. 2021 Jul 7;13(601):eabh3826.

doi: 10.1126/scitranslmed.abh3826. Epub 2021 Jun 22.

Undiagnosed SARS-CoV-2 seropositivity during the first 6 months of the COVID-19 pandemic in the United States

Heather Kalish¹, Carleen Klumpp-Thomas², Sally Hunsberger³, Holly Ann Baus⁴, Michael P Fay³, Nalyn Siripong⁵, Jing Wang⁶, Jennifer Hicks¹, Jennifer Mehalko⁷, Jameson Travers², Matthew Drew⁷, Kyle Pauly¹, Jacquelyn Spathies¹, Tran Ngo⁸, Kenneth M Adusei⁸, Maria Karkanitsa⁸, Jennifer A Croker⁹, Yan Li¹⁰, Barry I Graubard¹¹, Lindsay Czajkowski⁴, Olivia Belliveau¹², Cheryl Chairez¹², Kelly R Snead⁷, Peter Frank⁷, Anandakumar Shunmugavel⁸, Alison Han⁴, Luca T Giurgea⁴, Luz Angela Rosas⁴, Rachel Bean⁴, Rani Athota⁴, Adriana Cervantes-Medina⁴, Monica Gouzoulis⁴, Brittany Heffelfinger⁴, Shannon Valenti⁵, Rocco Caldararo¹³, Michelle M Kolberg¹⁴, Andrew Kelly², Reid Simon², Saifullah Shafiq², Vanessa Wall⁷, Susan Reed⁴, Eric W Ford⁹, Ravi Lokwani⁸, John-Paul Denson⁷, Simon Messing⁷, Sam G Michael², William Gillette⁷, Robert P Kimberly⁹, Steven E Reis⁵, Matthew D Hall², Dominic Esposito⁷, Matthew J Memoli¹⁵, Kaitlyn Sadtler¹⁶

Affiliations

¹ Trans-NIH Shared Resource on Biomedical Engineering and Physical Science, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20894, USA.
² National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
³ Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20894, USA.
⁴ Clinical Studies Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20894, USA.
⁵ Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
⁶ Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
⁷ Protein Expression Laboratory, NCI RAS Initiative, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
⁸ Section on Immuno-Engineering, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20894, USA.
⁹ Center for Clinical and Translational Science, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
¹⁰ Joint Program in Survey Methodology, Department of Epidemiology and Biostatistics, University of Maryland College Park, College Park, MD 20742, USA.
¹¹ Division of Cancer Epidemiology and Genetics, Biostatistics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20894, USA.
¹² Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20894, USA.
¹³ Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.
¹⁴ Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20894, USA.
¹⁵ Clinical Studies Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20894, USA. memolim@nih.gov kaitlyn.sadtler@nih.gov.
¹⁶ Section on Immuno-Engineering, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20894, USA. memolim@nih.gov kaitlyn.sadtler@nih.gov.

PMID: 34158410
PMCID: PMC8432952
DOI: 10.1126/scitranslmed.abh3826

Undiagnosed SARS-CoV-2 seropositivity during the first 6 months of the COVID-19 pandemic in the United States

Heather Kalish et al. Sci Transl Med. 2021.

. 2021 Jul 7;13(601):eabh3826.

doi: 10.1126/scitranslmed.abh3826. Epub 2021 Jun 22.

Authors

Affiliations

¹ Trans-NIH Shared Resource on Biomedical Engineering and Physical Science, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20894, USA.
² National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
³ Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20894, USA.
⁴ Clinical Studies Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20894, USA.
⁵ Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA.
⁶ Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
⁷ Protein Expression Laboratory, NCI RAS Initiative, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
⁸ Section on Immuno-Engineering, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20894, USA.
⁹ Center for Clinical and Translational Science, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
¹⁰ Joint Program in Survey Methodology, Department of Epidemiology and Biostatistics, University of Maryland College Park, College Park, MD 20742, USA.
¹¹ Division of Cancer Epidemiology and Genetics, Biostatistics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20894, USA.
¹² Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20894, USA.
¹³ Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD 21702, USA.
¹⁴ Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20894, USA.
¹⁵ Clinical Studies Unit, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20894, USA. memolim@nih.gov kaitlyn.sadtler@nih.gov.
¹⁶ Section on Immuno-Engineering, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD 20894, USA. memolim@nih.gov kaitlyn.sadtler@nih.gov.

PMID: 34158410
PMCID: PMC8432952
DOI: 10.1126/scitranslmed.abh3826

Abstract

Asymptomatic SARS-CoV-2 infection and delayed implementation of diagnostics have led to poorly defined viral prevalence rates in the United States and elsewhere. To address this, we analyzed seropositivity in 9089 adults in the United States who had not been diagnosed previously with COVID-19. Individuals with characteristics that reflected the U.S. population (n = 27,716) were selected by quota sampling from 462,949 volunteers. Enrolled participants (n = 11,382) provided medical, geographic, demographic, and socioeconomic information and dried blood samples. Survey questions coincident with the Behavioral Risk Factor Surveillance System survey, a large probability-based national survey, were used to adjust for selection bias. Most blood samples (88.7%) were collected between 10 May and 31 July 2020 and were processed using ELISA to measure seropositivity (IgG and IgM antibodies against SARS-CoV-2 spike protein and the spike protein receptor binding domain). The overall weighted undiagnosed seropositivity estimate was 4.6% (95% CI, 2.6 to 6.5%), with race, age, sex, ethnicity, and urban/rural subgroup estimates ranging from 1.1% to 14.2%. The highest seropositivity estimates were in African American participants; younger, female, and Hispanic participants; and residents of urban centers. These data indicate that there were 4.8 undiagnosed SARS-CoV-2 infections for every diagnosed case of COVID-19, and an estimated 16.8 million infections were undiagnosed by mid-July 2020 in the United States.

