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CLINICAL AND DEMOGRAPHIC FACTORS ASSOCIATED WITH COVID-19, SEVERE COVID-19, AND SARS-COV-2 INFECTION IN ADULTS: A SECONDARY CROSS-PROTOCOL ANALYSIS OF 4 RANDOMIZED CLINICAL TRIALS
Author
Theodore, Deborah A.
Branche, Angela R.
Zhang, Lily
Graciaa, Daniel S.
Choudhary, Madhu
Hatlen, Timothy J.
Osman, Raadhiya
Babu, Tara M.
Robinson, Samuel T.
Gilbert, Peter B.
Follmann, Dean
Janes, Holly
Kublin, James G.
Baden, Lindsey R.
Goepfert, Paul
Gray, Glenda E.
Grinsztejn, Beatriz
Kotloff, Karen L.
Gay, Cynthia L.
Leav, Brett
Miller, Jacqueline
Hirsch, Ian
Sadoff, Jerald
Dunkle, Lisa M.
Neuzil, Kathleen M.
Corey, Lawrence
Falsey, Ann R.
Sahly, Hana M. El
Sobieszczyk, Magdalena E.
Huang, Yunda
Branche, Angela R.
Zhang, Lily
Graciaa, Daniel S.
Choudhary, Madhu
Hatlen, Timothy J.
Osman, Raadhiya
Babu, Tara M.
Robinson, Samuel T.
Gilbert, Peter B.
Follmann, Dean
Janes, Holly
Kublin, James G.
Baden, Lindsey R.
Goepfert, Paul
Gray, Glenda E.
Grinsztejn, Beatriz
Kotloff, Karen L.
Gay, Cynthia L.
Leav, Brett
Miller, Jacqueline
Hirsch, Ian
Sadoff, Jerald
Dunkle, Lisa M.
Neuzil, Kathleen M.
Corey, Lawrence
Falsey, Ann R.
Sahly, Hana M. El
Sobieszczyk, Magdalena E.
Huang, Yunda
Affilliation
Columbia University Irving Medical Center. Division of Infectious Diseases. Department of Medicine. New York, NY, USA.
University of Rochester. Department of Medicine. Infectious Disease Division. Rochester, NY, USA.
Fred Hutchinson Cancer Center. Vaccine and Infectious Disease Division. Seattle, Washington, USA.
Emory University School of Medicine. Division of Infectious Diseases. Department of Medicine. Atlanta, Georgia, USA.
University of Pittsburgh School of Medicine. Division of Infectious Diseases. Pittsburgh, Pennsylvania, USA.
Harbor-UCLA Medical Center. Division of HIV. Torrance, California, USA.
Chris Hani Baragwanath Academic Hospital. Perinatal HIV Research Unit. Soweto, South Africa.
University of Washington. Department of Medicine. Division of Allergy & Infectious Diseases. Seattle, USA.
Fred Hutchinson Cancer Center. Vaccine and Infectious Disease Division. Seattle, Washington, USA.
Fred Hutchinson Cancer Center. Vaccine and Infectious Disease Division. Seattle, Washington, USA / University of Washington. Department of Biostatistics. Washington, Seattle, USA.
National Institutes of Health. National Institute of Allergy and Infectious Disease. Biostatistics Research Branch. Bethesda, Maryland.
Fred Hutchinson Cancer Center. Vaccine and Infectious Disease Division. Seattle, Washington, USA / University of Washington. Department of Biostatistics. Washington, Seattle, USA.
Fred Hutchinson Cancer Center. Vaccine and Infectious Disease Division. Seattle, Washington, USA.
Brigham and Women's Hospital. Boston, Massachusetts, USA.
University of Alabama at Birmingham. Department of Medicine. Division of Infectious Diseases. Birmingham, USA.
University of the Witwatersrand. Faculty of Health Sciences. Perinatal HIV Research Unit. Johannesburg, South Africa / South African Medical Research Council. Cape Town, South Africa.
Oswaldo Cruz Foundation. Evandro Chagas National Institute of Infectious Diseases. Rio de Janeiro, RJ, Brazil.
University of Maryland School of Medicine. Department of Pediatrics. Division of Infectious Disease and Tropical Pediatrics. Baltimore, USA / University of Maryland School of Medicine. Department of Medicine. Center for Vaccine Development and Global Health. Baltimore, USA.
University of North Carolina. Chapel Hill School of Medicine. Department of Medicine. Division of Infectious Diseases. UNC HIV Cure Center. Chapel Hill, USA.
