T o date, hundreds of thousands of deaths have been attributed to coronavirus disease 2019 (COVID-19) 1. Millions of infections by SARS-CoV-2, the virus responsible for COVID-19, have been reported, although its full extent has yet to be determined owing to limited testing 2. Government interventions to slow viral spread have disrupted daily life and economic activity for billions of people. Strategies to ease restraints on human mobility and interaction without provoking a major resurgence of transmission and mortality will depend on accurate estimates of population levels of infection and immunity 3. Current testing for the virus largely depends on labor-intensive molecular techniques 4. Individuals with positive molecular tests represent only a small fraction of all infections, given limited deployment and the brief time window when real-time (RT)-PCR testing has the highest sensitivity 5-7. The proportion of undocumented cases in the original epidemic focus was estimated to be as high as 86% 8 , and asymptomatic infections are suspected to play a substantial role in transmission 9-14. Widely available, reliable antibody detection assays would enable more accurate estimates of SARS-CoV-2 prevalence and incidence. On February 4, 2020, the Secretary of the US Department of Health and Human Services issued an emergency use authorization (EUA) for the diagnosis of SARS-CoV-2 15 , allowing nucleic acid detection and immunoassay tests to be offered based on manufacturer-reported data without formal US Food and Drug Administration (FDA) clearance 16. In response, dozens of companies began to market laboratory-based immunoassays and point-of-care (POC) tests. Rigorous, comparative performance data are crucial to inform clinical care and public health responses.
Neutralizing autoantibodies against type I interferons (IFNs) have been found in some patients with critical coronavirus disease 2019 (COVID-19), the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the prevalence of these antibodies, their longitudinal dynamics across the disease severity scale, and their functional effects on circulating leukocytes remain unknown. Here, in 284 patients with COVID-19, we found type I IFN-specific autoantibodies in peripheral blood samples from 19% of patients with critical disease and 6% of patients with severe disease. We found no type I IFN autoantibodies in individuals with moderate disease. Longitudinal profiling of over 600,000 peripheral blood mononuclear cells using multiplexed single-cell epitope and transcriptome sequencing from 54 patients with COVID-19 and 26 non-COVID-19 controls revealed a lack of type I IFN-stimulated gene (ISG-I) responses in myeloid cells from patients with critical disease. This was especially evident in dendritic cell populations isolated from patients with critical disease producing type I IFN-specific autoantibodies. Moreover, we found elevated expression of the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) on the surface of monocytes isolated from patients with critical disease early in the disease course. LAIR1 expression is inversely correlated with ISG-I expression response in patients with COVID-19 but is not expressed in healthy controls. The deficient ISG-I response observed in patients with critical COVID-19 with and without type I IFN-specific autoantibodies supports a unifying model for disease pathogenesis involving ISG-I suppression through convergent mechanisms.
Background SARS-CoV-2 infection can be detected indirectly by measuring the host immune response. For some viruses, antibody concentrations correlate with host protection and viral neutralization, but in rare cases, anti-viral antibodies can promote disease progression. Elucidation of the kinetics and magnitude of the SARS-CoV-2 antibody response is essential to understand the pathogenesis of COVID-19 and identify potential therapeutic targets. Methods Sera (n=533) from patients with RT-PCR confirmed COVID-19 (n=94 with acute infections and n=59 convalescent patients) were tested using a high-throughput quantitative IgM and IgG assay that detects antibodies to the spike protein receptor binding domain and nucleocapsid protein. Individual and serial samples covered the time of initial diagnosis, during the disease course, and following recovery. We evaluated antibody kinetics and correlation between magnitude of the response and disease severity. Results Patterns of SARS-CoV-2 antibody production varied considerably. Among 52 patients with 3 or more serial specimens, 44 (84.6%) and 42 (80.8%) had observed IgM and IgG seroconversion at a median of 8 and 10 days, respectively. Compared to those with milder disease, peak measurements were significantly higher for patients admitted to the intensive care unit for all time intervals between 6 and 20 days for IgM, and all intervals after 5 days for IgG. Conclusions High sensitivity assays with a robust dynamic range provide a comprehensive picture of host antibody response to SARS-CoV-2. IgM and IgG responses were significantly higher in patients with severe than mild disease. These differences may affect strategies for seroprevalence studies, therapeutics and vaccine development.
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