PMID- 36522265 OWN - NLM STAT- MEDLINE DCOM- 20230103 LR - 20230203 IS - 1873-2518 (Electronic) IS - 0264-410X (Linking) VI - 41 IP - 3 DP - 2023 Jan 16 TI - A phase 3, multicenter, randomized, double-blind study to evaluate the interchangeability of V114, a 15-valent pneumococcal conjugate vaccine, and PCV13 with respect to safety, tolerability, and immunogenicity in healthy infants (PNEU-DIRECTION). PG - 657-665 LID - S0264-410X(22)01344-5 [pii] LID - 10.1016/j.vaccine.2022.10.072 [doi] AB - BACKGROUND: Pneumococcal disease (PD) remains a major health concern globally. In children, pneumococcal conjugate vaccines (PCVs) provide protection against PD from most vaccine serotypes, but non-vaccine serotypes contribute to residual disease. V114 is a 15-valent PCV containing all 13 serotypes in Prevnar 13 (PCV13) and public health important serotypes 22F and 33F. This phase 3 study evaluated safety and immunogenicity of mixed PCV13/V114 regimens using a 3 + 1 dosing schedule when changing from PCV13 to V114 at doses 2, 3, or 4. METHODS: 900 healthy infants were randomized equally to 5 intervention groups. PCVs were administered in a 3-dose infant series at 2, 4, and 6 months of age followed by a toddler dose at 12-15 months along with concomitant routine vaccines. Safety was evaluated as the proportion of participants with adverse events (AEs). Immunoglobulin G (IgG) responses to the 15 serotypes in V114 were measured at 30 days post-dose 3 and 30 days post-dose 4 (PD4). RESULTS: Frequencies of injection-site and systemic AEs were generally comparable across all intervention groups. At 30 days PD4 (primary endpoint), IgG geometric mean concentrations (GMCs) for the 13 shared serotypes were generally comparable between mixed V114/PCV13 and 4-dose regimens of PCV13 or V114. In mixed regimens at 30 days PD4, a toddler dose of V114 was sufficient to achieve IgG GMCs comparable to a 4-dose regimen of V114 for serotype 22F, while at least one infant dose was needed in addition to the toddler dose to achieve IgG GMCs comparable to a 4-dose regimen of V114 for serotype 33F. CONCLUSIONS: V114 was well tolerated with a generally comparable safety profile to PCV13. For 13 shared serotypes, both mixed regimens and the V114 4-dose regimen induced generally comparable antibody responses to 4-dose regimen with PCV13. Study results support interchangeability of V114 with PCV13 in infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03620162; EudraCT: 2018-001151-12. CI - Copyright (c) 2022. Published by Elsevier Ltd. FAU - Bili, Androniki AU - Bili A AD - Merck & Co., Inc., Rahway, NJ, USA. FAU - Dobson, Scott AU - Dobson S AD - Parkside Clinical Research and Tribe Clinical Research, Greenville, SC, USA. FAU - Quinones, Jeffrey AU - Quinones J AD - Clinical Research of Puerto Rico, Guayama, Puerto Rico. FAU - Phongsamart, Wanatpreeya AU - Phongsamart W AD - Mahidol University, Bangkok, Thailand. FAU - Oberdorfer, Peninnah AU - Oberdorfer P AD - Chiang Mai University, Chiang Mai, Thailand. FAU - Kosalaraksa, Pope AU - Kosalaraksa P AD - Khon Kaen University, Khon Kaen, Thailand. FAU - Dagan, Ron AU - Dagan R AD - The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences of the Ben-Gurion University of the Negev Beer-Sheva, Israel. FAU - Richmond, Peter AU - Richmond P AD - University of Western Australia School of Medicine, Perth, Australia. FAU - Wilck, Marissa AU - Wilck M AD - Merck & Co., Inc., Rahway, NJ, USA. FAU - Vallejos, Waldimir AU - Vallejos W AD - Merck & Co., Inc., Rahway, NJ, USA. FAU - Nunn, Christine AU - Nunn C AD - Merck & Co., Inc., Rahway, NJ, USA. FAU - McFetridge, Richard AU - McFetridge R AD - Merck & Co., Inc., Rahway, NJ, USA. FAU - Tamms, Gretchen AU - Tamms G AD - Merck & Co., Inc., Rahway, NJ, USA. FAU - Fu, Rong AU - Fu R AD - MSD, China. FAU - Lupinacci, Robert AU - Lupinacci R AD - Merck & Co., Inc., Rahway, NJ, USA. FAU - Musey, Luwy AU - Musey L AD - Merck & Co., Inc., Rahway, NJ, USA. FAU - Banniettis, Natalie AU - Banniettis N AD - Merck & Co., Inc., Rahway, NJ, USA. Electronic address: Natalie.Banniettis@merck.com. FAU - Bickham, Kara AU - Bickham K AD - Merck & Co., Inc., Rahway, NJ, USA. CN - V114-027 PNEU-DIRECTION study group LA - eng SI - ClinicalTrials.gov/NCT03620162 SI - EudraCT/2018-001151-12 PT - Journal Article PT - Multicenter Study PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20221213 PL - Netherlands TA - Vaccine JT - Vaccine JID - 8406899 RN - 0 (Heptavalent Pneumococcal Conjugate Vaccine) RN - 0 (Vaccines, Conjugate) RN - 0 (Pneumococcal Vaccines) RN - 0 (Antibodies, Bacterial) RN - 0 (Immunoglobulin G) SB - IM MH - Humans MH - Infant MH - Heptavalent Pneumococcal Conjugate Vaccine MH - Vaccines, Conjugate MH - Double-Blind Method MH - *Pneumococcal Vaccines MH - Antibodies, Bacterial MH - *Pneumococcal Infections MH - Immunoglobulin G OTO - NOTNLM OT - Immunogenicity OT - Pediatric OT - Pneumococcal vaccine OT - Safety COIS- Declaration of Competing Interest A.B., M.W., W.V., C.N., R.M., G.T., R.F., R.L., and L.M. are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (MSD) and may hold stock in Merck & Co., Inc., Rahway, NJ, USA. K.B. was an employee of MSD at the time of the study, may hold stock in Merck & Co., Inc., Rahway, NJ, USA, and is currently employed by Affinivax Inc. R.D. reports i) grants or contracts from Pfizer, Medimmune, and MSD; ii) consulting fees from Pfizer, Biondvax, MeMed, and MSD; iii) serving on advisory boards of Pfizer, Biondvax, and MSD; iv) providing expert testimony for Pfizer; and v) participating on an advisory board for Pfizer, Biondvax, and MSD. P.R. has served on vaccine advisory boards for MSD, Pfizer, and GlaxoSmithKline and received institutional grant funding from GlaxoSmithKline and MSD outside the submitted work. EDAT- 2022/12/16 06:00 MHDA- 2023/01/04 06:00 CRDT- 2022/12/15 22:06 PHST- 2022/04/05 00:00 [received] PHST- 2022/10/24 00:00 [revised] PHST- 2022/10/26 00:00 [accepted] PHST- 2022/12/16 06:00 [pubmed] PHST- 2023/01/04 06:00 [medline] PHST- 2022/12/15 22:06 [entrez] AID - S0264-410X(22)01344-5 [pii] AID - 10.1016/j.vaccine.2022.10.072 [doi] PST - ppublish SO - Vaccine. 2023 Jan 16;41(3):657-665. doi: 10.1016/j.vaccine.2022.10.072. Epub 2022 Dec 13.