Moderna. Cambridge, Massachusetts, USA.
Moderna. Cambridge, Massachusetts, USA.
AstraZeneca BioPharmaceuticals. Cambridge, United Kingdom.
Janssen Vaccines and Prevention. Leiden, Netherlands.
Novavax. Gaithersburg, Maryland.
University of Maryland School of Medicine. Department of Medicine. Center for Vaccine Development and Global Health. Baltimore, USA.
Fred Hutchinson Cancer Center. Vaccine and Infectious Disease Division. Seattle, Washington, USA / University of Washington. Department of Laboratory Medicine and Pathology. Seattle, Washington, USA.
University of Rochester. Department of Medicine. Infectious Disease Division. Rochester, NY, USA.
Baylor College of Medicine. Department of Medicine. Infectious Diseases Section. Houston, Texas, USA / Baylor College of Medicine. Department of Molecular Virology and Microbiology. Houston, Texas, USA.
Columbia University Irving Medical Center. Division of Infectious Diseases. Department of Medicine. New York, NY, USA.
Fred Hutchinson Cancer Center. Vaccine and Infectious Disease Division. Seattle, Washington, USA / University of Washington. Department of Global Health. Seattle, Washington, USA.
University of Rochester. Department of Medicine. Infectious Disease Division. Rochester, NY, USA.
Fred Hutchinson Cancer Center. Vaccine and Infectious Disease Division. Seattle, Washington, USA.
Emory University School of Medicine. Division of Infectious Diseases. Department of Medicine. Atlanta, Georgia, USA.
University of Pittsburgh School of Medicine. Division of Infectious Diseases. Pittsburgh, Pennsylvania, USA.
Harbor-UCLA Medical Center. Division of HIV. Torrance, California, USA.
Chris Hani Baragwanath Academic Hospital. Perinatal HIV Research Unit. Soweto, South Africa.
University of Washington. Department of Medicine. Division of Allergy & Infectious Diseases. Seattle, USA.
Fred Hutchinson Cancer Center. Vaccine and Infectious Disease Division. Seattle, Washington, USA.
Fred Hutchinson Cancer Center. Vaccine and Infectious Disease Division. Seattle, Washington, USA / University of Washington. Department of Biostatistics. Washington, Seattle, USA.
National Institutes of Health. National Institute of Allergy and Infectious Disease. Biostatistics Research Branch. Bethesda, Maryland.
Fred Hutchinson Cancer Center. Vaccine and Infectious Disease Division. Seattle, Washington, USA / University of Washington. Department of Biostatistics. Washington, Seattle, USA.
Fred Hutchinson Cancer Center. Vaccine and Infectious Disease Division. Seattle, Washington, USA.
Brigham and Women's Hospital. Boston, Massachusetts, USA.
University of Alabama at Birmingham. Department of Medicine. Division of Infectious Diseases. Birmingham, USA.
University of the Witwatersrand. Faculty of Health Sciences. Perinatal HIV Research Unit. Johannesburg, South Africa / South African Medical Research Council. Cape Town, South Africa.
Oswaldo Cruz Foundation. Evandro Chagas National Institute of Infectious Diseases. Rio de Janeiro, RJ, Brazil.
University of Maryland School of Medicine. Department of Pediatrics. Division of Infectious Disease and Tropical Pediatrics. Baltimore, USA / University of Maryland School of Medicine. Department of Medicine. Center for Vaccine Development and Global Health. Baltimore, USA.
University of North Carolina. Chapel Hill School of Medicine. Department of Medicine. Division of Infectious Diseases. UNC HIV Cure Center. Chapel Hill, USA.
Moderna. Cambridge, Massachusetts, USA.
Moderna. Cambridge, Massachusetts, USA.
AstraZeneca BioPharmaceuticals. Cambridge, United Kingdom.
Janssen Vaccines and Prevention. Leiden, Netherlands.
Novavax. Gaithersburg, Maryland.
University of Maryland School of Medicine. Department of Medicine. Center for Vaccine Development and Global Health. Baltimore, USA.
Fred Hutchinson Cancer Center. Vaccine and Infectious Disease Division. Seattle, Washington, USA / University of Washington. Department of Laboratory Medicine and Pathology. Seattle, Washington, USA.
University of Rochester. Department of Medicine. Infectious Disease Division. Rochester, NY, USA.
Baylor College of Medicine. Department of Medicine. Infectious Diseases Section. Houston, Texas, USA / Baylor College of Medicine. Department of Molecular Virology and Microbiology. Houston, Texas, USA.
