Global SARS-CoV-2 seroprevalence: a systematic review and meta-analysis of standardized population-based studies from Jan 2020-May 2022

Background Our understanding of the global scale of SARS-CoV-2 infection remains incomplete: routine surveillance data underestimates 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 WHO’s Unity protocol for general population seroepidemiological studies, two years into the pandemic, to estimate the extent of population infection and remaining susceptibility. 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 2020-01-01 and 2022-05-20. 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 under-ascertainment; meta-analyzed differences in seroprevalence between demographic subgroups such as age and sex; and identified national factors associated with seroprevalence using meta-regression. The main limitations of our methodology include that some estimates were driven by certain countries or populations being over-represented. We identified 513 full texts reporting 965 distinct seroprevalence studies (41% LMIC) sampling 5,346,069 participants between January 2020 and April 2022, including 459 low/moderate risk of bias studies with national/sub-national scope in further analysis. By September 2021, global SARS-CoV-2 seroprevalence from infection or vaccination was 59.2%, 95% CI [56.1-62.2%]. Overall seroprevalence rose steeply in 2021 due to infection in some regions (e.g., 26.6% [24.6-28.8] to 86.7% [84.6-88.5%] in Africa in December 2021) and vaccination and infection in others (e.g., 9.6% [8.3-11.0%] to 95.9% [92.6-97.8%] in Europe high-income countries in December 2021). After the emergence of Omicron, infection-induced seroprevalence rose to 47.9% [41.0-54.9%] in EUR HIC and 33.7% [31.6-36.0%] in AMR HIC in March 2022. 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 0-9 years and adults 60+ were at lower risk of seropositivity than adults 20-29 ( p <0.0001 and p =0.005, respectively). In a multivariable model using pre-vaccination data, stringent public health and social measures were associated with lower seroprevalence ( p =0.02). Conclusions In this study, we observed that global seroprevalence has risen considerably over time and with regional variation, however around 40 % of the global population remains susceptible to SARS-CoV-2 infection. Our estimates of infections based on seroprevalence far exceed reported COVID-19 cases. Quality and standardized seroprevalence studies are essential to inform COVID-19 response, particularly in resource-limited regions. ### Competing Interest Statement 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). ### Funding Statement This work was supported by WHO (WHO COVID-19 Solidarity Response Fund, to IB; German Federal Ministry of Health COVID-19 Research and Development Fund, to IB; World Health Organisation funding, to RKA), the Public Health Agency of Canada (Canada's COVID-19 Immunity Task Force through the Public Health Agency of Canada, to RKA), the Canadian Medical Association (Joule Innovation Fund, to RKA), and the Robert Koch Institute (funding to RKA). IB, LS, AnV, LA, AR, JO, TA, PW, LL, AiV, RP, MVK are employed and receive salaries from WHO (one of the funders of this study), and AN, MV, BC and HCL are WHO consultants. Authors who are members of the SeroTracker Group (led by RKA, including MW, HW, ZL, XM, TY, CC, MYL, JP, MPC, DB, ML, MS, GRD, NI, CZ, SP, HPR, TY, KCN, DK, SAA, ND, CD, NAD, EL, RKI, ASB, ELB, AS, JC) were supported through the aforementioned grants from WHO, Canada's COVID-19 Immunity Task Force through the Public Health Agency of Canada, the Robert Koch Institute, and the Canadian Medical Association Joule Innovation Fund. WHO had a role in the study design, data collection, data analysis, data interpretation, and the writing of the report. No other funders had any such role. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Standardized results uploaded to Zenodo by UNITY study collaborators supporting the findings of this study are available at this community and DOIs for each included Zenodo study are cited in the Supplementary File (S5) . Detailed information on each study is available in Supplement S4. Other relevant data are available in a data repository (doi:10.5281/zenodo.5773152) and/or available from the Zenodo community upon reasonable request.