Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials

Type Journal Article Author Merryn Voysey Author Sue Ann Costa Clemens Author Shabir A. Madhi Author Lily Y. Weckx Author Pedro M. Folegatti Author Parvinder K. Aley Author Brian Angus Author Vicky L. Baillie Author Shaun L. Barnabas Author Qasim E. Bhorat Author Sagida Bibi Author Carmen Briner Author Paola Cicconi Author Elizabeth A. Clutterbuck Author Andrea M. Collins Author Clare L. Cutland Author Thomas C. Darton Author Keertan Dheda Author Christina Dold Author Christopher J. A. Duncan Author Katherine R. W. Emary Author Katie J. Ewer Author Amy Flaxman Author Lee Fairlie Author Saul N. Faust Author Shuo Feng Author Daniela M. Ferreira Author Adam Finn Author Eva Galiza Author Anna L. Goodman Author Catherine M. Green Author Christopher A. Green Author Melanie Greenland Author Catherine Hill Author Helen C. Hill Author Ian Hirsch Author Alane Izu Author Daniel Jenkin Author Carina C. D. Joe Author Simon Kerridge Author Anthonet Koen Author Gaurav Kwatra Author Rajeka Lazarus Author Vincenzo Libri Author Patrick J. Lillie Author Natalie G. Marchevsky Author Richard P. Marshall Author Ana V. A. Mendes Author Eveline P. Milan Author Angela M. Minassian Author Alastair McGregor Author Yama F. Mujadidi Author Anusha Nana Author Sherman D. Padayachee Author Daniel J. Phillips Author Ana Pittella Author Emma Plested Author Katrina M. Pollock Author Maheshi N. Ramasamy Author Adam J. Ritchie Author Hannah Robinson Author Alexandre V. Schwarzbold Author Andrew Smith Author Rinn Song Author Matthew D. Snape Author Eduardo Sprinz Author Rebecca K. Sutherland Author Emma C. Thomson Author M. Estée Török Author Mark Toshner Author David P. J. Turner Author Johan Vekemans Author Tonya L. Villafana Author Thomas White Author Christopher J. Williams Author Alexander D. Douglas Author Adrian V. S. Hill Author Teresa Lambe Author Sarah C. Gilbert Author Andrew J. Pollard Author Marites Aban Author Kushala W. M. Abeyskera Author Jeremy Aboagye Author Matthew Adam Author Kirsty Adams Author James P. Adamson Author Gbadebo Adewatan Author Syed Adlou Author Khatija Ahmed Author Yasmeen Akhalwaya Author Saajida Akhalwaya Author Andrew Alcock Author Aabidah Ali Author Elizabeth R. Allen Author Lauren Allen Author Felipe B. Alvernaz Author Fabio Santos Amorim Author Claudia Sala Andrade Author Foteini Andritsou Author Rachel Anslow Author Edward H. Arbe-Barnes Author Mark P. Ariaans Author Beatriz Arns Author Laiana Arruda Author Luiza Assad Author Paula De Almeida Azi Author Lorena De Almeida Azi Author Gavin Babbage Author Catherine Bailey Author Kenneth F. Baker Author Megan Baker Author Natalie Baker Author Philip Baker Author Ioana Baleanu Author Danieli Bandeira Author Anna Bara Author Marcella A. S. Barbosa Author Debbie Barker Author Gavin D. Barlow Author Eleanor Barnes Author Andrew S. Barr Author Jordan R. 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Datoo Author Chandrabali Datta Author Malika Davids Author Sarah L. Davies Author Kelly Davies Author Hannah Davies Author Sophie Davies Author Judith Davies Author Elizabeth J. Davis Author John Davis Author José A. M. de Carvalho Author Jeanne De Jager Author Sergio de Jesus Jnr Author Lis Moreno De Oliveira Kalid Author David Dearlove Author Tesfaye Demissie Author Amisha Desai Author Stefania Di Marco Author Claudio Di Maso Author Tanya Dinesh Author Claire Docksey Author Tao Dong Author Francesca R. Donnellan Author Tannyth Gomes Dos Santos Author Thainá G. Dos Santos Author Erika Pachecho Dos Santos Author Naomi Douglas Author Charlotte Downing Author Jonathan Drake Author Rachael Drake-Brockman Author Ruth Drury Author Joan Du Plessis Author Susanna J. Dunachie Author Andrew Duncan Author Nicholas J. W. Easom Author Mandy Edwards Author Nick J. Edwards Author Frances Edwards Author Omar M. El Muhanna Author Sean C. Elias Author Branwen Ellison-Handley Author Michael J. 