Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial
Authors: Maheshi N Ramasamy, Angela M Minassian, Katie J Ewer, Amy L Flaxman, Pedro M Folegatti, Daniel R Owens, Merryn Voysey, Parvinder K Aley, Brian Angus, Gavin Babbage, Sandra Belij-Rammerstorfer, Lisa Berry, Sagida Bibi, Mustapha Bittaye, Katrina Cathie, Harry Chappell, Sue Charlton, Paola Cicconi, Elizabeth A Clutterbuck, Rachel Colin-Jones, Christina Dold, Katherine R W Emary, Sofiya Fedosyuk, Michelle Fuskova, Diane Gbesemete, Catherine Green, Bassam Hallis, Mimi M Hou, Daniel Jenkin, Carina C D Joe, Elizabeth J Kelly, Simon Kerridge, Alison M Lawrie, Alice Lelliott, May N Lwin, Rebecca Makinson, Natalie G Marchevsky, Yama Mujadidi, Alasdair P S Munro, Mihaela Pacurar, Emma Plested, Jade Rand, Thomas Rawlinson, Sarah Rhead, Hannah Robinson, Adam J Ritchie, Amy L Ross-Russell, Stephen Saich, Nisha Singh, Catherine C Smith, Matthew D Snape, Rinn Song, Richard Tarrant, Yrene Themistocleous, Kelly M Thomas, Tonya L Villafana, Sarah C Warren, Marion E E Watson, Alexander D Douglas, Adrian V S Hill, Teresa Lambe, Sarah C Gilbert, Saul N Faust, Andrew J Pollard, Jeremy Aboagye, Kelly Adams, Aabidah Ali, Elizabeth R. Allen, Lauren Allen, Jennifer L. Allison, Foteini Andritsou, Rachel Anslow, Edward H. Arbe-Barnes, Megan Baker, Natalie Baker, Philip Baker, Ioana Baleanu, Debbie Barker, Eleanor Barnes, Jordan R. Barrett, Kelly Barrett, Louise Bates, Alexander Batten, Kirsten Beadon, Rebecca Beckley, Duncan Bellamy, Adam Berg, Laura Bermejo, Eleanor Berrie, Amy Beveridge, Kevin Bewley, Else M. Bijker, Geeta Birch, Luke Blackwell, Heather Bletchly, Caitlin L. Blundell, Susannah R. Blundell, Emma Bolam, Elena Boland, Daan Bormans, Nicola Borthwick, Konstantinos Boukas, Thomas Bower, Francesca Bowring, Amy Boyd, Tanja Brenner, Phillip Brown, Charlie Brown-O'Sullivan, Scott Bruce, Emily Brunt, Jamie Burbage, Joshua Burgoyne, Karen R. Buttigieg, Nicholas Byard, Ingrid Cabera Puig, Susana Camara, Michelangelo Cao, Federica Cappuccini, Melanie Carr, Miles W. Carroll, Paul Cashen, Ana Cavey, Jim Chadwick, Ruth Challis, David Chapman, David Charles, Irina Chelysheva, Jee-Sun Cho, Liliana Cifuentes, Elizabeth Clark, Sarah Collins, Christopher P. Conlon, Naomi S. Coombes, Rachel Cooper, Cushla Cooper, Wendy E.M. Crocker, Sarah Crosbie, Dan Cullen, Christina Cunningham, Fiona Cuthbertson, Brad E. Datoo, Lynne Dando, Mehreen S. Datoo, Chandrabali Datta, Hannah Davies, Sarah Davies, Elizabeth J. Davis, Judith Davis, David Dearlove, Tesfaye Demissie, Stefania Di Marco, Claudio Di Maso, Danielle DiTirro, Claire Docksey, Tao Dong, Francesca R. Donnellan, Naomi Douglas, Charlotte Downing, Jonathan Drake, Rachael Drake-Brockman, Ruth E. Drury, Susanna J. Dunachie, Christopher J. Edwards, Nick J. Edwards, Omar El Muhanna, Sean C. Elias, Ryan S. Elliott, Michael J. Elmore, Marcus Rex English, Sally Felle, Shuo Feng, Carla Ferreira Da Silva, Samantha Field, Richard Fisher, Carine Fixmer, Karen J. Ford, Jamie Fowler, Emma Francis, John Frater, Julie Furze, Pablo Galian-Rubio, Celine Galloway, Harriet Garlant, Madita Gavrila, Felicity Gibbons, Karyna Gibbons, Ciaran Gilbride, Hardeep Gill, Kerry Godwin, Katherine Gordon-Quayle, Giacomo Gorini, Lyndsey Goulston, Caroline Grabau, Lara Gracie, Nichola Graham, Nicola Greenwood, Oliver Griffiths, Gaurav Gupta, Elizabeth Hamilton, Brama Hanumunthadu, Stephanie A. Harris, Tara Harris, Daisy Harrison, Thomas C. Hart, Birgit Hartnell, Louise Haskell, Sophia Hawkins, John Aaron Henry, Macarena Hermosin Herrera, David Hill, Jennifer Hill, Gina Hodges, Susanne H.C. Hodgson, Katie L. Horton, Elizabeth Howe, Nicola Howell, Jessica Howes, Ben Huang, Jonathan Humphreys, Holly E. Humphries, Poppy Iveson, Frederic Jackson, Susan Jackson, Sam Jauregui, Helen Jeffers, Bryony Jones, Christine E. Jones, Elizabeth Jones, Kathryn Jones, Amar Joshi, Reshma Kailath, Jade Keen, Dearbhla M. Kelly, Sarah Kelly, Debbie Kelly, David Kerr, Liaquat Khan, Baktash Khozoee, Annabel Killen, Jasmin Kinch, Lloyd D.W. King, Thomas B. King, Lucy Kingham, Paul Klenerman, Julian C. Knight, Daniel Knott, Stanislava Koleva, Gail Lang, Colin W. Larkworthy, Jessica P.J. Larwood, Rebecca Law, Arlene Lee, Kim Y.N. Lee, Emily