Copyright © 2021 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).

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Figures

**Fig. 1. SARS-CoV-2 serosurvey study overview and statistical workflow.**
A flow chart of participant recruitment through data analysis displays steps in data acquisition and lists participant attrition. Ovals show the start and end of data analysis or data acquisition; gray rectangles indicate subsets of participants in this study; blue parallelograms represent individuals from outside data sets that contributed to adjusted prevalence estimates; blue rounded rectangles present analysis processes.

**Fig. 2. Geographic distribution of undiagnosed seropositivity in the United States from May to July 2020.**
Raw serology data for (A) IgG, (B) IgM, and (C) IgA against SARS-CoV-2 spike protein and the receptor binding domain (RBD) of spike protein are displayed. Cut points for positivity are shown as red dashed lines; data are optical density (OD). (D) Serologic phenotype of antibody presence in 304 seropositive participants. (E) The map of the United States displays seropositivity in the six regions surveyed: Northeast: ME, NH, VT, MA, NY, CT, RI, PA, and NJ, 7.5% (95% CI, 3.9% to 12.4%); Midwest: MN, IA, WI, IL, IN, MI, and OH, 1.6% (95% CI, 0.3% to 2.4%); Mid-Atlantic: MD, DE, DC, VA, WV, KY, TN, NC, SC, and GA, 8.6% (95% CI, 2.6% to 18.9%); South/Central: FL, MS, AL, LA, AR, MO, KS, and OK, 3.0% (95% CI, 1.2% to 5.0%); Mountain/Southwest: TX, NM, AZ, CO, UT, WY, NE, SD, ND, MT, and ID, 4.5% (95% CI, 1.3% to 9.5%); West/Pacific: WA, OR, NV, CA, AK, and HI, 1.9% (95% CI, 0.2% to 3.8%). Each person in (E) represents 100 participants; orange represents weighted prevalence estimate within the geographic region.

**Fig. 3. Undiagnosed SARS-CoV-2 seroprevalence in the main demographic categories.**
Six main categories were used during quota-based sampling: region, age, sex, race, ethnicity, and urban/rural. Seropositivity estimates of blood samples that had a full clinical questionnaire completed and successful sampling are shown. Data are weighted estimates ± 95% CIs. Black dashed vertical line, weighted national seroprevalence estimate; *, n value too low to make a proper weighted estimate so raw positivity is displayed.

**Fig. 4. Seroprevalence estimates according to socioeconomic and health characteristics.**
(A to C) Evaluation of the effect of nondemographic traits on seroprevalence estimates for blood samples that had a full clinical questionnaire completed and successful sampling. Nondemographic traits included (B) socioeconomic and (C) health characteristics. Data are weighted estimates ± 95% CIs. Gray dashed vertical line, weighted national seroprevalence estimate.

See this image and copyright information in PMC

Update of

Mapping a Pandemic: SARS-CoV-2 Seropositivity in the United States.
Kalish H, Klumpp-Thomas C, Hunsberger S, Baus HA, Fay MP, Siripong N, Wang J, Hicks J, Mehalko J, Travers J, Drew M, Pauly K, Spathies J, Ngo T, Adusei KM, Karkanitsa M, Croker JA, Li Y, Graubard BI, Czajkowski L, Belliveau O, Chairez C, Snead K, Frank P, Shunmugavel A, Han A, Giurgea LT, Rosas LA, Bean R, Athota R, Cervantes-Medina A, Gouzoulis M, Heffelfinger B, Valenti S, Caldararo R, Kolberg MM, Kelly A, Simon R, Shafiq S, Wall V, Reed S, Ford EW, Lokwani R, Denson JP, Messing S, Michael SG, Gillette W, Kimberly RP, Reis SE, Hall MD, Esposito D, Memoli MJ, Sadtler K. Kalish H, et al. medRxiv [Preprint]. 2021 Jan 31:2021.01.27.21250570. doi: 10.1101/2021.01.27.21250570. medRxiv. 2021. Update in: Sci Transl Med. 2021 Jul 7;13(601):eabh3826. doi: 10.1126/scitranslmed.abh3826. PMID: 33532807 Free PMC article. Updated. Preprint.

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Undiagnosed SARS-CoV-2 seropositivity during the first 6 months of the COVID-19 pandemic in the United States

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Undiagnosed SARS-CoV-2 seropositivity during the first 6 months of the COVID-19 pandemic in the United States

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