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Background: The humoral and T-cell responses to booster COVID-19 vaccine types in multidisease immunocompromised individuals who do not generate adequate antibody responses to two COVID-19 vaccine doses, is not fully understood. The OCTAVE DUO trial aimed to determine the value of third vaccinations in a wide range of patients with primary and secondary immunodeficiencies., Methods: OCTAVE-DUO was a prospective, open-label, multicentre, randomised, controlled, phase 3 trial investigating humoral and T-cell responses in patients who are immunocompromised following a third vaccine dose with BNT162b2 or mRNA-1273, and of NVX-CoV2373 for those with lymphoid malignancies. We recruited patients who were immunocompromised from 11 UK hospitals, aged at least 18 years, with previous sub-optimal responses to two doses of SARS-CoV-2 vaccine. Participants were randomly assigned 1:1 (1:1:1 for those with lymphoid malignancies), stratified by disease, previous vaccination type, and anti-spike antibody response following two doses. Individuals with lived experience of immune susceptibility were involved in the study design and implementation. The primary outcome was vaccine-specific immunity defined by anti-SARS-CoV-2 spike antibodies (Roche Diagnostics UK and Ireland, Burgess Hill, UK) and T-cell responses (Oxford Immunotec, Abingdon, UK) before and 21 days after the third vaccine dose analysed by a modified intention-to-treat analysis. The trial is registered with the ISRCTN registry, ISRCTN 15354495, and the EU Clinical Trials Register, EudraCT 2021-003632-87, and is complete., Findings: Between Aug 4, 2021 and Mar 31, 2022, 804 participants across nine disease cohorts were randomly assigned to receive BNT162b2 (n=377), mRNA-1273 (n=374), or NVX-CoV2373 (n=53). 356 (45%) of 789 participants were women, 433 (55%) were men, and 659 (85%) of 775 were White. Anti-SARS-CoV-2 spike antibodies measured 21 days after the third vaccine dose were significantly higher than baseline pre-third dose titres in the modified intention-to-treat analysis (median 1384 arbitrary units [AU]/mL [IQR 4·3-7990·0] compared with median 11·5 AU/mL [0·4-63·1]; p<0·001). Of participants who were baseline low responders, 380 (90%) of 423 increased their antibody concentrations to more than 400 AU/mL. Conversely, 166 (54%) of 308 baseline non-responders had no response after the third dose. Detectable T-cell responses following the third vaccine dose were seen in 494 (80%) of 616 participants. There were 24 serious adverse events (BNT612b2 eight [33%] of 24, mRNA-1273 12 [50%], NVX-CoV2373 four [17%]), two (8%) of which were categorised as vaccine-related. There were seven deaths (1%) during the trial, none of which were vaccine-related., Interpretation: A third vaccine dose improved the serological and T-cell response in the majority of patients who are immunocompromised. Individuals with chronic renal disease, lymphoid malignancy, on B-cell targeted therapies, or with no serological response after two vaccine doses are at higher risk of poor response to a third vaccine dose., Funding: Medical Research Council, Blood Cancer UK., Competing Interests: Declaration of interests DR reports research funding from Roche, Biotheranostics, RNA diagnostics, and Celgene; and honoraria or consultancy fees from Novartis, Pfizer, Lily, Roche, and AstraZeneca–Diiachi Sankyo. EB reports research funding from Vaccitech; consultancy fees from Roche, Vaccitech, and AstraZeneca; and holds patents in ChAdOx1 hepatitis B virus and hepatitis C virus vaccines. HP reports honoraria from AstraZeneca. IBM reports research funding or consultancy fees from AbbVie, Amgen, Bristol-Myers Squibb (BMS), Causeway Therapeutics Cabaletta, Eli Lilly, Evelo Biosciences, Gilead, GSK, Janssen, Novartis, Pfizer, Sanofi Regeneron, and UCB; consultancy fees from AbbVie, Amgen, BMS, Causeway Therapeutics Cabaletta, Eli Lilly, Gilead, Janssen, Novartis, Pfizer, Sanofi Regeneron, and UCB; and is on the board of directors of Evelo Biosciences. KO reports royalties to his institution from Telix Pharmaceuticals for Radiolabelled anti-CD66 antibody; consulting fees from Sanofi and Takeda; and stocks in GSK. KLY reports honoraria from Sanofi Genzyme, Takeda, and Amgen; support for meeting attendance from Takeda; and participation on a trial steering committee for Sanofi and an advisory board for Janssen. MJA reports research funding from Pfizer. MW reports research funding from Oxford Immunotech. MBCK reports honoraria from Gilead. MC reports consultancy fees from VacciTech. PK reports research funding from Bayer; and consultancy fees from AstraZeneca, Merck, and BMS. SM reports stock options in TCB BioPharm. SHL reports honoraria from AstraZeneca. SS reports research funding from Amgen, Boehringer-Ingelheim, BMS, GSK, Janssen, and UCB; and consultancy fees or honoraria from AbbVie, Eli Lilly, GSK, Janssen, and UCB. SOB reports research funding from CSL Behring; and consultancy fees, honoraria, or support for attending meetings from GSK, Baxalta US, and Biotest. JAS reports honoraria from Novartis and Gilead; advisory board fees from the Kiadis clinical trial, Medac, and NHS England National Specialised Commissioning Clinical Reference Group for Blood and Marrow Transplantation; and unpaid roles as President of British Society of Blood and Marrow Transplantation and Cellular Therapy, secretary of the European Society for Blood and Marrow Transplantation and as a board member of the British Society of Haematology. SJD is a Scientific Advisor to the Scottish Parliament on COVID-19 for which she receives a fee. All other authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)