LAUSR

Over the past year, the COVID-19 pandemic placed unprecedented demands on clinical laboratory providers, in vitro diagnostics manufacturers, and public health agencies to respond to the testing needs of an international public health emergency. These efforts included developing and implementing a wide array of testing strategies to detect symptomatic and asymptomatic infections, monitor the acute and convalescent phases, and determine adaptive immune responses to SARS-CoV-2. To date, it is estimated that >400 million SARS-CoV-2 tests have been performed for diagnostic, screening, and surveillance purposes in the United States alone (1). The reference method for diagnosing a SARS-CoV2 infection continues to be nucleic acid amplification tests (2). Unfortunately, the initial limited availability of these tests (exacerbated by supply chain shortages), lengthy turnaround times, and expense drove efforts to find other suitable alternatives to increase COVID-19 testing capacity—both inside the clinical laboratory and at the point of care. Serologic (antibody test) methods that have been used effectively in the management of other infectious diseases were soon introduced worldwide and touted as a potential solution to help address COVID-19 testing challenges. However, the use of these tests and their widespread clinical adoption were almost immediately called into question. These concerns centered on the quality and accuracy of the tests and the absence of data to support analytic and clinical performance claims. There was also a general lack of understanding of how to appropriately utilize and interpret these tests in different target populations. In particular, the impact of disease prevalence on predictive values was underappreciated by most clinicians. Unknowns such as the timing and frequency of antibody testing for early detection and limited information on the duration and interindividual variation of adaptive immune responses were also confounding issues. Today, >440 different SARS-CoV-2 antibody tests are being marketed globally, but only 75 of these assays have formally received emergency use authorization (EUA) from the US Food and Drug Administration (FDA) (3). These tests range from simple CLIA-waived, single-step, cartridge-based immunochromatographic assays to nonwaived, plate-based enzyme immunosorbent immunoassays and chemiluminescence-based immunoassays on high-throughput, random access autoanalyzers. Many of the initial assay formats qualitatively detected the presence or absence of antibodies directed against one or more of the SARS-CoV-2 viral proteins. The main targets are the nucleocapsid and spike proteins. More recently, semiquantitative and quantitative SARS-CoV-2 antibody assays received EUAs that recognize these viral protein targets with a higher degree of sensitivity and specificity. Some laboratory-developed and commercialized neutralizing antibody tests have also been used to evaluate the function of antibody responses. One of the major problems that has plagued SARSCoV-2 antibody tests since their introduction into the US market—and has helped undermine both provider and consumer confidence—was the FDA’s initial stance allowing early availability during the public health emergency by using a less rigorous review and oversight process than other COVID-19 diagnostics that required EUA submission and approval. In its March 16, 2020, policy, the FDA indicated that a higher level of flexibility was appropriate for antibody tests than for molecular (and antigen) tests that detect the presence of the virus that causes COVID-19, given that antibody tests were not intended for use in diagnosing active SARS-CoV-2 infections (4). Antibody tests were permitted to be used in the appropriate CLIA setting as long as the tests were properly validated and labeled as outlined in this policy and the developer notified the FDA. Regrettably, many of these tests started to be deployed in unregulated settings and without the necessary validation and safeguards required, including the issuance of EUA. Around the country, including Southern California, many state and local public health agencies had to intervene and issue “cease and desist” orders for opportunistic facilities offering antibody tests to screen and diagnose acute infections. By May 2020, the FDA responded to the mounting concerns and revised its policies to address issues of improved transparency in prioritizing access Department of Pathology, University of California San Diego, San Diego, CA, USA *Address correspondence to this author at: UCSD Center for Advanced Laboratory Medicine, 10300 Campus Point Drive, Suite 150, San Diego, CA, 92121, USA. Fax 858-657-5025; e-mail [email protected]. Received April 15, 2021; accepted April 21, 2021. DOI: 10.1093/clinchem/hvab072