{ "abstract": "Introduction Immunosuppression is associated with an increased risk of delayed SARS-CoV-2 viral clearance, severe COVID-19 and related death. This heterogeneous group of affected patients includes but is not limited to those with a haematological malignancy, people on immunosuppressive therapy for the treatment of autoimmune/inflammatory diseases and those following bone marrow transplantation (BMT). Immunosuppression is associated with decreased rates of anti-spike IgG seroconversion following COVID-19 vaccination. While clinical guidelines have been established to guide vaccination pre-splenectomy and post-BMT, there are limited data to guide timing of COVID-19 or other booster vaccines in adults commencing new or intensified moderate to severe immunosuppression. The comparison of immunity-boosting regimens for COVID-19 upon initiation of immunosuppressive therapy (CIRCUIT) study was designed to address this knowledge gap. CIRCUIT investigates whether administration of a third (or subsequent) COVID-19 booster vaccine ≤2 weeks prior to immunosuppression provides greater anti-spike IgG-mediated immunity than a booster given 24 weeks after new or intensified immunosuppression, that is, week 24 timepoint (Group 1; n=280). Additionally, the research will investigate whether giving a fourth post-BMT COVID-19 booster vaccine at 9 months post-transplant provides greater anti-spike IgG-mediated immunity than a booster given 15 months post-transplant (Group 2; n=40).Methods and analysis The CIRCUIT study is an open-label, multicentre randomised clinical trial. Participants will be randomised 1:1 to receive either an additional COVID-19 booster ≤2 weeks pre-immunosuppression and a diphtheria/tetanus toxoids (DT) booster at 24 weeks following new or intensified immunosuppression (week 24 timepoint) or receive a DT booster ≤2 weeks pre-immunosuppression and an additional COVID-19 booster at week 24 (Group 1). Group 2 participants who underwent autologous or allogenic BMT in the last 9 months will be randomised 1:1 to either receive a fourth post-BMT COVID-19 booster at 9 or 15 months post-transplant. The primary outcome will be the integrated time-weighted area under the curve anti-SARS-CoV-2 neutralising antibody (NAb) response over 12 months from a SARS-CoV-2 booster as assessed by a high-throughput SARS-CoV-2 NAb platform assay. Key secondary outcomes of the CIRCUIT randomised control trial will include safety and generation of SARS-CoV-2 antigen specific T and B cell responses.Ethics and dissemination The research protocol was approved by the Western Sydney Local Health District Human Research Ethics Committee on 25 August 2022 (Ref no. 2022/PID00782 – 20022/ETH0069). Study results will be published in peer-reviewed medical journals and presented at local and international conferences. All findings regardless of the outcome will be reported.Trial registration number NCT05415267.", "authors": [ { "affiliations": [ "The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia" ], "name": "Dianne L Carey" }, { "affiliations": [ "Department of Gastroenterology, Blacktown and Mount Druitt Hospital, Sydney, New South Wales, Australia", "Western Sydney University, Sydney, New South Wales, Australia" ], "name": "Golo Ahlenstiel" }, { "affiliations": [ "Kids Research, The Sydney Children’s Hospitals Network, Sydney, New South Wales, Australia", "The University of Sydney, Sydney, New South Wales, Australia" ], "name": "Fabienne Brilot" }, { "affiliations": [ "The University of Sydney, Sydney, New South Wales, Australia", "New South Wales Health Pathology, ICPMR, Sydney, New South Wales, Australia", "University of New South Wales, Sydney, New South Wales, Australia", "Department of Clinical Immunology and Immunopathology, Westmead Hospital, Sydney, New South Wales, Australia" ], "name": "David A Brown" }, { "affiliations": [ "The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia", "School of Biomedical Sciences, University of New South Wales, Sydney, New South Wales, Australia" ], "name": "Rowena Bull" }, { "affiliations": [ "Department of Haematology, Blacktown and Mount Druitt Hospital, Blacktown, New South Wales, Australia", "Western Sydney University, Penrith, New South Wales, Australia" ], "name": "Helen Crowther" }, { "affiliations": [ "The University of Sydney, Sydney, New South Wales, Australia", "Westmead Institute for Medical Research, Sydney, New South Wales, Australia" ], "name": "Anthony Cunningham" }, { "affiliations": [ "The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia" ], "name": "Miles P Davenport" }, { "affiliations": [ "Leukaemia Foundation, Brisbane, Queensland, Australia" ], "name": "Peter Diamond" }, { "affiliations": [ "University of New South Wales, Sydney, New South Wales, Australia", "Department of Haematology, St Vincent’s Hospital Sydney, Darlinghurst, New South Wales, Australia", "The University of Notre Dame Australia, Perth, Western Australia, Australia" ], "name": "Nada Hamad" }, { "affiliations": [ "New South Wales Health Pathology, ICPMR, Sydney, New South Wales, Australia", "Department of Haematology, Westmead Hospital, Sydney, New South Wales, Australia" ], "name": "Amanda Johnston" }, { "affiliations": [ "Department of Clinical Immunology, St Vincent’s Hospital Sydney, Sydney, New South Wales, Australia" ], "name": "Anthony D Kelleher" }, { "affiliations": [ "The University of Sydney, Sydney, New South Wales, Australia", "New South Wales Health Pathology, Newcastle, New South Wales, Australia" ], "name": "Frederick J Lee" }, { "affiliations": [ "Department of Infectious Diseases, St Vincent’s Hospital Sydney, Sydney, New South Wales, Australia" ], "name": "Gail V Matthews" }, { "affiliations": [ "The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia" ], "name": "Kathy Petoumenos" }, { "affiliations": [ "The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia" ], "name": "Gesalit C Quichua" }, { "affiliations": [ "Western Sydney University, Sydney, New South Wales, Australia", "The University of Sydney, Sydney, New South Wales, Australia", "Department of Clinical Immunology and Immunopathology, Westmead Hospital, Sydney, New South Wales, Australia" ], "name": "Sanjay Swaminathan" }, { "affiliations": [ "The University of Sydney, Sydney, New South Wales, Australia", "Department of Haematology, Concord Hospital, Sydney, New South Wales, Australia" ], "name": "Judith Trotman" }, { "affiliations": [ "The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia" ], "name": "Stuart Turville" }, { "affiliations": [ "Brain and Nerve Research Centre, The University of Sydney, Sydney, New South Wales, Australia", "Department of Neurology, Concord Hospital, Sydney, New South Wales, Australia" ], "name": "Steve Vukic" }, { "affiliations": [ "The University of Sydney, Sydney, New South Wales, Australia", "Departments of Rheumatology Blacktown and Westmead Hospitals and Westmead Clinical School, The University of Sydney Faculty of Medicine and Health, Sydney, New South Wales, Australia" ], "name": "Peter Wong" }, { "affiliations": [ "The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia", "Department of Clinical Immunology and Immunopathology, Westmead Hospital, Sydney, New South Wales, Australia", "New South Wales Health Pathology, ICPMR, Wentworthville, New South Wales, Australia" ], "name": "Sarah C Sasson" } ], "title": "Comparison of immunity-boosting regimens for COVID-19 upon initiation of immunosuppressive therapy (CIRCUIT): study protocol for a randomised, controlled clinical trial", "uid": "d061a8de-251a-526c-b7c9-e222d98aa583" }