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      Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial

      research-article
      1 , 2 , 3 , * , , 4 , 5 , 1 , 2 , 6 , 7 , 7 , 8 , 8 , 8 , 8 , 5 , 5 , 5 , 4 , 4 , 4 , 1 , 1 , 1 , 1 , 1 , 9 , 8 , 7 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 1 , 1 , 1 , 17 , 18 , 1 , 7 , 19 , 8 , 5 , Immune Assays Team §, Moderna, Inc. Team §, Coronavirus Vaccine Prevention Network (CoVPN)/Coronavirus Efficacy (COVE) Team §, United States Government (USG)/CoVPN Biostatistics Team §
      Science (New York, N.y.)
      American Association for the Advancement of Science

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          Abstract

          Antibody levels predict vaccine efficacy

          Symptomatic COVID-19 infection can be prevented by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. A “correlate of protection” is a molecular biomarker to measure how much immunity is needed to fight infection and is key for successful global immunization programs. Gilbert et al. determined that antibodies are the correlate of protection in vaccinated individuals enrolled in the Moderna COVE phase 3 clinical trial (see the Perspective by Openshaw). By measuring binding and neutralizing antibodies against the viral spike protein, the authors found that the levels of both antibodies correlated with the degree of vaccine efficacy. The higher the antibody level, the greater the protection afforded by the messenger RNA (mRNA) vaccine. Antibody levels that predict mRNA vaccine efficacy can therefore be used to guide vaccine regimen modifications and support regulatory approvals for a broader spectrum of the population. —PNK

          Abstract

          SARS-CoV-2 binding and neutralizing antibodies correlate with the degree of vaccine efficacy and protection for the Moderna mRNA COVID-19 vaccine.

          Abstract

          In the coronavirus efficacy (COVE) phase 3 clinical trial, vaccine recipients were assessed for neutralizing and binding antibodies as correlates of risk for COVID-19 disease and as correlates of protection. These immune markers were measured at the time of second vaccination and 4 weeks later, with values reported in standardized World Health Organization international units. All markers were inversely associated with COVID-19 risk and directly associated with vaccine efficacy. Vaccine recipients with postvaccination 50% neutralization titers 10, 100, and 1000 had estimated vaccine efficacies of 78% (95% confidence interval, 54 to 89%), 91% (87 to 94%), and 96% (94 to 98%), respectively. These results help define immune marker correlates of protection and may guide approval decisions for messenger RNA (mRNA) COVID-19 vaccines and other COVID-19 vaccines.

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          Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

