Immunogenicity of third dose COVID-19 vaccine strategies in patients who are immunocompromised with suboptimal immunity following two doses (OCTAVE-DUO): an open-label, multicentre, randomised, controlled, phase 3 trial.
Creators: name: Goodyear, Carl S
name: Patel, Amit
name: Barnes, Eleanor
name: Willicombe, Michelle
name: Siebert, Stefan
name: de Silva, Thushan I
name: Snowden, John A
name: Lim, Sean H
name: Bowden, Sarah J
name: Billingham, Lucinda
name: Richter, Alex
name: Carroll, Miles
name: Carr, Edward J
name: Beale, Rupert
name: Rea, Daniel
name: Parry, Helen
name: Pirrie, Sarah
name: Lim, Zixiang
name: Satsangi, Jack
name: Dunachie, Susanna J
name: Cook, Gordon
name: Miller, Paul
name: Basu, Neil
name: Gilmour, Ashley
name: Hodgkins, Anne-Marie
name: Evans, Lili
name: Hughes, Ana
name: Longet, Stephanie
name: Meacham, Georgina
name: Yong, Kwee L
name: A'Hearne, Matthew J
name: Koh, Mickey BC
name: Burns, Siobhan O
name: Orchard, Kim
name: Paterson, Caron
name: McIlroy, Graham
name: Murray, Sam M
name: Thomson, Tina
name: Dimitriadis, Stavros
name: Goulston, Lyndsey
name: Miller, Samantha
name: Keillor, Victoria
name: Prendecki, Maria
name: Thomas, David
name: Kirkham, Amanda
name: McInnes, Iain B
name: Kearns, Pamela
name: investigators, OCTAVE-DUO
Publisher: name: The Francis Crick Institute
Year: 2024
Subjects: classificationCode: Infectious Disease
subject: Infectious Disease
classificationCode: Immunology
subject: Immunology
subject: FOS: Clinical medicine
classificationCode: Cell Biology
subject: Cell Biology

description: 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&lt;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.