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      Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine

      research-article
      , M.D., , M.D., M.P.H., , Ph.D., , M.Math., , M.D., , M.D., , M.D., , M.D., , Ph.D., , M.D., , M.D., M.P.H., , M.D., , D.O., , M.D., , M.D., M.P.H., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., M.S.P.H., , M.D., , M.D., , M.D., , M.D., , M.D., , M.D., , M.S., , M.D., M.P.H., , Ph.D., , Ph.D., , Ph.D., , M.D., Ph.D., , Ph.D., , M.D., , Ph.D., , M.S., , B.S., , M.D., Ph.D., , F.Med.Sci, Ph.D., , Ph.D., M.P.H. , , M.D., Ph.D., M.P.H. *
      The New England Journal of Medicine
      Massachusetts Medical Society
      Keyword part (code): 18Keyword part (keyword): Infectious DiseaseKeyword part (code): 18_2Keyword part (keyword): VaccinesKeyword part (code): 18_6Keyword part (keyword): Viral InfectionsKeyword part (code): 18_12Keyword part (keyword): Coronavirus , 18, Infectious Disease, Keyword part (code): 18_2Keyword part (keyword): VaccinesKeyword part (code): 18_6Keyword part (keyword): Viral InfectionsKeyword part (code): 18_12Keyword part (keyword): Coronavirus , 18_2, Vaccines, 18_6, Viral Infections, 18_12, Coronavirus

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          Abstract

          Background

          The safety and efficacy of the AZD1222 (ChAdOx1 nCoV-19) vaccine in a large, diverse population at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the United States, Chile, and Peru has not been known.

          Methods

          In this ongoing, double-blind, randomized, placebo-controlled, phase 3 clinical trial, we investigated the safety, vaccine efficacy, and immunogenicity of two doses of AZD1222 as compared with placebo in preventing the onset of symptomatic and severe coronavirus disease 2019 (Covid-19) 15 days or more after the second dose in adults, including older adults, in the United States, Chile, and Peru.

          Results

          A total of 32,451 participants underwent randomization, in a 2:1 ratio, to receive AZD1222 (21,635 participants) or placebo (10,816 participants). AZD1222 was safe, with low incidences of serious and medically attended adverse events and adverse events of special interest; the incidences were similar to those observed in the placebo group. Solicited local and systemic reactions were generally mild or moderate in both groups. Overall estimated vaccine efficacy was 74.0% (95% confidence interval [CI], 65.3 to 80.5; P<0.001) and estimated vaccine efficacy was 83.5% (95% CI, 54.2 to 94.1) in participants 65 years of age or older. High vaccine efficacy was consistent across a range of demographic subgroups. In the fully vaccinated analysis subgroup, no severe or critical symptomatic Covid-19 cases were observed among the 17,662 participants in the AZD1222 group; 8 cases were noted among the 8550 participants in the placebo group (<0.1%). The estimated vaccine efficacy for preventing SARS-CoV-2 infection (nucleocapsid antibody seroconversion) was 64.3% (95% CI, 56.1 to 71.0; P<0.001). SARS-CoV-2 spike protein binding and neutralizing antibodies increased after the first dose and increased further when measured 28 days after the second dose.

          Conclusions

          AZD1222 was safe and efficacious in preventing symptomatic and severe Covid-19 across diverse populations that included older adults. (Funded by AstraZeneca and others; ClinicalTrials.gov number, NCT04516746.)

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          Most cited references21

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          Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

          Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; p interaction =0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. Funding UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D’Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
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            A modified poisson regression approach to prospective studies with binary data.

            G Zou (2004)
            Relative risk is usually the parameter of interest in epidemiologic and medical studies. In this paper, the author proposes a modified Poisson regression approach (i.e., Poisson regression with a robust error variance) to estimate this effect measure directly. A simple 2-by-2 table is used to justify the validity of this approach. Results from a limited simulation study indicate that this approach is very reliable even with total sample sizes as small as 100. The method is illustrated with two data sets.
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              Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial

              Summary Background The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. Methods We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18–55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. Findings Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493–1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96–317; n=127), and were boosted following a second dose (639 EU, 360–792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R 2=0·67 by Marburg VN; p<0·001). Interpretation ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme. Funding UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen.
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                Author and article information

                Journal
                N Engl J Med
                N Engl J Med
                nejm
                The New England Journal of Medicine
                Massachusetts Medical Society
                0028-4793
                1533-4406
                29 September 2021
                : NEJMoa2105290
                Affiliations
                From the University of Rochester School of Medicine and Dentistry (A.R.F., M.C.K.) and Rochester Regional Health (A.R.F.), Rochester, and Vagelos College of Physicians and Surgeons, New York Presbyterian Columbia University Irving Medical Center, Department of Medicine, Division of Infectious Diseases (M.E.S.) and the New York University Vaccine Center (M.J.M.), New York — all in New York; Biometrics (I.H.) and Infectious Diseases (J.A.G.), Late-Stage Development, Respiratory and Immunology (R.P.M.), Biopharmaceuticals Research and Development (M.N.P.), AstraZeneca, Cambridge, United Kingdom; Biometrics (S.S., K.S.) and Infectious Diseases, Late-Stage Development, Respiratory and Immunology (J.M., T. Takas, T.V., A.G.-L.), Translational Medicine, Microbial Sciences, Biopharmaceuticals Research and Development (E.J.K.), and Clinical Development, Early Global Development, Oncology Research and Development (N.M.), AstraZeneca, Gaithersburg, the Walter Reed Army Institute of Research, Silver Spring (M.L.R.), the University of Maryland School of Medicine (K.M.N.) and the Johns Hopkins Bloomberg School of Public Health (A.D.), Baltimore, the Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense, Edgewood (J.C.), and the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda (T. Tong, M.B.I., M.C.N.) — all in Maryland; the University of Washington (L.C., W.H.) and the Fred Hutchinson Cancer Research Center (L.C., W.H., J.H., H.E.J.), Seattle; HealthPartners Institute, St. Paul, MN (C.M.); Orlando Immunology Center, Orlando (E.D.), and JEM Headlands Research, Lake Worth Beach (L.B.) — both in Florida; Hassman Research Institute, Berlin, NJ (M.H.); the University of California San Diego, La Jolla (S.J.L.), the Lundquist Institute at Harbor–UCLA Medical Center, Torrance (E.S.D.), and the San Francisco Department of Public Health, San Francisco (S.B.) — all in California; Children’s Mercy Kansas City, Kansas City, MO (B.A.P.); Tekton Research, Austin (P.P.), and Centex Studies, McAllen (J.S.) — both in Texas; Medpharmics, Albuquerque, NM (Q.O.C.); John H. Stroger, Jr. Hospital of Cook County, Chicago (T.O.); Instituto de Ciencias Biomédicas, Facultad de Medicina Universidad de Chile, Santiago, Chile (S.L.V.); Clínica Internacional Sede Lima, Lima, Peru (A.G.B.); Clinical Research Partners, Richmond, VA (R.C.); the University of Vermont Larner College of Medicine and UVM Medical Center, Burlington (B.D.K.); Mercury Street Medical Group, Butte, MT (J.P.); and the Rollins School of Public Health at Emory University, Atlanta (D.B.).
                Author notes
                Dr. Villafana can be contacted at tonya.villafana@ 123456astrazeneca.com or at AstraZeneca, 1 Medimmune Way, Gaithersburg, MD 20878-2204.
                [*]

                A complete list of the members of the AstraZeneca AZD1222 Clinical Study Group is provided in the Supplementary Appendix, available at NEJM.org.

                Drs. Falsey and Sobieszczyk contributed equally to this article.

                Author information
                http://orcid.org/0000-0002-2179-2436
                http://orcid.org/0000-0002-7645-9737
                http://orcid.org/0000-0002-1019-8343
                http://orcid.org/0000-0002-0110-881X
                Article
                NJ202109290000001
                10.1056/NEJMoa2105290
                8522798
                34587382
                3c686256-3e88-4258-aca1-a1787ca33537
                Copyright © 2021 Massachusetts Medical Society. All rights reserved.

                This article is made available via the PMC Open Access Subset for unrestricted re-use, except commercial resale, and analyses in any form or by any means with acknowledgment of the original source. These permissions are granted for the duration of the Covid-19 pandemic or until revoked in writing. Upon expiration of these permissions, PMC is granted a license to make this article available via PMC and Europe PMC, subject to existing copyright protections.

                History
                Funding
                Funded by: United States Government, FundRef http://dx.doi.org/10.13039/100000016;
                Award ID: Agreement No. W15QKN-20-9-1003
                Funded by: National Institute of Allergy and Infectious Diseases (NIAID), FundRef http://dx.doi.org/10.13039/100000060;
                Award ID: UM1 AI 148372
                Award ID: UM1 AI 148450
                Award ID: UM1 AI 148574
                Award ID: UM1 AI 148684
                Award ID: UM1 AI 148684-03
                Award ID: UM1 AI 68614HVTN
                Award ID: UM1 AI 68618
                Award ID: UM1 AI 68619
                Award ID: UM1 AI 68635
                Award ID: UM1 AI 68636
                Funded by: Biomedical Advanced Research and Development Authority, FundRef ;
                Award ID: W15QKN-21-9-1003
                Categories
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                Custom metadata
                2021-09-29T17:00:00-04:00
                2021
                09
                29
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