          Abstract Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. Conclusions The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)
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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
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: Visualization
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - review & editing
                Role: Formal analysisRole: SoftwareRole: Validation
                Role: ConceptualizationRole: Data curationRole: Software
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing - review & editing
                Role: ConceptualizationRole: Project administrationRole: ResourcesRole: Writing - review & editing
                Role: ConceptualizationRole: Project administrationRole: ResourcesRole: Writing - review & editing
                Role: Investigation
                Role: MethodologyRole: Validation
                Role: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: Validation
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: ValidationRole: Writing - original draft
                Role: Investigation
                Role: InvestigationRole: Project administrationRole: ResourcesRole: Validation
                Role: MethodologyRole: Resources
                Role: Formal analysisRole: SoftwareRole: Validation
                Role: Formal analysis
                Role: Software
                Role: Formal analysisRole: MethodologyRole: Software
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: MethodologyRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: SupervisionRole: Writing - review & editing
                Role: ConceptualizationRole: Project administrationRole: Supervision
                Role: ConceptualizationRole: Data curationRole: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: Writing - review & editing
                Role: InvestigationRole: Resources
                Role: InvestigationRole: Project administrationRole: ResourcesRole: Writing - review & editing
                Role: Data curationRole: InvestigationRole: Project administrationRole: SupervisionRole: Writing - review & editing
                Role: InvestigationRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - review & editing
                Role: Project administrationRole: SupervisionRole: ValidationRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: Project administrationRole: Supervision
                Role: ConceptualizationRole: Funding acquisitionRole: InvestigationRole: Project administrationRole: SupervisionRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: SupervisionRole: Writing - review & editing
                Role: VisualizationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: InvestigationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - review & editing
                Role: ConceptualizationRole: MethodologyRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - original draftRole: Writing - review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - review & editing
                Journal
                Science
                Science
                science
                Science (New York, N.y.)
                American Association for the Advancement of Science
                0036-8075
                1095-9203
                23 November 2021
                07 January 2022
                23 November 2021
                : 375
                : 6576
                : 43-50
                Affiliations
                [1 ]Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
                [2 ]Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
                [3 ]Department of Biostatistics, University of Washington, Seattle, WA, USA.
                [4 ]Department of Surgery and Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC, USA.
                [5 ]Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
                [6 ]Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
                [7 ]Moderna, Inc., Cambridge, MA, USA.
                [8 ]Biomedical Advanced Research and Development Authority, Washington, DC, USA.
                [9 ]Division of Biostatistics, School of Public Health, University of California Berkeley, Berkeley, CA, USA.
                [10 ]Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.
                [11 ]Brigham and Women’s Hospital, Boston, MA, USA.
                [12 ]Palm Beach Research Center, West Palm Beach, FL, USA.
                [13 ]Keystone Vitalink Research, Greenville, SC, USA.
                [14 ]Department of Medicine, Division of Infectious Diseases, UNC HIV Cure Center, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
                [15 ]Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
                [16 ]Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine and the Grady Health System, Atlanta, GA, USA.
                [17 ]Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA.
                [18 ]Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.
                [19 ]Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
                Author notes
                [* ]Corresponding author. Email: pgilbert@ 123456fredhutch.org
                [†]

                These authors contributed equally to this work.

                [‡]

                These authors contributed equally to this work.

                [§]

                The members of the Immune Assays Team; Moderna, Inc. Team; CoVPN/COVE Team; and USG/CoVPN Biostatistics Team and their affiliations are listed in the supplementary materials.

                Author information
                https://orcid.org/0000-0002-2662-9427
                https://orcid.org/0000-0003-0856-6319
                https://orcid.org/0000-0003-0616-9117
                https://orcid.org/0000-0001-8125-4173
                https://orcid.org/0000-0001-6536-3492
                https://orcid.org/0000-0003-0384-2388
                https://orcid.org/0000-0003-3064-2947
                https://orcid.org/0000-0002-7083-2182
                https://orcid.org/0000-0003-0489-0074
                https://orcid.org/0000-0001-8833-3659
                https://orcid.org/0000-0001-5611-0119
                https://orcid.org/0000-0003-1952-7825
                https://orcid.org/0000-0003-1279-3741
                https://orcid.org/0000-0002-2179-2436
                https://orcid.org/0000-0001-9480-2714
                https://orcid.org/0000-0003-0333-5925
                https://orcid.org/0000-0003-4073-0393
                https://orcid.org/0000-0001-6137-8312
                https://orcid.org/0000-0002-3090-7282
                Article
                abm3425
                10.1126/science.abm3425
                9017870
                34812653
                762d786c-4246-463a-82a7-c4dc30e108e5
                Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

                This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 16 September 2021
                : 16 November 2021
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000060, National Institute of Allergy and Infectious Diseases;
                Award ID: UM1AI068635
                Funded by: FundRef http://dx.doi.org/10.13039/100012399, Biomedical Advanced Research and Development Authority;
                Award ID: Contract No. 75A50120C00034
                Funded by: FundRef http://dx.doi.org/10.13039/100016958, Office of Research Infrastructure Programs, National Institutes of Health;
                Award ID: S10OD028685
                Funded by: Moderna, Inc.;
                Categories
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                Comp/Math
                Immunology
                Coronavirus
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