Bergeri I, Whelan MG, Ware H, Subissi L, Nardone A, Lewis HC, Li Z, Ma X, Valenciano M, Cheng B, Al Ariqi L, Rashidian A, Okeibunor J, Azim T, Wijesinghe P, Le LV, Vaughan A, Pebody R, Vicari A, Yan T, Yanes-Lane M, Cao C, Clifton DA, Cheng MP, Papenburg J, Buckeridge D, Bobrovitz N, Arora RK, and Van Kerkhove MD
Background: Our understanding of the global scale of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection remains incomplete: Routine surveillance data underestimate infection and cannot infer on population immunity; there is a predominance of asymptomatic infections, and uneven access to diagnostics. We meta-analyzed SARS-CoV-2 seroprevalence studies, standardized to those described in the World Health Organization's Unity protocol (WHO Unity) for general population seroepidemiological studies, to estimate the extent of population infection and seropositivity to the virus 2 years into the pandemic., Methods and Findings: We conducted a systematic review and meta-analysis, searching MEDLINE, Embase, Web of Science, preprints, and grey literature for SARS-CoV-2 seroprevalence published between January 1, 2020 and May 20, 2022. The review protocol is registered with PROSPERO (CRD42020183634). We included general population cross-sectional and cohort studies meeting an assay quality threshold (90% sensitivity, 97% specificity; exceptions for humanitarian settings). We excluded studies with an unclear or closed population sample frame. Eligible studies-those aligned with the WHO Unity protocol-were extracted and critically appraised in duplicate, with risk of bias evaluated using a modified Joanna Briggs Institute checklist. We meta-analyzed seroprevalence by country and month, pooling to estimate regional and global seroprevalence over time; compared seroprevalence from infection to confirmed cases to estimate underascertainment; meta-analyzed differences in seroprevalence between demographic subgroups such as age and sex; and identified national factors associated with seroprevalence using meta-regression. We identified 513 full texts reporting 965 distinct seroprevalence studies (41% low- and middle-income countries [LMICs]) sampling 5,346,069 participants between January 2020 and April 2022, including 459 low/moderate risk of bias studies with national/subnational scope in further analysis. By September 2021, global SARS-CoV-2 seroprevalence from infection or vaccination was 59.2%, 95% CI [56.1% to 62.2%]. Overall seroprevalence rose steeply in 2021 due to infection in some regions (e.g., 26.6% [24.6 to 28.8] to 86.7% [84.6% to 88.5%] in Africa in December 2021) and vaccination and infection in others (e.g., 9.6% [8.3% to 11.0%] in June 2020 to 95.9% [92.6% to 97.8%] in December 2021, in European high-income countries [HICs]). After the emergence of Omicron in March 2022, infection-induced seroprevalence rose to 47.9% [41.0% to 54.9%] in Europe HIC and 33.7% [31.6% to 36.0%] in Americas HIC. In 2021 Quarter Three (July to September), median seroprevalence to cumulative incidence ratios ranged from around 2:1 in the Americas and Europe HICs to over 100:1 in Africa (LMICs). Children 0 to 9 years and adults 60+ were at lower risk of seropositivity than adults 20 to 29 (p < 0.001 and p = 0.005, respectively). In a multivariable model using prevaccination data, stringent public health and social measures were associated with lower seroprevalence (p = 0.02). The main limitations of our methodology include that some estimates were driven by certain countries or populations being overrepresented., Conclusions: In this study, we observed that global seroprevalence has risen considerably over time and with regional variation; however, over one-third of the global population are seronegative to the SARS-CoV-2 virus. Our estimates of infections based on seroprevalence far exceed reported Coronavirus Disease 2019 (COVID-19) cases. Quality and standardized seroprevalence studies are essential to inform COVID-19 response, particularly in resource-limited regions., Competing Interests: I have read the journal policy and the authors of this manuscript have the following competing interests: RKA, MW, HW, ZL, XM, CC, MYL, DB, JP, MPC, ML, MS, GRD, NI, CZ, SP, HPR, TY, KCN, DK, SAA, ND, CD, NAD, EL, RKI, ASB, ELB, AS, JC and NB report grants from Canada’s COVID-19 Immunity Task Force through the Public Health Agency of Canada, and the Canadian Medical Association Joule Innovation Fund. RKA, MW, HW, ZL, CC, MYL, NB also report grants from the World Health Organisation and the Robert Koch Institute. RKA reports personal fees from the Public Health Agency of Canada and the Bill and Melinda Gates Foundation Strategic Investment Fund, as well as equity in Alethea Medical (Outside the submitted work). MPC reports grants from McGill Interdisciplinary Initiative in Infection and Immunity and Canadian Institute of Health Research, and personal fees from GEn1E Lifesciences (Outside the submitted work), nplex biosciences (Outside the submitted work), Kanvas biosciences (Outside the submitted work). JP reports grants from MedImmune (Outside the submitted work) and Sanofi-Pasteur (Outside the submitted work), grants and personal fees from Merck (Outside the submitted work) and AbbVie (Outside the submitted work), and personal fees from AstraZeneca (Outside the submitted work). DB reports grants from the World Health Organization, Canadian Institutes of Health Research, Natural Sciences and Engineering Council of Canada (Outside the submitted work), Institute national d excellence en sante et service sociaux (Outside the submitted work), and personal fees from McGill University Health Centre (Outside the submitted work) and Public Health Agency of Canada (Outside the submitted work). CC reports funding from Sanofi Pasteur (Outside of the submitted work). TY reports working for Health Canada as a part-time Senior Policy Analyst with the COVID-19 Testing and Screening Expert Panel, from Nov 2020-Jun 2021 (Outside of the submitted work). TH reports funding recieved from the United States Centers for Disease Control and Prevention for Columbia University (Outside of the submitted work). Author HCL declares receiving funding as a WHO consultant from WHO Solidarity Response Fund and the German Federal Ministry of Health COVID-19 Research and Development., (Copyright: © 2022 Bergeri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)