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Objectives: To assess the safety and immunogenicity of a fourth vaccination (second booster) in individuals aged ≥75 years., Methods: Participants were randomized to BNT162b2 (Comirnaty, 30 µg) or messenger RNA (mRNA)-1273 (Spikevax, 100 µg). The primary end point was the rate of two-fold antibody titer increase 14 days after vaccination, targeting the receptor binding domain (RBD) region of wild-type SARS-CoV-2. The secondary end points included changes in neutralizing activity against wild-type and 25 variants. Safety was assessed by monitoring solicited adverse events (AEs) for 7 days., Results: A total of 269 participants (mean age 81 years, mRNA-1273 n = 135/BNT162b2 n = 134) were included. Two-fold anti-RBD immunoglobulin (Ig) G titer increase was achieved by 101 of 129 (78%) and 116 of 133 (87%) subjects in the BNT162b2 and the mRNA-1273 group, respectively (P = 0.054). A second booster of mRNA-1273 provided higher anti-RBD IgG geometric mean titer: 21.326 IU/mL (95% confidence interval: 18.235-24.940) vs BNT162b2: 15.181 IU/mL (95% confidence interval: 13.172-17.497). A higher neutralizing activity was noted for the mRNA-1273 group. The most frequent AE was pain at the injection site (51% in mRNA-1273 and 48% in BNT162b2). Participants in the mRNA-1273 group had less vaccine-related AEs (30% vs 39%)., Conclusions: A second booster of either BNT162b2 or mRNA-1273 provided substantial IgG increase. Full-dose mRNA-1273 provided higher IgG levels and neutralizing capacity against SARS-CoV-2, with similar safety profile for subjects of advanced age., Competing Interests: Declarations of competing interest JS has received research grants by the German Federal Ministry of Education and Research (BMBF), Noscendo and Basilea Pharmaceuticals; has received speaker honoraria by AbbVie, Hikma, Pfizer and Gilead; has been a consultant to Gilead, Produkt&Markt GmbH, Alvea Vax and Micron Research and has received travel grants by German Society for Infectious Diseases (DGI) and Meta-Alexander Foundation, all outside the submitted work. MA has received research grants from Pfizer and Gilead. Contributed to educational activities organized/supported by Pfizer, Roche, Gilead, GSK, Moderna and Sanofi. All honoraria from these activities are paid to the Institution. JSG has received speaker honoraria from Gilead and Pfizer, outside of the submitted work. MZ has received honoraria for lecturing courses by Pfizer Malaysia; is now an employee with AiCuris AG. RS has received lecture honoraria from Pfizer and Hikma, outside of the submitted work. JFI has received research grants by the Instituto de Salud Carlos III, Ministry of Science. Spain has received grants or research contracts from Laboratorios Faes, Normon, Pfizer, Italfarmaco, GSK, Prestige; has been a consultant or has received speaker honoraria from Faes, Normon, Cinfa, Mundipharma, Abbott, Novartis, and collaborations from AbbVie. PWGM has received honoraria and/or grant funding from Gilead, Janssen, MSD, ViiV Healthcare, GSK, and AstraZeneca, outside of the submitted work. SMK has received grants from Pfizer, MSD, Huvepharma, AiCuris, Astra Zeneca, Mylan, Janssen pharma. PK reports grants or contracts from German Federal Ministry of Research and Education (BMBF) B-FAST (Bundesweites Forschungsnetz Angewandte Surveillance und Testung) and NAPKON (Nationales Pandemie Kohorten Netz, German National Pandemic Cohort Network) of the Network University Medicine and the State of North Rhine-Westphalia; Consulting fees Ambu GmbH, Gilead Sciences, Mundipharma Resarch Limited, Noxxon N.V. and Pfizer Pharma; Honoraria for lectures from Akademie für Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, BioRad Laboratories Inc., Datamed GmbH, European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, HELIOS Kliniken GmbH, Lahn-Dill-Kliniken GmbH, medupdate GmbH, MedMedia GmbH, MSD Sharp & Dohme GmbH, Pfizer Pharma GmbH, Scilink Comunicación Científica SC, streamedup! GmbH and University Hospital and LMU Munich; Participation on an Advisory Board from Ambu GmbH, Gilead Sciences, Mundipharma Resarch Limited and Pfizer Pharma; A pending patent currently reviewed at the German Patent and Trade Mark Office (DE 10 2021 113 007.7); Other non-financial interests from Elsevier, Wiley and Taylor & Francis online outside the submitted work. OAC reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis; Consulting fees from AbbVie, Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, Pfizer, PSI, Scynexis, Seres; Honoraria for lectures from Abbott, AbbVie, Al-Jazeera Pharmaceuticals, Astellas, Gilead, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Noscendo, Pfizer, Shionogi; 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. Kristin G-I Mohn has received honoraria for lectures from Takeda, IQVIA and BioNTech, has received a Research Grant from Norwegian Regional Health authorities, West, grant nr F12626 and is a Member of an advisory board on committee for National vaccination programs, Norwegian Public Health Institute. The remaining authors have no competing interest to declare., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Vaccination remains crucial for protection against severe SARS-CoV-2 infection, especially for people of advanced age, however, optimal dosing regimens are as yet lacking., Methods: EU-COVAT-1-AGED Part A is a randomised controlled, adaptive, multicentre phase II trial evaluating safety and immunogenicity of a 3rd vaccination (1st booster) in individuals ≥75 years. Fifty-three participants were randomised to full-doses of either mRNA-1273 (Spikevax®, 100 µg) or BNT162b2 (Comirnaty®, 30 µg). The primary endpoint was the rate of 2-fold circulating antibody titre increase 14 days post-vaccination measured by quantitative electrochemiluminescence (ECL) immunoassay, targeting RBD region of Wuhan wild-type SARS-CoV-2. Secondary endpoints included the changes in neutralising capacity against wild-type and 25 variants of concern at 14 days and up to 12 months. Safety was assessed by monitoring of solicited adverse events (AEs) for seven days after on-study vaccination. Unsolicited AEs were collected until the end of follow-up at 12 months, SAEs were pursued for a further 30 days., Results: Between 08th of November 2021 and 04th of January 2022, 53 participants ≥75 years received a COVID-19 vaccine as 1st booster. Fifty subjects (BNT162b2 n = 25/mRNA-1273 n = 25) were included in the analyses for immunogenicity at day 14. The primary endpoint of a 2-fold anti-RBD IgG titre increase 14 days after vaccination was reached for all subjects. A 3rd vaccination of full-dose mRNA-1273 provided higher anti-RBD IgG titres (Geometric mean titre) D14 mRNA-127310711 IU/mL (95 %-CI: 8003;14336) vs. BNT162b2: 7090 IU/mL (95 %-CI: 5688;8837). We detected a pattern showing higher neutralising capacity of full-dose mRNA-1273 against wild-type as well as for 23 out of 25 tested variants., Interpretation: Third doses of either BNT162b2 or mRNA-1273 provide substantial circulating antibody increase 14 days after vaccination. Full-dose mRNA-1273 provides higher antibody levels with an overall similar safety profile for people ≥75 years., Funding: This trial was funded by the European Commission (Framework Program HORIZON 2020)., Competing Interests: Declaration of Competing Interest JN no conflicts declared. JS has received research grants by the Ministry of Education and Research (BMBF) and Basilea Pharmaceuticals; has received speaker honoraria by AbbVie, Pfizer and Gilead; has been a consultant to Gilead, Produkt & Markt GmbH, Alvea Vax and Micron Research and has received travel grants by German Society for Infectious Diseases (DGI) and Meta-Alexander Foundation. AJC no conflicts declared. JFI has received research grants by the Instituto de Salud Carlos III, Ministry of Science. Spain. Has received grants or research contracts from Laboratorios Faes, Normon, Pfizer, Italfarmaco, GSK, Prestige, has been a consultant or has received speaker honoraria from Faes, Normon, Cinfa, Mundipharma, Abbott, Novartis and docency colaborations from Abbvie. MA has received research grants from Pfizer and Gilead. Contributed to educational activities organized/supported by Pfizer, Roche, Gilead, GSK, Moderna and Sanofi. All honoraria from these activities are paid to the Institution. UB no conflicts declared. SH no conflicts declared. JSG has received speaker honoraria from Gilead and Pfizer, outside of the submitted work. LT no conflicts declared. MZ has received honoraria for lecturing courses by Pfizer Malaysia; is now an employee with AiCuris AG. AC no conflicts declared. JG no conflicts declared. AGL no conflicts declared. PM has received honoraria from Gilead and AstraZeneca, outside of the submitted work. RN no conflicts declared. CG no conflicts declared. GS no conflicts declared. AH no conflicts declared. SKS no conflicts declared. KL no conflicts declared. CL no conflicts declared. HG no conflicts declared. SMK has received grants from Pfizer, MSD, Huvepharma, AiCuris, Astra Zeneca, Mylan, Janssen pharma. FK no conflicts declared. LY no conflicts declared. MP no conflicts declared. PK reports grants or contracts from German Federal Ministry of Research and Education (BMBF) B-FAST (Bundesweites Forschungsnetz Angewandte Surveillance und Testung) and NAPKON (Nationales Pandemie Kohorten Netz, German National Pandemic Cohort Network) of the Network University Medicine (NUM) and the State of North Rhine-Westphalia; Consulting fees Ambu GmbH, Gilead Sciences, Mundipharma Resarch Limited, Noxxon N.V. and Pfizer Pharma; Honoraria for lectures from Akademie für Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, BioRad Laboratories Inc., Datamed GmbH, European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, HELIOS Kliniken GmbH, Lahn-Dill-Kliniken GmbH, medupdate GmbH, MedMedia GmbH, MSD Sharp & Dohme GmbH, Pfizer Pharma GmbH, Scilink Comunicación Científica SC, streamedup! GmbH and University Hospital and LMU Munich; Participation on an Advisory Board from Ambu GmbH, Gilead Sciences, Mundipharma Resarch Limited and Pfizer Pharma; A pending patent currently reviewed at the German Patent and Trade Mark Office (DE 10 2021 113 007.7); Other non-financial interests from Elsevier, Wiley and Taylor & Francis online outside the submitted work. OAC reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis; Consulting fees from Abbvie, Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, Pfizer, PSI, Scynexis, Seres; Honoraria for lectures from Abbott, Abbvie, Al-Jazeera Pharmaceuticals, Astellas, Gilead, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Noscendo, Pfizer, Shionogi; 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, The Prime Meridian Group; A patent at the German Patent and Trade Mark Office (DE 10 2021 113 007.7); Stocks from CoRe Consulting, EasyRadiology; Other interests from DGHO, DGI, ECMM, EHA, ISHAM, MSG-ERC, Wiley., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)