Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002)
Authors: Amy Flaxman, Natalie G Marchevsky, Daniel Jenkin, Jeremy Aboagye, Parvinder K Aley, Brian Angus, Sandra Belij-Rammerstorfer, Sagida Bibi, Mustapha Bittaye, Federica Cappuccini, Paola Cicconi, Elizabeth A Clutterbuck, Sophie Davies, Wanwisa Dejnirattisai, Christina Dold, Katie J Ewer, Pedro M Folegatti, Jamie Fowler, Adrian V S Hill, Simon Kerridge, Angela M Minassian, Juthathip Mongkolsapaya, Yama F Mujadidi, Emma Plested, Maheshi N Ramasamy, Hannah Robinson, Helen Sanders, Emma Sheehan, Holly Smith, Matthew D Snape, Rinn Song, Danielle Woods, Gavin Screaton, Sarah C Gilbert, Merryn Voysey, Andrew J Pollard, Teresa Lambe, Syed Adlou, Robert Aley, Aabidah Ali, Rachel Anslow, Megan Baker, Phillip Baker, Jordan R. Barrett, Louise Bates, Kirsten Beadon, Rebecca Beckley, Jonathan Bell, Duncan Bellamy, Amy Beveridge, Cameron Bissett, Luke Blackwell, Heather Bletchly, Amy Boyd, Alice Bridges-Webb, Charlie Brown, Nicholas Byard, Susana Camara, Liliana Cifuentes Gutierrez, Andrea M. Collins, Rachel Cooper, Wendy E.M. Crocker, Thomas C. Darton, Hannah Davies, Judith Davies, Tesfaye Demissie, Claudio Di Maso, Tanya Dinesh, Francesca R. Donnellan, Alexander D. Douglas, Rachael Drake-Brockman, Christopher J.A. Duncan, Sean C. Elias, Katherine R.W. Emary, Mutjaba Ghulam Farooq, Saul N. Faust, Sally Felle, Daniela Ferreira, Carla Ferreira Da Silva, Adam Finn, Karen J. Ford, Emma Francis, Julie Furze, Michelle Fuskova, Eva Galiza, Ana Gibertoni Cruz, Leila Godfrey, Anna L. Goodman, Catherine Green, Christopher A. Green, Nicola Greenwood, Daisy Harrison, Thomas C. Hart, Sophia Hawkins, Paul T. Heath, Helen Hill, Kushalinii Hillson, Bryn Horsington, Mimi M. Hou, Elizabeth Howe, Nicola Howell, Carina Joe, Elizabeth Jones, Mwila Kasanyinga, Jade Keen, Sarah Kelly, David Kerr, Liaquat Khan, Baktash Khozoee, Jasmin Kinch, Patrick Kinch, Stanislava Koleva, Jonathan Kwok, Colin W. Larkworthy, Alison M. Lawrie, Rajeka Lazarus, Emily A. Lees, Grace Li, Vincenzo Libri, Patrick J. Lillie, Aline Linder, Fei Long, Raquel Lopez Ramon, Reece Mabbett, Rebecca Makinson, Spyridoula Marinou, Emma Marlow, Julia L. Marshall, Olga Mazur, Joanne McEwan, Alastair C. McGregor, Jolynne Mokaya, Ella Morey, Gertraud Morshead, Richard Morter, Jilly Muller, Philomena Mweu, Rabiullah Noristani, Nelly Owino, Marco Polo Peralta Alvarez, Abigail Platt, Katrina M. Pollock, Ian Poulton, Samuel Provstgaard-Morys, David Pulido-Gomez, Matthew Rajan, Fernando Ramos Lopez, Adam Ritchie, Hannah Roberts, Christine Rollier, Indra Rudiansyah, Katherine Sanders, Jack E. Saunders, Samiullah Seddiqi, Hannah R. Sharpe, Robert Shaw, Laura Silva-Reyes, Nisha Singh, David J. Smith, Catherine C. Smith, Andrew Smith, Alexandra J. Spencer, Arabella S.V. Stuart, Rebecca Sutherland, Anna Szigeti, Karly Tang, Merin Thomas, Tonia M. Thomas, Amber Thompson, Emma C. Thomson, Estée M. Török, Mark Toshner, Nguyen Tran, Rose Trivett, Iain Turnbull, Cheryl Turner, David P.J. Turner, Marta Ulaszewska, Iason Vichos, Laura Walker, Marion E. Watson, Conor Whelan, Rachel White, Sarah J. Williams, Christopher J.A. Williams, Daniel Wright, Andy Yao
Journal: The Lancet (2021)

SummaryBackgroundCOVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between the first and second dose becomes longer. Conversely, countries with no supply constraints are considering administering a third dose. We assessed the persistence of immunogenicity after a single dose of ChAdOx1 nCoV-19 (AZD1222), immunity after an extended interval (44–45 weeks) between the first and second dose, and response to a third dose as a booster given 28–38 weeks after the second dose.MethodsIn this substudy, volunteers aged 18–55 years who were enrolled in the phase 1/2 (COV001) controlled trial in the UK and had received either a single dose or two doses of 5 × 1010 viral particles were invited back for vaccination. Here we report the reactogenicity and immunogenicity of a delayed second dose (44–45 weeks after first dose) or a third dose of the vaccine (28–38 weeks after second dose). Data from volunteers aged 18–55 years who were enrolled in either the phase 1/2 (COV001) or phase 2/3 (COV002), single-blinded, randomised controlled trials of ChAdOx1 nCoV-19 and who had previously received a single dose or two doses of 5 × 1010 viral particles are used for comparison purposes. COV001 is registered with ClinicalTrials.gov, NCT04324606, and ISRCTN, 15281137, and COV002 is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137, and both are continuing but not recruiting.FindingsBetween March 11 and 21, 2021, 90 participants were enrolled in the third-dose boost substudy, of whom 80 (89%) were assessable for reactogenicity, 75 (83%) were assessable for evaluation of antibodies, and 15 (17%) were assessable for T-cells responses. The two-dose cohort comprised 321 participants who had reactogenicity data (with prime-boost interval of 8–12 weeks: 267 [83%] of 321; 15–25 weeks: 24 [7%]; or 44–45 weeks: 30 [9%]) and 261 who had immunogenicity data (interval of 8–12 weeks: 115 [44%] of 261; 15–25 weeks: 116 [44%]; and 44–45 weeks: 30 [11%]). 480 participants from the single-dose cohort were assessable for immunogenicity up to 44–45 weeks after vaccination. Antibody titres after a single dose measured approximately 320 days after vaccination remained higher than the titres measured at baseline (geometric mean titre of 66·00 ELISA units [EUs; 95% CI 47·83–91·08] vs 1·75 EUs [1·60–1·93]). 32 participants received a late second dose of vaccine 44–45 weeks after the first dose, of whom 30 were included in immunogenicity and reactogenicity analyses. Antibody titres were higher 28 days after vaccination in those with a longer interval between first and second dose than for those with a short interval (median total IgG titre: 923 EUs [IQR 525–1764] with an 8–12 week interval; 1860 EUs [917–4934] with a 15–25 week interval; and 3738 EUs [1824–6625] with a 44–45 week interval). Among participants who received a third dose of vaccine, antibody titres (measured in 73 [81%] participants for whom samples were available) were significantly higher 28 days after a third dose (median total IgG titre: 3746 EUs [IQR 2047–6420]) than 28 days after a second dose (median 1792 EUs [IQR 899–4634]; Wilcoxon signed rank test p=0·0043). T-cell responses were also boosted after a third dose (median response increased from 200 spot forming units [SFUs] per million peripheral blood mononuclear cells [PBMCs; IQR 127–389] immediately before the third dose to 399 SFUs per milion PBMCs [314–662] by day 28 after the third dose; Wilcoxon signed rank test p=0·012). Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose.InterpretationAn extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titres. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlates with high efficacy after second dose and boosts T-cell responses.FundingUK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, AstraZeneca, and Wellcome.