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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

      research-article
      , DPhil a , , * , , DPhil b , , , PhD b , , , DPhil b , , , MD b , , , MRCPCH e , , , DPhil a , , , PhD a , , MD b , , MPhil b , , PhD b , , BSc e , , PhD a , , PhD b , , MD f , , MBBS e , , PhD g , , PhD b , , PhD a , h , , MSc a , , PhD a , h , , BM BCh a , , PhD b , , MSc b , , MRCPCH e , , PhD c , , PhD g , , MRCPCH b , , MRCP b , , PhD b , , PhD i , , MSc a , , PhD b , , BMBS a , , MSc e , , MBiol b , , MSc a , , MSc a , , MRCPCH e , , MD e , a , , BA e , , DPhil b , , MBChB a , h , , DipHE d , h , , PhD b , , MA e , , BA e , , DPhil a , , PhD a , , MD a , , MD a , k , , PhD c , , MBChB b , , PhD g , , PhD j , , MBBC e , , PhD b , , DPhil b , h , , , Prof, FMedSci b , h , , , PhD b , h , , , Prof, PhD b , h , , , Prof, FRCPCH l , , , Prof, FMedSci a , h , , Oxford COVID Vaccine Trial Group
      Lancet (London, England)
      The Authors. Published by Elsevier Ltd.

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          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, 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 × 10 10 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 × 10 10 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 (MNA 80). 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 MNA 80 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.

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          Most cited references27

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          Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

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            A global clinical measure of fitness and frailty in elderly people.

            There is no single generally accepted clinical definition of frailty. Previously developed tools to assess frailty that have been shown to be predictive of death or need for entry into an institutional facility have not gained acceptance among practising clinicians. We aimed to develop a tool that would be both predictive and easy to use. We developed the 7-point Clinical Frailty Scale and applied it and other established tools that measure frailty to 2305 elderly patients who participated in the second stage of the Canadian Study of Health and Aging (CSHA). We followed this cohort prospectively; after 5 years, we determined the ability of the Clinical Frailty Scale to predict death or need for institutional care, and correlated the results with those obtained from other established tools. The CSHA Clinical Frailty Scale was highly correlated (r = 0.80) with the Frailty Index. Each 1-category increment of our scale significantly increased the medium-term risks of death (21.2% within about 70 mo, 95% confidence interval [CI] 12.5%-30.6%) and entry into an institution (23.9%, 95% CI 8.8%-41.2%) in multivariable models that adjusted for age, sex and education. Analyses of receiver operating characteristic curves showed that our Clinical Frailty Scale performed better than measures of cognition, function or comorbidity in assessing risk for death (area under the curve 0.77 for 18-month and 0.70 for 70-month mortality). Frailty is a valid and clinically important construct that is recognizable by physicians. Clinical judgments about frailty can yield useful predictive information.
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              Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates

              Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the resulting disease, coronavirus disease 2019 (Covid-19), have spread to millions of persons worldwide. Multiple vaccine candidates are under development, but no vaccine is currently available. Interim safety and immunogenicity data about the vaccine candidate BNT162b1 in younger adults have been reported previously from trials in Germany and the United States. Methods In an ongoing, placebo-controlled, observer-blinded, dose-escalation, phase 1 trial conducted in the United States, we randomly assigned healthy adults 18 to 55 years of age and those 65 to 85 years of age to receive either placebo or one of two lipid nanoparticle–formulated, nucleoside-modified RNA vaccine candidates: BNT162b1, which encodes a secreted trimerized SARS-CoV-2 receptor–binding domain; or BNT162b2, which encodes a membrane-anchored SARS-CoV-2 full-length spike, stabilized in the prefusion conformation. The primary outcome was safety (e.g., local and systemic reactions and adverse events); immunogenicity was a secondary outcome. Trial groups were defined according to vaccine candidate, age of the participants, and vaccine dose level (10 μg, 20 μg, 30 μg, and 100 μg). In all groups but one, participants received two doses, with a 21-day interval between doses; in one group (100 μg of BNT162b1), participants received one dose. Results A total of 195 participants underwent randomization. In each of 13 groups of 15 participants, 12 participants received vaccine and 3 received placebo. BNT162b2 was associated with a lower incidence and severity of systemic reactions than BNT162b1, particularly in older adults. In both younger and older adults, the two vaccine candidates elicited similar dose-dependent SARS-CoV-2–neutralizing geometric mean titers, which were similar to or higher than the geometric mean titer of a panel of SARS-CoV-2 convalescent serum samples. Conclusions The safety and immunogenicity data from this U.S. phase 1 trial of two vaccine candidates in younger and older adults, added to earlier interim safety and immunogenicity data regarding BNT162b1 in younger adults from trials in Germany and the United States, support the selection of BNT162b2 for advancement to a pivotal phase 2–3 safety and efficacy evaluation. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)
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                Author and article information

                Journal
                Lancet
                Lancet
                Lancet (London, England)
                The Authors. Published by Elsevier Ltd.
                0140-6736
                1474-547X
                19 November 2020
                19 November 2020
                Affiliations
                [a ]Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK
                [b ]The Jenner Institute, University of Oxford, Oxford, UK
                [c ]Clinical Biomanufacturing Facility, University of Oxford, Oxford, UK
                [d ]Nuffield Department of Medicine, and Oxford Centre for Clinical Tropical Medicine and Global Health, University of Oxford, Oxford, UK
                [e ]NIHR Clinical Research Facility, University Hospital Southampton NHS Trust, Southampton, UK
                [f ]Paediatric Medicine, University of Southampton, Southampton, UK
                [g ]National Infection Service, Public Health England, Porton Down, Salisbury, UK
                [h ]NIHR Oxford Biomedical Research Centre, Oxford, UK
                [i ]AstraZeneca BioPharmaceuticals Research and Development, Washington, DC, USA
                [j ]AstraZeneca BioPharmaceuticals Research and Development, Bethesda, MA, USA
                [k ]Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA
                [l ]NIHR Southampton Clinical Research Facility and Biomedical Research Centre, University Hospital Southampton NHS Trust and Faculty of Medicine and Institute for Life Sciences, University of Southampton, Southampton, UK
                Author notes
                [* ]Correspondence to: Dr Maheshi N Ramasamy, Department of Paediatrics, University of Oxford, Oxford OX3 9DU, UK
                [†]

                Contributed equally

                Article
                S0140-6736(20)32466-1
                10.1016/S0140-6736(20)32466-1
                7674972
                33220855
                e04648b4-f150-4443-b81b-977083ec0a6a
                © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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