On Jun. 22, 2021, National Institutes of Health researchers reported that the prevalence of COVID-19 in the U.S. during spring and summer of 2020 far exceeded the known number of cases and that infection affected the country unevenly. For every diagnosed COVID-19 case in this time frame, the researchers estimate that there were 4.8 undiagnosed cases, representing an additional 16.8 million cases by July alone. The team’s analysis of blood samples from people who did not have a previously diagnosed SARS-CoV-2 infection, along with socioeconomic, health, and demographic data, offers insight into the undetected spread of the virus and subgroup vulnerability to undiagnosed infection.

In addition to NIBIB, the research team includes scientists from the National Institute of Allergy and Infectious Diseases (NIAID), the National Center for Advancing Translational Sciences (NCATS); and the Frederick National Laboratory for Cancer Research, sponsored by the National Cancer Institute (NCI). Their report in the June 22, 2021, early online issue of Science Translational Medicine represents the first data from the 12-month NIH study that was launched in April 2020.

COVID-19 illness can range from short-lived cough, fatigue and fever to severe illness that could lead to hospitalization and death. Asymptomatic SARS-CoV-2 infection, which is rarely diagnosed, is a silent source of viral spread. While not causing overt signs of illness, undiagnosed infection poses a danger to the public and is a critical factor necessitating public health resources and strategies for addressing the pandemic.

The team recruited over 240,000 volunteers from across the country, then selected 8,058 individuals from that pool through quota sampling to ensure that their study cohort was representative of the U.S. population. Each participant received a sample kit to return to NIH with a dab of dried blood or had blood drawn at NIH, most of which they supplied in an 11-week span between May 10 and July 31. Participants also completed a questionnaire that enabled further analysis of the study results.

The researchers used an enzyme-linked immunosorbent assay to detect antibodies that recognize protein regions from the SARS-CoV-2 virus, referred to as antigens. Antibodies in a blood sample can bind to these antigens. The team found that 304 of the approximately 8,000 blood samples were seropositive, meaning that they contained antibodies against the SARS-CoV-2 virus. The researchers estimated that 4.6% of U.S. adults had undiagnosed COVID-19 during their study period. They determined that each diagnosed case of COVID-19 corresponds to an estimated 4.8 undiagnosed cases of the disease during this time frame.