Comparison of the analytical and clinical sensitivity of thirty-four rapid antigen tests with the most prevalent SARS-CoV-2 variants of concern during the COVID-19 pandemic in the UK

Background The continued emergence of SARS-CoV-2 variants of concern (VOC) requires timely analytical and clinical evaluation of antigen-based rapid diagnostic tests (Ag-RDTs) especially those that are recommended for at home use. Methods The limit of detection (LOD) of 34 Ag-RDTs was evaluated using the most encountered SARS-CoV-2 VOC viral isolates (Alpha, Delta, Gamma, Omicron BA.1, Omicron BA.5) and the wild type (WT). Clinical sensitivity was further evaluated for five Ag-RDT utilising retrospective samples (Alpha, Delta, Omicron BA.1) and one Ag-RDT utilising prospective clinical samples (Delta and Omicron BA.1). Findings For the WT, Alpha, Delta, Gamma and Omicron (BA.1) variants 22, 32, 29, 31 and 32 of the 34 Ag-RDTs evaluated met the World Health Organisations (WHO) target product profile (TPP), respectively. Of the 31 Ag-RDTs included for Omicron BA.5 evaluation 29 met the WHO TPP. Additionally, the LODs for samples spiked with Omicron BA.5 were significantly lower than all other VOCs included (p<0.001). In the retrospective clinical evaluation when comparing RNA copies/mL, the Ag-RDTs detected Alpha and Omicron (BA.1) more sensitively than the Delta VOC. Samples with high RT-qPCR Cts (Ct>25) resulted in reduced test sensitivities across all variants. We used linear regression to model the 50% and 95% LOD of clinical samples and observed statistically similar results for all tests. In the prospective clinical samples, the sensitivity was statistically similar for the Delta VOC 71.9% (CI 95% 53.3-86.6%) and Omicron VOC 84.4% (CI95% 75.3-91.2%). Interpretation Test performance differs between SARS-CoV-2 VOCs, and high sensitivity was achieved when testing the Omicron BA.5 VOC compared to the WHO Ag-RDT requirements. Continuous evaluations must be performed to monitor test performance. Funding This work was funded as part of FIND’s work as a co-convener of the diagnostics pillar of the Access to COVID-19 Tools (ACT) Accelerator, including support from Unitaid (grant number 2019-32-FIND MDR), the government of the Netherlands (grant number MINBUZA-2020.961444), and the UK Department for International Development (grant number 300341-102). Funding was also obtained from the MRC for RLB and CGB. The Facilitating Accelerated Clinical Evaluation of Clinical Diagnostics for COVID-19 (FALCON C-19) study was funded by the UK National Institute of Health and Care Research (NIHR). ### Competing Interest Statement Emily R Adams (ERA) is a Director of Epidemics and Neglected Tropical Diseases at Global Access Diagnostics. Camille Escadafal (CE) and Margaretha de Vos (MDV) are employees of FIND. ERA, CE and MDV had no role in data collection and analysis. ### Funding Statement This work was funded as part of FINDs work as a co-convener of the diagnostics pillar of the Access to COVID-19 Tools (ACT) Accelerator, including support from Unitaid (grant number 2019-32-FIND MDR), the government of the Netherlands (grant number MINBUZA-2020.961444), and the UK Department for International Development (grant number 300341-102). Funding was also obtained from the MRC for RLB and CGB. The Facilitating Accelerated Clinical Evaluation of Clinical Diagnostics for COVID-19 (FALCON C-19) study was funded by the UK National Institute of Health and Care Research (NIHR). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval was obtained from the National Research Ethics Service and the Health Research Authority (IRAS ID:28422, clinical trial ID: [NCT04408170][1]). 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04408170&atom=%2Fmedrxiv%2Fearly%2F2023%2F07%2F26%2F2023.07.24.23293072.atom