A. Lees, Stephanie Leung, Yuanyuan Li, Amelia M. Lias, Aline Linder, Samuel Lipworth, Shuchang Liu, Xinxue Liu, Stephanie Lloyd, Lisa Loew, Raquel Lopez Ramon, Meera Madhavan, David O. Mainwaring, Garry Mallett, Kushal Mansatta, Spyridoula Marinou, Phedra Marius, Emma Marlow, Paula Marriott, Julia L. Marshall, Jane Martin, Shauna Masters, Joanne McEwan, Joanna L. McGlashan, Lorna McInroy, Nicky McRobert, Clare Megson, Alexander J. Mentzer, Neginsadat Mirtorabi, Celia Mitton, Maria Moore, Marni Moran, Ella Morey, Róisín Morgans, Susan J. Morris, Hazel Morrison Morrison, Gertraud Morshead, Richard Morter, Nathifa A. Moya, Ekta Mukhopadhyay, Jilly Muller, Claire Munro, Sarah Murphy, Philomena Mweu, Andrés Noé, Fay L. Nugent, Katie O'Brien, Daniel O'Connor, Blanché Oguti, Victoria Olchawski, Catarina Oliveira, Peter John O'Reilly, Piper Osborne, Lydia Owen, Nelly Owino, Panagiotis Papageorgiou, Helena Parracho, Karen Parsons, Bhumika Patel, Maia Patrick-Smith, Yanchun Peng, Elizabeth J. Penn, Marco Polo Peralta-Alvarez, James Perring, Christos Petropoulos, Daniel J. Phillips, Dimitra Pipini, Samuel Pollard, Ian Poulton, Danny Pratt, Laura Presland, Pamela C. Proud, Samuel Provstgaard-Morys, Sophie Pueschel, David Pulido, Ria Rabara, Kajal Radia, Durga Rajapaska, Fernando Ramos Lopez, Helen Ratcliffe, Sara Rayhan, Byron Rees, Emilia Reyes Pabon, Hannah Roberts, Isla Robertson, Sophie Roche, Christine S. Rollier, Rossana Romani, Zoe Rose, Indra Rudiansyah, Sabeha Sabheha, Stephannie Salvador, Helen Sanders, Katherine Sanders, Iman Satti, Chloe Sayce, Annina B. Schmid, Ella Schofield, Gavin Screaton, Cynthia Sedik, Samiullah Seddiqi, Rameswara R. Segireddy, Beatrice Selby, Imam Shaik, Hannah R. Sharpe, Robert Shaw, Adam Shea, Sarah Silk, Laura Silva-Reyes, Donal T. Skelly, David J. Smith, Daniel C. Smith, Nicholas Smith, Alexandra J. Spencer, Louise Spoors, Elizabeth Stafford, Imogen Stamford, Lisa Stockdale, David Stockley, Lisa V. Stockwell, Matthew Stokes, Louise H. Strickland, Arabella Stuart, Sulaiman Sulaiman, Eloise Summerton, Zoe Swash, Anna Szigeti, Abdessamad Tahiri-Alaoui, Rachel Tanner, Iona Taylor, Keja Taylor, Ursula Taylor, Rebecca te Water Naude, Andreas Themistocleous, Merin Thomas, Tonia M. Thomas, Amber Thompson, Kevin Thompson, Viv Thornton-Jones, Lan Tinh, Adriana Tomic, Susan Tonks, James Towner, Nguyen Tran, Julian A. Tree, Adam Truby, Cheryl Turner, Richard Turner, Marta Ulaszewska, Rachel Varughese, Dennis Verbart, Marije K. Verheul, Iason Vichos, Laura Walker, Matthew E. Wand, Bridget Watkins, Jessica Welch, Alison J. West, Caroline White, Rachel White, Paul Williams, Mark Woodyer, Andrew T. Worth, Daniel Wright, Terri Wrin, Xin Li Yao, Diana-Andreea Zbarcea, Dalila Zizi
Journal: The Lancet (2020)

Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19 (AZD1222), in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older.In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18-55 years, 56-69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18-55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56-69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5-6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18-55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137.Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18-55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56-69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18-55 years group, 22 (73%) of 30 in the 56-69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18-55 years group, 23 (77%) in the 56-69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18-55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898-33 550], n=39; 56-69 years, 16 170 AU/mL [10 233-40 353], n=26; and ≥70 years 17 561 AU/mL [9705-37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18-55 years, 193 [IQR 113-238], n=39; 56-69 years, 144 [119-347], n=20; and ≥70 years, 161 [73-323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18-55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841-2428], n=24; 56-69 years: 797 SFCs [383-1817], n=29; and ≥70 years: 977 SFCs [458-1914], n=48).ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities.UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.