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
Authors: Carl S Goodyear, Amit Patel, Eleanor Barnes, Michelle Willicombe, Stefan Siebert, Thushan I de Silva, John A Snowden, Sean H Lim, Sarah J Bowden, Lucinda Billingham, Alex Richter, Miles Carroll, Edward J Carr, Rupert Beale, Daniel Rea, Helen Parry, Sarah Pirrie, Zixiang Lim, Jack Satsangi, Susanna J Dunachie, Gordon Cook, Paul Miller, Neil Basu, Ashley Gilmour, Anne-Marie Hodgkins, Lili Evans, Ana Hughes, Stephanie Longet, Georgina Meacham, Kwee L Yong, Matthew J A'Hearne, Mickey B C Koh, Siobhan O Burns, Kim Orchard, Caron Paterson, Graham McIlroy, Sam M Murray, Tina Thomson, Stavros Dimitriadis, Lyndsey Goulston, Samantha Miller, Victoria Keillor, Maria Prendecki, David Thomas, Amanda Kirkham, Iain B McInnes, Pamela Kearns, Richard Beesley, Vicky Churchill, Elspeth Insch, Holly Loughton, Eilean MacDonald, Siân Lax, Faye Lowe, Sophia Magwaro, Mark Gradwell, Francesca Kinsella, Hayley Rolfe, Stacey McIntyre, Paige Mortimer, Saly Al-Taei, Susan Tadros, Sarita Workman, Maxine Arnott, James Brock, Andrew Melville, Aurelie Najm, Matthew Rutherford, Flavia Sunzini, Lou S Herman, Agnieszka Hobbs, Martina Ragno, Mary Y Wu, Rachael Selby, Jennifer Clay, Clare Hutchison, Robert Lown, May N Lwin, Naomi Meardon, Peter Kelleher, Liz Lightstone, Thomas Walters, Jayne Denyer, Rahima Ibrahim, Sarah Gleeson, Paul Martin, Stephen McAdoo, Helena Baker, Sarah Horswill, Nina Parungao, Stephen Saich, James Cullinane, Sophie Irwin, Paul Klenerman, Thomas Marjot, Ronjon Chakraverty, Christopher Holroyd, Janki Kavi, Doreen Trown, Gavin Babbage, Julia Chackathayil, Patricia Faria, Karen Ingham, Murad Miah, Mauro Miranda, Nicola O'Reilly, Callie Smith, Kimberley Driver, Kaylee Gauntlett, Andrew Farthing, Suzann Rundell, Emily Smith, Andrew Tong, Kieran Woolcock, Daniel Hanke, Stephen Laidlaw, Zainab Malik, Dung Nguyen, Nicholas Provine, Tom Tipton, Victoria Walker
Journal: The Lancet Rheumatology (2024)

BackgroundThe 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.MethodsOCTAVE-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.FindingsBetween 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.InterpretationA 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.FundingMedical Research Council, Blood Cancer UK.