Columbia University Irving Medical Center. Division of Infectious Diseases. Department of Medicine. New York, NY, USA.
Fred Hutchinson Cancer Center. Vaccine and Infectious Disease Division. Seattle, Washington, USA / University of Washington. Department of Global Health. Seattle, Washington, USA.
Abstract
Importance: Current data identifying COVID-19 risk factors lack standardized outcomes and insufficiently control for confounders. Objective: To identify risk factors associated with COVID-19, severe COVID-19, and SARS-CoV-2 infection. Design, setting, and participants: This secondary cross-protocol analysis included 4 multicenter, international, randomized, blinded, placebo-controlled, COVID-19 vaccine efficacy trials with harmonized protocols established by the COVID-19 Prevention Network. Individual-level data from participants randomized to receive placebo within each trial were combined and analyzed. Enrollment began July 2020 and the last data cutoff was in July 2021. Participants included adults in stable health, at risk for SARS-CoV-2, and assigned to the placebo group within each vaccine trial. Data were analyzed from April 2022 to February 2023. Exposures: Comorbid conditions, demographic factors, and SARS-CoV-2 exposure risk at the time of enrollment. Main outcomes and measures: Coprimary outcomes were COVID-19 and severe COVID-19. Multivariate Cox proportional regression models estimated adjusted hazard ratios (aHRs) and 95% CIs for baseline covariates, accounting for trial, region, and calendar time. Secondary outcomes included severe COVID-19 among people with COVID-19, subclinical SARS-CoV-2 infection, and SARS-CoV-2 infection. Results: A total of 57 692 participants (median [range] age, 51 [18-95] years; 11 720 participants [20.3%] aged ≥65 years; 31 058 participants [53.8%] assigned male at birth) were included. The analysis population included 3270 American Indian or Alaska Native participants (5.7%), 7849 Black or African American participants (13.6%), 17 678 Hispanic or Latino participants (30.6%), and 40 745 White participants (70.6%). Annualized incidence was 13.9% (95% CI, 13.3%-14.4%) for COVID-19 and 2.0% (95% CI, 1.8%-2.2%) for severe COVID-19. Factors associated with increased rates of COVID-19 included workplace exposure (high vs low: aHR, 1.35 [95% CI, 1.16-1.58]; medium vs low: aHR, 1.41 [95% CI, 1.21-1.65]; P < .001) and living condition risk (very high vs low risk: aHR, 1.41 [95% CI, 1.21-1.66]; medium vs low risk: aHR, 1.19 [95% CI, 1.08-1.32]; P < .001). Factors associated with decreased rates of COVID-19 included previous SARS-CoV-2 infection (aHR, 0.13 [95% CI, 0.09-0.19]; P < .001), age 65 years or older (aHR vs age <65 years, 0.57 [95% CI, 0.50-0.64]; P < .001) and Black or African American race (aHR vs White race, 0.78 [95% CI, 0.67-0.91]; P = .002). Factors associated with increased rates of severe COVID-19 included race (American Indian or Alaska Native vs White: aHR, 2.61 [95% CI, 1.85-3.69]; multiracial vs White: aHR, 2.19 [95% CI, 1.50-3.20]; P < .001), diabetes (aHR, 1.54 [95% CI, 1.14-2.08]; P = .005) and at least 2 comorbidities (aHR vs none, 1.39 [95% CI, 1.09-1.76]; P = .008). In analyses restricted to participants who contracted COVID-19, increased severe COVID-19 rates were associated with age 65 years or older (aHR vs <65 years, 1.75 [95% CI, 1.32-2.31]; P < .001), race (American Indian or Alaska Native vs White: aHR, 1.98 [95% CI, 1.38-2.83]; Black or African American vs White: aHR, 1.49 [95% CI, 1.03-2.14]; multiracial: aHR, 1.81 [95% CI, 1.21-2.69]; overall P = .001), body mass index (aHR per 1-unit increase, 1.03 [95% CI, 1.01-1.04]; P = .001), and diabetes (aHR, 1.85 [95% CI, 1.37-2.49]; P < .001). Previous SARS-CoV-2 infection was associated with decreased severe COVID-19 rates (aHR, 0.04 [95% CI, 0.01-0.14]; P < .001). Conclusions and relevance: In this secondary cross-protocol analysis of 4 randomized clinical trials, exposure and demographic factors had the strongest associations with outcomes; results could inform mitigation strategies for SARS-CoV-2 and viruses with comparable epidemiological characteristics.
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