We conducted the sensitivity analysis with a different source of data on time from onset to death and considered time-varying IFR instead of constant IFR, and found that results were robust to these changes (Table S2). Detection of antibodies by serological assays may not correlate to protection from reinfection or disease, and thus, time from seroconversion to seroreversion estimated in our study is not necessarily equivalent to the duration of protective immunity. maximum seroprevalence measures (22.1% and 6.1%), respectively. == Interpretation: == The cumulative incidence of SARS-CoV-2 infection is underestimated using cross-sectional serology data without adjustment for waning antibodies. Our approach can help quantify the magnitude of underestimation and adjust estimates for waning antibodies. == Funding: == This study was supported by the US National Science Foundation and the National Institute of Allergy and Infectious Diseases. Keywords:Antibody, ascertainment bias, case ascertainment ratio, COVID-19, cumulative incidence, infection fatality ratio, SARS-CoV-2, seroconversion, seroprevalence, seroreversion, waning antibody == Introduction == Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Coronavirus Disease 2019 (COVID-19), rapidly spread across the world in 2020.1Globally, there have been 36 million documented cases and more than one million COVID-19 associated fatalities as of October 15, 2020, with case counts continuing to increase.2Reliable measurement of infection history in a population is a critical epidemiologic outcome, and is needed to derive several key epidemiologic indices such as the infection fatality ratio (IFR). However, the number of SARS-CoV-2 infections reported through public health surveillance mechanisms is underestimated because of the limited capacity of testing and surveillance systems, an overwhelmed healthcare system, low healthcare-seeking behavior among those with mild disease, imperfect sensitivity of diagnostic tests (especially rapid antigen tests) and ICEC0942 HCl a large fraction of infections that are asymtomatic.3Assays that detect viral antigen or genomic material cannot identify individuals who were previously infected once viral material is no longer present. Rabbit Polyclonal to ITGA5 (L chain, Cleaved-Glu895) In contrast, serology tests measuring the level of immunoglobulins have the potential to identify those previously infected. Serology results can be used to generate an estimate of the cumulative incidence, but this requires the relatively strong assumption that antibodies persist permanently after infection. Because antibody levels for SARS-CoV-2 wane over time ICEC0942 HCl and can become undetectable, some previously infected individuals could have already returned to a seronegative status at the time of testing (i.e. seroreversion). Hence, new methods are needed to account for waning antibodies when using ICEC0942 HCl cross-sectional serology data to estimate cumulative incidence of SARS-CoV-2 infection. The adjusted cumulative incidence can then be used to obtain more accurate estimates of critical epidemiologic measures, such as the IFR and the case ascertainment ratio. Population-level serosurveys for SARS-CoV-2 have been conducted across the world, with variation in geographic scale, sample demographics, sampling mechanisms, and testing methods.4,5Although the reported incidence of COVID-19 varies widely by location, a consistent finding in all settings is that total estimated infections vastly outnumber confirmed cases. For example, the Centers for Disease Control and Prevention (CDC) and commercial laboratories conducted large-scale geographic longitudinal serosurveys in 10 sites in the United States in the spring and summer of 2020.6Seroprevalence ranged from 1% to 6.9% across sites. That study estimated that the number of total infections was 624 times higher than that of documented cases, while acknowledging that these ratios varied widely depending on the timing of sampling or the stage of the epidemic in each location. These early population-level serosurveys provided critical insights on the ICEC0942 HCl true burden of COVID-19; however, as we enter the 10th month of the US epidemic, the ability to estimate the cumulative incidence directly from serosurveys is increasingly ICEC0942 HCl limited because antibody levels continue to wane and the corresponding serologic record of historical infection is lost. Indeed, Ibarrondoet al.estimated that the half-life of anti-SARS-CoV-2 spike receptor-binding domain IgG was 36 days.7Patelet al.reported that over half (11/19) of health care personnel who tested seropositive in early April became seronegative at a second visit in June (approximately 60 days after the baseline).8Taken together, these findings suggest that serosurveys have likely failed to recognize previous infection in those whose antibody levels have already waned below the detectable limit at the time of sampling. An adjustment for waning antibody kinetics must account for.