This rapid review summarizes the methods, sampling frames, results, and potential sources of bias of the subnational, national, and international serology studies that have been used to estimate the seroprevalence of SARS-CoV-2. Our review builds on a previously published seroprevalence review(19) by using a more comprehensive search strategy that identified more published studies, as well as pre-prints and ongoing studies. In accordance with prior work,(19) we found substantial diversity in seroprevalence study characteristics, including their sampling frames, assay sensitivity and specificity, and study locations. For example, most studies (n = 20, 77%) derived seroprevalence estimates from a single sampling frame, such as healthcare workers or close contacts of patients with RT-PCR-confirmed COVID-19. Few studies were able to provide reliable and precise estimates of the burden of COVID-19: only 7 studies (26%) used representative sampling frames of the general population, and only 9 studies (33%) had samples of 1,000 participants or more. Most studies recruited participants whose mean age was < 65 years old, despite the predominance of non-representative sampling frames and higher risk of COVID-19-related complications among older adults. There were also very limited reports of studies or ongoing studies from middle-income countries, and none from low-income countries despite an increasing burden of disease in these large populations.(1) The lone study from the Guilan Province in Iran, an upper-middle-income country with an early onset of the pandemic, had the highest reported seroprevalence estimate (21%, n = 528) among studies that used a representative, general population sampling frame, though the study’s relatively small sample size limits the precision of this estimate (calculated 95% Confidence Intervals: 18–25%).
These overall results suggest that both representative and more targeted studies, stratified by participants’ risk of exposure, geography, and symptomology, with larger sample sizes across more countries, are needed to more accurately estimate SARS-CoV-2 seroprevalence, differential spread of the virus across groups, and infection fatality rate. These findings will prove useful to inform future policy creation and implementation. Researchers and health departments should focus on integrating biospecimen collection into demographic health surveys and routine blood tests at the state or county level to obtain sufficient sample sizes for generalizability at the local or regional levels.(20) To collect representative samples, investigators will need to use household enumeration data to identify eligible participants and adapt testing at sites that are convenient and safe for local community members, such as parks, libraries, schools, or community centers. Home-based, dried-blood-spot (DBS) assays may also be used for data collection either by the individual or community health workers for either targeted or population representative sampling.(21) Researchers and national health statistics agencies should leverage existing infrastructure for population surveillance, such as national census and demographic health surveys where blood tests are already integrated, given the importance and urgency in ascertaining the true COVID-19 seroprevalence across and between regions and populations.(20)
To derive a more complete picture of individuals’ immune response to SARS-CoV-2, future research should also characterize lasting T cell responses in parallel to serological responses. Early evidence suggests that SARS-recovered patients can possess long-lasting memory T cells reactive to SARS-CoV-2 Nucleocapsid protein and that SARS-CoV-2 specific T cells may be detected in individuals with no known history of SARS, COVID-19, or contact with SARS or COVID-19 patients.(22) Likewise, only 1 study was identified that evaluated seroprevalence of neutralizing antibodies; therefore, further research is needed to understand the prevalence and importance of neutralizing antibody seroprevalence estimates compared with other antibody assay types. Results from such studies may shift management strategies for the pandemic by impacting forecasts about patients’ susceptibility to SARS-CoV-2 infection from serosurveys.
Similarly, when considering how to generate more accurate forecasts of future SARS-CoV-2 pandemic curves, these findings suggest the potential utility of additional longitudinal cohort studies using quantitative assays. These studies are needed to explore the effects of containment measures and to understand the degree to which SARS-CoV-2 antibodies confer protective immunity, at what antibody threshold, and for how long. For example, some evidence suggests that asymptomatic individuals have waning levels of antibodies or may become seronegative over time.(23)
To achieve more accurate seroprevalence estimates, more studies using assays with high diagnostic accuracy, including high IgM and IgG sensitivity and specificity, are also needed. More high quality, independently-conducted validation studies assessing the diagnostic accuracy of these assays is also urgently needed.(24)
This review has potential limitations. First, there is a rapid influx of new information related to SARS-CoV-2 serology studies. It is possible that some published or ongoing studies may not have been included in this review. However, we used a comprehensive search strategy and identified 85 ongoing studies, the results of which may be included in future updates to this review. Second, data from this review include studies that were published on pre-print servers and have not undergone peer review. Thus, estimates from these reports may change. Third, epidemiological studies are often not prospectively registered, so this review may underestimate the number of ongoing studies and may not fully represent the characteristics of such ongoing studies, including study design, sampling frame, and sample size.