@article{Flaxman_A-2021_59859,
title = {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)},
author = {Flaxman, A. and Marchevsky, N. and Jenkin, D. and Aboagye, J. and Aley, P. and Angus, B. and Belij-Rammerstorfer, S. and Bibi, S. and Bittaye, M. and Cappuccini, F. and Cicconi, P. and Clutterbuck, E. and Davies, S. and Dejnirattisai, W. and Dold, C. and Ewer, K. and Folegatti, P. and Fowler, J. and Hill, A. and Kerridge, S. and Minassian, A. and Mongkolsapaya, J. and Mujadidi, Y. and Plested, E. and Ramasamy, M. and Robinson, H. and Sanders, H. and Sheehan, E. and Smith, H. and Snape, M. and Song, R. and Woods, D. and Screaton, G. and Gilbert, S. and Voysey, M. and Pollard, A. and Lambe, T. and Adlou, S. and Aley, R. and Ali, A. and Anslow, R. and Baker, M. and Baker, P. and Barrett, J. and Bates, L. and Beadon, K. and Beckley, R. and Bell, J. and Bellamy, D. and Beveridge, A. and Bissett, C. and Blackwell, L. and Bletchly, H. and Boyd, A. and Bridges-Webb, A. and Brown, C. and Byard, N. and Camara, S. and Cifuentes Gutierrez, L. and Collins, A. and Cooper, R. and Crocker, W. and Darton, T. and Davies, H. and Davies, J. and Demissie, T. and Di Maso, C. and Dinesh, T. and Donnellan, F. and Douglas, A. and Drake-Brockman, R. and Duncan, C. and Elias, S. and Emary, K. and Ghulam Farooq, M. and Faust, S. and Felle, S. and Ferreira, D. and Ferreira Da Silva, C. and Finn, A. and Ford, K. and Francis, E. and Furze, J. and Fuskova, M. and Galiza, E. and Gibertoni Cruz, A. and Godfrey, L. and Goodman, A. and Green, C. and Green, C. and Greenwood, N. and Harrison, D. and Hart, T. and Hawkins, S. and Heath, P. and Hill, H. and Hillson, K. and Horsington, B. and Hou, M. and Howe, E. and Howell, N. and Joe, C. and Jones, E. and Kasanyinga, M. and Keen, J. and Kelly, S. and Kerr, D. and Khan, L. and Khozoee, B. and Kinch, J. and Kinch, P. and Koleva, S. and Kwok, J. and Larkworthy, C. and Lawrie, A. and Lazarus, R. and Lees, E. and Li, G. and Libri, V. and Lillie, P. and Linder, A. and Long, F. and Lopez Ramon, R. and Mabbett, R. and Makinson, R. and Marinou, S. and Marlow, E. and Marshall, J. and Mazur, O. and McEwen, J. and McGregor, A. and Mokaya, J. and Morey, E. and Morshead, G. and Morter, R. and Muller, J. and Mweu, P. and Noristani, R. and Owino, N. and Polo Peralta Alvarez, M. and Platt, A. and Pollock, K. and Poulton, I. and Provstgaard-Morys, S. and Pulido-Gomez, D. and Rajan, M. and Ramos Lopez, F. and Ritchie, A. and Roberts, H. and Rollier, C. and Rudiansyah, I. and Sanders, K. and Saunders, J. and Seddiqi, S. and Sharpe, H. and Shaw, R. and Silva-Reyes, L. and Singh, N. and Smith, D. and Smith, C. and Smith, A. and Spencer, A. and Stuart, A. and Sutherland, R. and Szigeti, A. and Tang, K. and Thomas, M. and Thomas, T. and Thompson, A. and Thomson, E. and Török, E. and Toshner, M. and Tran, N. and Trivett, R. and Turnbull, I. and Turner, C. and Turner, D. and Ulaszewska, M. and Vichos, I. and Walker, L. and Watson, M. and Whelan, C. and White, R. and Williams, S. and Williams, C. and Wright, D. and Yao, A.},
month = {sep},
year = {2021},
abstract = {Background: COVID-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. Methods: In 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. Findings: Between 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. Interpretation: An 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. Funding: UK 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.},
pages = {981-990},
volume = {398},
issue = {10304},
journal = {Lancet},
publisher = {Elsevier},
url = {http://dx.doi.org/10.1016/S0140-6736(21)01699-8},
}
