Bacteriophage Analysis Technique Reveals Details of COVID-19’s Impact on the Immune System

An analytical technique that can determine which of more than 1,000 different viruses have infected a person, has been utilized for a detailed study of the SARS-CoV-2 (COVID-19) virus and its impact on the immune system.

Investigators at Harvard Medical School (Boston, MA, USA) worked with VirScan, a technology in which peptide-displaying bacteriophages were incubated with a single drop of patient’s blood. Antiviral antibodies in the blood bound to their target epitopes on the bacteriophages. Antibody bound bacteriophages were then captured. DNA sequencing of these bacteriophages indicated which viral peptides were bound to antibodies. In this way, an individual’s complete viral serological history, including both vaccination and infection, could be determined.

For the current study, the investigators used VirScan to analyze blood samples from 232 COVID-19 patients and 190 pre-COVID-19 era controls.

Results revealed over 800 epitopes (sites recognized by the immune system) in the SARS-CoV-2 proteome, including 10 epitopes likely recognized by neutralizing antibodies. Pre-existing antibodies in control samples 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.

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 (Cytomegalovirus) and HSV-1 (Herpes simplex virus 1). Among hospitalized patients, males had greater SARS-CoV-2 antibody responses than females.

"This may be the deepest serological analysis of any virus in terms of resolution," said senior author Dr. Stephen Elledge, professor of genetics at Harvard Medical School. "We now understand much, much more about the antibodies generated in response to SARS-CoV-2 and how frequently they are made. The next question is, what do those antibodies do? We need to identify which antibodies have an inhibitory capacity or which, if any, may promote the virus and actually help it enter into immune cells."

"Our paper illuminates the landscape of antibody responses in COVID-19 patients," said Dr. Elledge. "Next, we need to identify the antibodies that bind these recurrently recognized epitopes to determine whether they are neutralizing antibodies or antibodies that might exacerbate patient outcomes. This could inform the production of improved diagnostics and vaccines for SARS-CoV-2."

The VirScan analysis of COVID-19 was published in the September 29, 2020, online edition of the journal Science.

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