Viral epitope profiling of COVID-19 patients reveals cross-reactivity and correlates of severity

TLDR

Understanding humoral responses to SARS‑CoV‑2 is critical for improving diagnostics, therapeutics, and vaccines. A machine‑learning model trained on VirScan data predicted SARS‑CoV‑2 exposure with 99 % sensitivity and 98 % specificity, and a rapid Luminex‑based diagnostic was developed from the most discriminatory peptides. Deep serological profiling of 232 COVID‑19 patients and 190 controls identified over 800 SARS‑CoV‑2 epitopes, including 10 likely neutralizing, with patient antibodies targeting spike and nucleoprotein while controls recognized ORF1; severe disease was associated with stronger, broader responses, weaker prior‑infection antibodies, higher CMV/HSV‑1 incidence, and male patients mounted stronger responses than females.

Abstract

Understanding humoral responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for improving diagnostics, therapeutics, and vaccines. Deep serological profiling of 232 coronavirus disease 2019 (COVID-19) patients and 190 pre–COVID-19 era controls using VirScan revealed more than 800 epitopes in the SARS-CoV-2 proteome, including 10 epitopes likely recognized by neutralizing antibodies. Preexisting antibodies in controls recognized SARS-CoV-2 ORF1, whereas only COVID-19 patient antibodies primarily recognized spike protein 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 cytomegalovirus and herpes simplex virus 1, possibly influenced by demographic covariates. Among hospitalized patients, males produce stronger SARS-CoV-2 antibody responses than females.