Understanding humoral responses to SARS-CoV-2 is critical for improving diagnostics, therapeutics, and vaccines. Deep serological profiling of 232 COVID-19 patients and 190 pre-COVID-19 era controls using VirScan revealed over 800 epitopes in the SARS-CoV-2 proteome, including 10 epitopes likely recognized by neutralizing antibodies. Pre-existing antibodies in controls recognized SARS-CoV-2 ORF1, while only COVID-19 patients primarily recognized spike and nucleoprotein. A machine learning model trained on VirScan data predicted SARS-CoV-2 exposure history with 99% sensitivity and 98% specificity; a rapid Luminex-based diagnostic was developed from the most discriminatory SARS-CoV-2 peptides. Individuals with more severe COVID-19 exhibited stronger and broader SARS-CoV-2 responses, weaker antibody responses to prior infections, and higher incidence of CMV and HSV-1, possibly influenced by demographic covariates. Among hospitalized patients, males make greater SARS-CoV-2 antibody responses than females.

The relationship between SARS-CoV-2 viral load and risk of disease progression remains largely undefined in coronavirus disease 2019 (COVID-19). Here, we quantify SARS-CoV-2 viral load from participants with a diverse range of COVID-19 disease severity, including those requiring hospitalization, outpatients with mild disease, and individuals with resolved infection. We detected SARS-CoV-2 plasma RNA in 27% of hospitalized participants, and 13% of outpatients diagnosed with COVID-19. Amongst the participants hospitalized with COVID-19, we report that a higher prevalence of detectable SARS-CoV-2 plasma viral load is associated with worse respiratory disease severity, lower absolute lymphocyte counts, and increased markers of inflammation, including C-reactive protein and IL-6. SARS-CoV-2 viral loads, especially plasma viremia, are associated with increased risk of mortality. Our data show that SARS-CoV-2 viral loads may aid in the risk stratification of patients with COVID-19, and therefore its role in disease pathogenesis should be further explored.

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CD4 + T cells are central to long-term immunity against viruses through the functions of T helper-1 (Th1) and T follicular helper (Tfh) cell subsets. To better understand the role of these subsets in COVID-19 immunity, we conducted a longitudinal study of SARS-CoV-2-specific CD4 + T cell and antibody responses in convalescent subjects who seroconverted during the first wave of the pandemic in Boston, Massachusetts, United States, across a range of COVID-19 disease severities. Analyses of spike (S) and nucleocapsid (N) epitope-specific CD4 + T cells using peptide and major histocompatibility complex class II (peptide:MHCII) tetramers demonstrated expanded populations of T cells recognizing the different SARS-CoV-2 epitopes in most subjects compared to pre-pandemic controls. Individuals who experienced a milder disease course not requiring hospitalization had a greater percentage of circulating Tfh (cTfh) and Th1 cells among SARS-CoV-2-specific cells. Analysis of SARS-CoV-2-specific CD4 + T cells responses in a subset of individuals with sustained anti-S antibody responses following viral clearance also revealed an increased proportion of memory cTfh cells. Our findings indicate efficient early disease control also predicts favorable long-term adaptive immunity.

SARS-CoV-2 kinetics remain understudied, including the impact of remdesivir. In hospitalized individuals, peak sputum viral load occurred in week 2 of symptoms while peak viremia occurred within a week of symptom-onset, suggesting early systemic seeding of SARS-CoV-2. Remdesivir treatment was associated with faster rates of viral decay.