCE; Merck, Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA), a 15-valent pneumococcal conjugate vaccine (PCV), when given to allo-HCT recipients., Methods: Participants received 3 doses of V114 or PCV13 (Prevnar 13; Wyeth LLC) in 1-month intervals starting 3-6 months after allo-HCT. Twelve months after HCT, participants received either PNEUMOVAX 23 or a fourth dose of PCV (if they experienced chronic graft vs host disease). Safety was evaluated as the proportion of participants with adverse events (AEs). Immunogenicity was evaluated by measuring serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) for all V114 serotypes in each vaccination group., Results: A total of 274 participants were enrolled and vaccinated in the study. The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at day 90., Conclusions: V114 was well tolerated in allo-HCT recipients, with a generally comparable safety profile to PCV13. V114 induced comparable immune responses to PCV13 for the 13 shared serotypes, and was higher for V114 serotypes 22F and 33F. Study results support the use of V114 in allo-HCT recipients. Clinical Trials Registration. clinicaltrials.gov (NCT03565900) and European Union at EudraCT 2018-000066-11., Competing Interests: Potential conflicts of interest. M. W., Q. C., C. D., K. G., G. T., T. Sterling, S. M. P., T. Shekar, and U. K. B. are employees of MSD, and may hold stock in Merck & Co, Inc., Rahway, NJ, USA. L. M. was an employee of MSD at the time of the study and may hold stock in Merck & Co, Inc., Rahway, NJ, USA. L. M. is a co-inventor of a dozen patents related to the development of several pneumococcal conjugate vaccines, including the one being evaluated in this study. O. A. C. reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, and Scynexis (payments all made to the University Hospital of Cologne); consulting fees from Abbvie, Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, Pardes, Pfizer, PSI, Scynexis, and Seres (all payments to the author); honoraria for lectures from Abbott, Abbvie, Al-Jazeera Pharmaceuticals, Astellas, Gilead, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, MSD, Mylan, Noscendo, Pfizer, and Shionogi (all payments to the author); payment for expert testimony from Cidara; participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Janssen, MedPace, Paratek, PSI, Pulmocide, Shionogi, and The Prime Meridian Group; a patent at the German Patent and Trade Mark Office (DE 10 2021 113 007.7: German patent [“Geschlossene Inkubationssysteme mit verbessertem Atemwegszugang für Untersuchungsvorrichtungen”] filed by the University of Cologne and the listing author as 1 of 3 inventors); and stocks from CoRe Consulting and stock or stock options from EasyRadiology. O. A. C. also reports other financial or nonfinancial interests with DGHO, DGI, ECMM, EHA, ISHAM, MSG-ERC, and Wiley (Chair Infectious Diseases Working Party [DGHO], Chair SWG Infections in Hematology [EHA], Advisory Committee Member [DGI], Educational Officer [ECMM], Treasurer [ISHAM], Board of Directors Member [MSG-ERC], Editor-in-Chief for Mycoses [Wiley]). R. D. has received grants/research support from Pfizer, MSD, and Medimmune (to Ben Gurion University); has been a scientific consultant for Pfizer, MeMed, MSD, and Biondvax (Pfizer and MSD fees to ISRAVAX); has served on advisory boards of Pfizer, MSD, and Biondvax; has been a speaker for Pfizer, MSD, Sanofi Pasteur, and GSK (payment or honoraria to ISRAVAX); and reports payment for expert testimony from Pfizer to ISRAVAX. P. R. has served on vaccine advisory boards for MSD (Pneumococcal Vaccine Scientific Advisory Board March 2020, ongoing; institutional payments; no personal remuneration and RSV Monoclonal Antibody Scientific Advisory Board May 2022–February 2023; institutional payments; no personal remuneration), Pfizer (Meningococcal Vaccine Advisory Board November 2020, ongoing; institutional payments; no personal remuneration; and RSV Vaccine Advisory Board December 2022; institutional payments; no personal remuneration), and GlaxoSmithKline (RSV Scientific Advisory Board May 2021; institutional payments, no personal remuneration; and Meningococcal Vaccines Advisory Boards March 2021 to May 2023; institutional payments, no personal remuneration); received institutional grant funding from GlaxoSmithKline and MSD outside the submitted work (MSD: investigator-initiated research grants to Institution 2021 on RSV and pneumococcal diseases, no personal remuneration); and reports payment or honoraria from GlaxoSmithKline for lectures on meningococcal disease and vaccines October 2021 to October 2022; institutional payments, no personal remuneration; support to attend the International Society for Pneumococci and Pneumococcal Diseases Conference, Toronto, Canada, June 2022, to present at the Pneumonia Symposium from GlaxoSmithKline and to attend the Meningococcal Advisory Board meeting, Madrid, Spain, November 2022, from Pfizer. U. K. B. reports support for attending meetings and/or travel as an employee of MSD. P. L. reports consulting fees paid to their institution from Moderna; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Moderna and MSD (payment to institution); and participation on a Data Safety Monitoring Board or Advisory Board for MSD for a completely different topic (CMV) (paid to the author). J. M. reports consulting fees from Gilead Sciences, Mundipharma, F2G, and Pfizer, Inc (paid to the author); payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events; and support for attending meetings and/or travel from Gilead Sciences, Mundipharma, and F2G (paid to the author). K. M. M. reports grants or contracts and payment for honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from MSD; and participation on a Data Safety Monitoring Board or Advisory Board for Micrologics (purchased by Ferring Pharmaceuticals). S. N. reports consulting fees from Abbvie, AstraZeneca, Kite, Janssen, Lilly, Roche; payment or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing, or educational events from Abbvie, AstraZeneca, Kite, Takeda, Janssen, Novartis, and MSD; support for attending meetings and/or travel from Abbvie, AstraZeneca, Kite, Janssen, and Novartis. M. W. reports support for attending meetings and/or travel as an employee of MSD. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)