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Morris Author Sheila Morris Author Hazel Morrison Author Franca Morselli Author Gertraud Morshead Author Richard Morter Author Lynelle Mottay Author Andrew Moultrie Author Nathifa Moyo Author Mushiya Mpelembue Author Sibekezelo Msomi Author Yvonne Mugodi Author Ekta Mukhopadhyay Author Jilly Muller Author Alasdair Munro Author Sarah Murphy Author Philomena Mweu Author Christopher Myerscough Author Gurudutt Naik Author Kush Naker Author Eleni Nastouli Author Bongani Ndlovu Author Elissavet Nikolaou Author Cecilia Njenga Author Helena C. Noal Author Andrés Noé Author Gabrielle Novaes Author Fay L. Nugent Author Géssika Lanzillo A. Nunes Author Katie O'Brien Author Daniel O'Connor Author Suzette Oelofse Author Blanche Oguti Author Victoria Olchawski Author Neil J. Oldfield Author Marianne G. Oliveira Author Catarina Oliveira Author Isabelle Silva Queiroz Oliveira Author Aylin Oommen-Jose Author Angela Oosthuizen Author Paula O'Reilly Author Peter J. 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Smith Author Airanuédida S. Soares Author Carla Solórzano Author Guilherme L. Sorio Author Kim Sorley Author Tiffany Sosa-Rodriguez Author Cinthia M. C. D. L. Souza Author Bruno S. D. F. Souza Author Alessandra R. Souza Author Thamyres Souza Lopez Author Luciana Sowole Author Alexandra J. Spencer Author Louise Spoors Author Lizzie Stafford Author Imogen Stamford Author Ricardo Stein Author Lisa Stockdale Author Lisa V. Stockwell Author Louise H. Strickland Author Arabella Stuart Author Ann Sturdy Author Natalina Sutton Author Anna Szigeti Author Abdessamad Tahiri-Alaoui Author Rachel Tanner Author Carol Taoushanis Author Alexander W. Tarr Author Richard Tarrant Author Keja Taylor Author Ursula Taylor Author Iona Jennifer Taylor Author Justin Taylor Author Rebecca te Water Naude Author Kate Templeton Author Yrene Themistocleous Author Andreas Themistocleous Author Merin Thomas Author Kelly Thomas Author Tonia M. Thomas Author Asha Thombrayil Author Julia Thompson Author Fawziyah Thompson Author Ameeka Thompson Author Amber Thompson Author Kevin Thompson Author Viv Thornton-Jones Author Larissa H. S. Thotusi Author Patrick J. Tighe Author Lygia Accioly Tinoco Author Gerlynn Ferreras Tiongson Author Bonolo Tladinyane Author Michele Tomasicchio Author Adriana Tomic Author Susan Tonks Author James Towner Author Nguyen Tran Author Julia A. Tree Author Gerry Trillana Author Charlotte Trinham Author Rose Trivett Author Adam Truby Author Betty Lebogang Tsheko Author Philippa Tubb Author Aadil Turabi Author Richard Turner Author Cheryl Turner Author Nicola Turner Author Bhavya Tyagi Author Marta Ulaszewska Author Benjamin R. Underwood Author Samual van Eck Author Rachel Varughese Author Dennis Verbart Author Marije K. Verheul Author Iason Vichos Author Taiane A. Vieira Author Gemma Walker Author Laura Walker Author Matthew E. Wand Author Theresa Wardell Author George M. Warimwe Author Sarah C. Warren Author Bridget Watkins Author Marion E. E. Watson Author Ekaterina Watson Author Stewart Webb Author Angela Webster Author Jessica Welch Author Zoe Wellbelove Author Jeanette H. Wells Author Alison J. West Author Beth White Author Caroline White Author Rachel White Author Paul Williams Author Rachel L. Williams Author Silvia Willingham Author Rebecca Winslow Author Danielle Woods Author Mark Woodyer Author Andrew T. Worth Author Danny Wright Author Marzena Wroblewska Author Andy Yao Author Yee Ting Nicole Yim Author Marina Bauer Zambrano Author Rafael Leal Zimmer Author Dalila Zizi Author Peter Zuidewind URL https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00432-3/abstract Volume 397 Issue 10277 Pages 881-891 Publication The Lancet ISSN 0140-6736, 1474-547X Date 19/02/2021 Extra Publisher: Elsevier PMID: 33617777 Journal Abbr The Lancet DOI 10.1016/S0140-6736(21)00432-3 Accessed 2021-03-20 15:28:43 Library Catalog www.thelancet.com Language English Abstract Background The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4–12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. Methods We present data from three single-blind randomised controlled trials—one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)—and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). Findings Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4–74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3–85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59–0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3–91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0–69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18–55 years (GMR 2·32 [2·01–2·68]). Interpretation The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. Short Title Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine