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      Correlates of protection against symptomatic and asymptomatic SARS-CoV-2 infection

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          Abstract

          The global supply of COVID-19 vaccines remains limited. An understanding of the immune response that is predictive of protection could facilitate rapid licensure of new vaccines. Data from a randomized efficacy trial of the ChAdOx1 nCoV-19 (AZD1222) vaccine in the United Kingdom was analyzed to determine the antibody levels associated with protection against SARS-CoV-2. Binding and neutralizing antibodies at 28 days after the second dose were measured in infected and noninfected vaccine recipients. Higher levels of all immune markers were correlated with a reduced risk of symptomatic infection. A vaccine efficacy of 80% against symptomatic infection with majority Alpha (B.1.1.7) variant of SARS-CoV-2 was achieved with 264 (95% CI: 108, 806) binding antibody units (BAU)/ml: and 506 (95% CI: 135, not computed (beyond data range) (NC)) BAU/ml for anti-spike and anti-RBD antibodies, and 26 (95% CI: NC, NC) international unit (IU)/ml and 247 (95% CI: 101, NC) normalized neutralization titers (NF 50) for pseudovirus and live-virus neutralization, respectively. Immune markers were not correlated with asymptomatic infections at the 5% significance level. These data can be used to bridge to new populations using validated assays, and allow extrapolation of efficacy estimates to new COVID-19 vaccines.

          Abstract

          Defined levels of SARS-CoV-2-specific binding and neutralizing antibodies elicited by the COVID-19 vaccine ChAdOx1 nCoV-19 are identified as correlates of protection against symptomatic infection.

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          Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

          Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)
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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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              Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection

              Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4-28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7-13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.
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                Author and article information

                Contributors
                merryn.voysey@paediatrics.ox.ac.uk
                Journal
                Nat Med
                Nat Med
                Nature Medicine
                Nature Publishing Group US (New York )
                1078-8956
                1546-170X
                29 September 2021
                29 September 2021
                2021
                : 27
                : 11
                : 2032-2040
                Affiliations
                [1 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Oxford Vaccine Group, Department of Paediatrics, , University of Oxford, ; Oxford, UK
                [2 ]GRID grid.417815.e, ISNI 0000 0004 5929 4381, Late-stage development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, , AstraZeneca, ; Cambridge, UK
                [3 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, The Jenner Institute, Nuffield Department of Medicine, , University of Oxford, ; Oxford, UK
                [4 ]GRID grid.271308.f, ISNI 0000 0004 5909 016X, National Infection Service, , Public Health England, ; Salisbury, UK
                [5 ]GRID grid.418152.b, ISNI 0000 0004 0543 9493, Late-stage development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, , AstraZeneca, ; Gaithersburg, MD, USA
                [6 ]GRID grid.417720.7, ISNI 0000 0004 0384 7389, Cytel Inc., ; Cambridge, MA, USA
                [7 ]GRID grid.418152.b, ISNI 0000 0004 0543 9493, Microbial Sciences, BioPharmaceuticals R&D, , AstraZeneca, ; Gaithersburg, MD, USA
                [8 ]GRID grid.418151.8, ISNI 0000 0001 1519 6403, Late-stage development Respiratory and Immunology (R&I), BioPharmaceuticals R&D, , AstraZeneca, ; Gothenburg, Sweden
                [9 ]GRID grid.4991.5, ISNI 0000 0004 1936 8948, Chinese Academy of Medical Science (CAMS) Oxford Institute (COI), , University of Oxford, ; Oxford, UK
                [10 ]NIHR Oxford Biomedical Centre, Oxford, UK
                [11 ]GRID grid.48004.38, ISNI 0000 0004 1936 9764, Department of Clinical Sciences, , Liverpool School of Tropical Medicine, ; Liverpool, UK
                [12 ]GRID grid.10025.36, ISNI 0000 0004 1936 8470, Liverpool University Hospitals NHS Foundation Trust, ; Liverpool, UK
                [13 ]GRID grid.9024.f, ISNI 0000 0004 1757 4641, Institute of Global Health, , University of Siena, ; Siena, Italy
                [14 ]GRID grid.420004.2, ISNI 0000 0004 0444 2244, Department of Infection and Tropical Medicine, , Newcastle upon Tyne Hospitals NHS Foundation Trust, ; Newcastle, UK
                [15 ]GRID grid.1006.7, ISNI 0000 0001 0462 7212, Translational and Clinical Research Institute, Immunity and Inflammation Theme, , Newcastle University, ; Newcastle, UK
                [16 ]GRID grid.5337.2, ISNI 0000 0004 1936 7603, School of Population Health Sciences, , University of Bristol, ; Bristol, UK
                [17 ]GRID grid.410421.2, ISNI 0000 0004 0380 7336, University Hospitals Bristol and Weston NHS Foundation Trust, ; Bristol, UK
                [18 ]GRID grid.425213.3, Department of Infectious Diseases, , Guy’s and St Thomas’ NHS Foundation Trust, St Thomas’ Hospital, ; London, UK
                [19 ]GRID grid.415052.7, ISNI 0000 0004 0606 323X, MRC Clinical Trials Unit at University College London, ; London, UK
                [20 ]GRID grid.412563.7, ISNI 0000 0004 0376 6589, NIHR/Wellcome Trust Clinical Research Facility, , University Hospitals Birmingham NHS Foundation Trust, ; Birmingham, UK
                [21 ]GRID grid.6572.6, ISNI 0000 0004 1936 7486, Institute of Microbiology & Infection, , University of Birmingham, ; Birmingham, UK
                [22 ]GRID grid.264200.2, ISNI 0000 0000 8546 682X, St George’s Vaccine Institute, , St George’s, University of London, ; London, UK
                [23 ]GRID grid.451056.3, ISNI 0000 0001 2116 3923, NIHR UCLH Clinical Research Facility, ; London, UK
                [24 ]GRID grid.451056.3, ISNI 0000 0001 2116 3923, NIHR UCLH Biomedical Research Centre, ; London, UK
                [25 ]Hull University Teaching Hospitals NHS Trust and Hull York Medical School, Hull, UK
                [26 ]GRID grid.439803.5, London North West University Healthcare NHS Trust, ; London, UK
                [27 ]GRID grid.7445.2, ISNI 0000 0001 2113 8111, Department of Medicine, , Imperial College London, ; London, UK
                [28 ]GRID grid.419316.8, ISNI 0000 0004 0550 1859, Labcorp-Monogram Biosciences, ; South San Francisco, CA USA
                [29 ]GRID grid.500643.4, NIHR Imperial Clinical Research Facility and NIHR Imperial Biomedical Research Centre, ; London, UK
                [30 ]GRID grid.8756.c, ISNI 0000 0001 2193 314X, College of Medical, Veterinary & Life Sciences, Glasgow Dental Hospital & School, , University of Glasgow, ; Glasgow, UK
                [31 ]GRID grid.39489.3f, ISNI 0000 0001 0388 0742, Clinical Infection Research Group, Regional Infectious Diseases Unit, , NHS Lothian, ; Edinburgh, UK
                [32 ]GRID grid.511123.5, ISNI 0000 0004 5988 7216, MRC - University of Glasgow Centre for Virus Research & Department of Infectious Diseases, Queen Elizabeth University Hospital, ; Glasgow, UK
                [33 ]GRID grid.240404.6, ISNI 0000 0001 0440 1889, University of Nottingham and Nottingham University Hospitals NHS Trust, ; Nottingham, UK
                [34 ]GRID grid.464526.7, ISNI 0000 0001 0581 7464, Aneurin Bevan University Health Board, ; Newport, UK
                Author information
                http://orcid.org/0000-0003-0686-5091
                http://orcid.org/0000-0002-2146-4299
                http://orcid.org/0000-0002-6823-9750
                http://orcid.org/0000-0002-0348-654X
                http://orcid.org/0000-0001-7711-897X
                http://orcid.org/0000-0001-7361-719X
                http://orcid.org/0000-0001-6324-6559
                Article
                1540
                10.1038/s41591-021-01540-1
                8604724
                34588689
                4e834539-5e0c-48bc-9019-7d7161614f49
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 21 June 2021
                : 14 September 2021
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100000272, DH | National Institute for Health Research (NIHR);
                Award ID: NA
                Award Recipient :
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                © The Author(s), under exclusive licence to Springer Nature America, Inc. 2021

                Medicine
                infectious diseases,vaccines
                Medicine
                infectious diseases, vaccines

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