VirScan offers new insights into COVID-19 antibody response

"This may be the deepest serological analysis of any virus in terms of resolution," said corresponding author Stephen Elledge, PhD, the Gregor Mendel Professor of Genetics at the Brigham and HMS. "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."

In their analysis, Elledge and colleagues looked in depth at antibody responses to SARS CoV-2 by using VirScan to analyze blood samples from 232 COVID-19 patients and 190 pre-COVID-19 era controls. The team identified 800 sites of the virus that the immune system can recognize, known as epitopes. Not all epitopes are created equal; some may be recognized by neutralizing antibodies, which can elicit a response that eliminates the infection. However, if the body creates antibodies against other epitopes, it may launch a less effective response, giving the virus an advantage. In some cases, including the related coronavirus that causes SARS, viruses may even be able to benefit from the body's antibody response, using antibodies to enter cells in a phenomenon known as antibody-dependent enhancement.

In the case of SARS-CoV-2, the team detected a range of antibody frequencies against various epitopes. Many were public epitopes -- regions recognized by the immune systems of large numbers of patients. One public epitope was recognized by 79 percent of COVID-19 patients. Others are considered private and recognized by only a few or even one individual. Ten epitopes were in regions essential for viral entry and are likely recognized by neutralizing antibodies. The team used the most discriminatory epitopes to develop a rapid diagnostic test.

The team's epitope findings may have important implications for vaccines. If the immune system's response to public epitopes isn't found to be protective -- or even gives the virus an advantage -- vaccines will need to target other regions of the virus to give the immune system a boost.

In addition, the team found that there are several epitopes conserved across coronaviruses, and that the immune system is likely to try to reuse antibodies against them when infected with SARS-CoV-2 -- a possible explanation for why so many serology tests for COVID-19 produce false positives.

The team further analyzed where and when different antibody responses occurred, finding that patients with severe COVID-19 were more likely to launch a stronger, broader response against SARS-CoV-2, possibly because their initial immune response failed to control the infection early. Within hospitalized patients, males made more antibodies than females. The researchers also compared the viral histories of hospitalized and non-hospitalized COVID-19 patients and found that hospitalized patients were much more likely to have had CMV and HSV-1, two common herpes viruses. However, the researchers note that it is difficult to draw conclusions about causality given that the group of non-hospitalized patients was younger and consisted of a higher percentage of white people and women, a demographic group that generally have lower CMV infection rates.

Elledge envisions their studies as a stepping stone for identifying the most effective antibodies and eliciting them.

"Our paper illuminates the landscape of antibody responses in COVID-19 patients," said 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."

Funding for this work was provided by grants from the National Institutes of Health (NIH, AI121394, AI139538), the Burroughs Wellcome Fund, the Division of Intramural Research at the National Institute of Allergy and Infectious Disease, the Value of Vaccination Research Network (VoVRN), from the Executive Committee on Research at Massachusetts General Hospital, the Massachusetts Consortium on Pathogen Readiness, NIH/NIAID (U24 grant), the Pemberton-Trinity Fellowship, a Sir Henry Wellcome Fellowship (201387/Z/16/Z), the National Science Foundation Graduate Research Fellowship Program Enid Schwartz, and the Howard Hughes Medical Institute. Elledge and a co-author are founders of TSCAN Therapeutics, Elledge is a founder of MAZE Therapeutics and Mirimus, Elledge serves on the scientific advisory board of Homology Medicines, TSCAN Therapeutics, MAZE, XChem, and is an advisor for MPM, none of which impact this work. Elledge and two co-authors are inventors on a patent application filed by the Brigham and Women's Hospital (US20160320406A) that covers the use of the VirScan library to identify pathogen antibodies in blood.