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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.
Ramasamy, Maheshi N; Minassian, Angela M; Ewer, Katie J; Flaxman, Amy L; Folegatti, Pedro M; Owens, Daniel R; Voysey, Merryn; Aley, Parvinder K; Angus, Brian; Babbage, Gavin; Belij-Rammerstorfer, Sandra; Berry, Lisa; Bibi, Sagida; Bittaye, Mustapha; Cathie, Katrina; Chappell, Harry; Charlton, Sue; Cicconi, Paola; Clutterbuck, Elizabeth A; Colin-Jones, Rachel; Dold, Christina; Emary, Katherine R W; Fedosyuk, Sofiya; Fuskova, Michelle; Gbesemete, Diane; Green, Catherine; Hallis, Bassam; Hou, Mimi M; Jenkin, Daniel; Joe, Carina C D; Kelly, Elizabeth J; Kerridge, Simon; Lawrie, Alison M; Lelliott, Alice; Lwin, May N; Makinson, Rebecca; Marchevsky, Natalie G; Mujadidi, Yama; Munro, Alasdair P S; Pacurar, Mihaela; Plested, Emma; Rand, Jade; Rawlinson, Thomas; Rhead, Sarah; Robinson, Hannah; Ritchie, Adam J; Ross-Russell, Amy L; Saich, Stephen; Singh, Nisha; Smith, Catherine C.
  • Ramasamy MN; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. Electronic address: maheshi.ramasamy@paediatrics.ox.ac.uk.
  • Minassian AM; The Jenner Institute, University of Oxford, Oxford, UK.
  • Ewer KJ; The Jenner Institute, University of Oxford, Oxford, UK.
  • Flaxman AL; The Jenner Institute, University of Oxford, Oxford, UK.
  • Folegatti PM; The Jenner Institute, University of Oxford, Oxford, UK.
  • Owens DR; NIHR Clinical Research Facility, University Hospital Southampton NHS Trust, Southampton, UK.
  • Voysey M; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
  • Aley PK; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
  • Angus B; The Jenner Institute, University of Oxford, Oxford, UK.
  • Babbage G; The Jenner Institute, University of Oxford, Oxford, UK.
  • Belij-Rammerstorfer S; The Jenner Institute, University of Oxford, Oxford, UK.
  • Berry L; NIHR Clinical Research Facility, University Hospital Southampton NHS Trust, Southampton, UK.
  • Bibi S; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
  • Bittaye M; The Jenner Institute, University of Oxford, Oxford, UK.
  • Cathie K; Paediatric Medicine, University of Southampton, Southampton, UK.
  • Chappell H; NIHR Clinical Research Facility, University Hospital Southampton NHS Trust, Southampton, UK.
  • Charlton S; National Infection Service, Public Health England, Porton Down, Salisbury, UK.
  • Cicconi P; The Jenner Institute, University of Oxford, Oxford, UK.
  • Clutterbuck EA; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.
  • Colin-Jones R; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
  • Dold C; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.
  • Emary KRW; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
  • Fedosyuk S; The Jenner Institute, University of Oxford, Oxford, UK.
  • Fuskova M; The Jenner Institute, University of Oxford, Oxford, UK.
  • Gbesemete D; NIHR Clinical Research Facility, University Hospital Southampton NHS Trust, Southampton, UK.
  • Green C; Clinical Biomanufacturing Facility, University of Oxford, Oxford, UK.
  • Hallis B; National Infection Service, Public Health England, Porton Down, Salisbury, UK.
  • Hou MM; The Jenner Institute, University of Oxford, Oxford, UK.
  • Jenkin D; The Jenner Institute, University of Oxford, Oxford, UK.
  • Joe CCD; The Jenner Institute, University of Oxford, Oxford, UK.
  • Kelly EJ; AstraZeneca BioPharmaceuticals Research and Development, Washington, DC, USA.
  • Kerridge S; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
  • Lawrie AM; The Jenner Institute, University of Oxford, Oxford, UK.
  • Lelliott A; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
  • Lwin MN; NIHR Clinical Research Facility, University Hospital Southampton NHS Trust, Southampton, UK.
  • Makinson R; The Jenner Institute, University of Oxford, Oxford, UK.
  • Marchevsky NG; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
  • Mujadidi Y; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
  • Munro APS; NIHR Clinical Research Facility, University Hospital Southampton NHS Trust, Southampton, UK.
  • Pacurar M; NIHR Clinical Research Facility, University Hospital Southampton NHS Trust, Southampton, UK.
  • Plested E; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
  • Rand J; NIHR Clinical Research Facility, University Hospital Southampton NHS Trust, Southampton, UK.
  • Rawlinson T; The Jenner Institute, University of Oxford, Oxford, UK.
  • Rhead S; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.
  • Robinson H; Nuffield Department of Medicine, and Oxford Centre for Clinical Tropical Medicine and Global Health, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.
  • Ritchie AJ; The Jenner Institute, University of Oxford, Oxford, UK.
  • Ross-Russell AL; NIHR Clinical Research Facility, University Hospital Southampton NHS Trust, Southampton, UK.
  • Saich S; NIHR Clinical Research Facility, University Hospital Southampton NHS Trust, Southampton, UK.
  • Singh N; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
  • Smith CC; Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.
Lancet ; 396(10267): 1979-1993, 2021 12 19.
Article in English | MEDLINE | ID: covidwho-933547
ABSTRACT

BACKGROUND:

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.

METHODS:

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, 11 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56-69 years group, 3131 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, 5151 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 51 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.

FINDINGS:

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).

INTERPRETATION:

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.

FUNDING:

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.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Document Type: Article Main subject: Immunogenicity, Vaccine / COVID-19 Vaccines Subject: Immunogenicity, Vaccine / COVID-19 Vaccines Type of study: Controlled clinical trial Language: English Journal: Lancet Clinical aspect: Etiology Year: 2021

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Full text: Available Collection: International databases Database: MEDLINE Document Type: Article Main subject: Immunogenicity, Vaccine / COVID-19 Vaccines Subject: Immunogenicity, Vaccine / COVID-19 Vaccines Type of study: Controlled clinical trial Language: English Journal: Lancet Clinical aspect: Etiology Year: 2021
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