The human body is capable of creating a vast, diverse repertoire of antibodies: immune proteins that find and flag invaders such as viruses.

Yet humans create antibodies that target the same viral regions again and again, according to a new study led by investigators from Harvard Medical School (HMS) and Brigham and Women’s Hospital.

This means that the generation of new antibodies is far from random and that a virus may be able to reinfect a population of previously immune hosts by changing a single one of its amino acids, the researchers found.

The team’s discoveries have implications for our understanding of immunity, durability of immune response, and public health and could inform the design of treatments and vaccines for SARS-CoV-2. The findings are published April 7 in Science.

“Our research may help explain a lot of the patterns we’ve seen during the COVID-19 pandemic, especially in terms of reinfection,” said corresponding author Stephen Elledge, the Gregor Mendel Professor of Genetics in the Blavatnik Institute at HMS and professor of medicine at Brigham and Women’s.

“Our findings could help inform immune predictions and may change the way people think about immune strategies,” he added.

How — and how often — antibodies target the same viral regions

Before the new study, there were hints, but no clear evidence, that the human immune system doesn’t target sites on a viral protein at random.

In isolated examples, investigators had seen recurrent, similar antibody responses across individuals. People’s immune systems were recreating antibodies that homed in on the same part of a virus.

“Our findings could help inform immune predictions and may change the way people think about immune strategies.”

The new study by Elledge and colleagues helps explain the extent and underlying mechanisms of this phenomenon.

The team used a tool that the Elledge lab developed in 2015 called VirScan, which can detect thousands of viral epitopes—sites on viruses that antibodies recognize and bind to—and give a snapshot of a person’s immunological history from a single drop of blood.

For the new study, the researchers used VirScan to analyze 569 blood samples from participants in the U.S., Peru, and France. They found that generating antibodies that recurrently target the same viral regions was a general feature of the human immune response.

The researchers mapped 376 of these commonly targeted epitopes, uncovering exactly where antibodies bind to them. They discovered that specific antibody parts called GRAB motifs allow the antibodies to recognize these epitopes.

GRAB motifs (short for germline-encoded amino acid binding motifs) are particularly good at picking out one specific amino acid. So, instead of randomly choosing a target, human antibodies tend to focus on regions where these amino acids are available for binding. Thus, they repeatedly bind to the same spots on viruses.

This means a virus can make a small number of mutations to avoid detection by these common antibodies and reinfect populations that were previously immune.

“We find an underlying architecture in the immune system that causes people, no matter where in the world they live, to make essentially the same antibodies that give the virus a very small number of targets to evade in order to reinfect people and continue to expand and further evolve,” said first author Ellen Shrock, a graduate student in the Elledge lab.

Unique antibodies could help prevent viral reinfection

The team noted that nonhuman species produce antibodies that recognize different viral epitopes from those that human immune systems recognize.

“The more unique antibodies may be a lot harder to evade, which is important to consider as we think about the design of better therapies and vaccines.”

They also found that while it is more likely for a person to produce antibodies against a common epitope, some people do produce rarer antibodies, which may more effectively protect them from reinfection.

These insights have important implications for COVID-19 treatments, such as monoclonal antibodies, and vaccine design.

“The more unique antibodies may be a lot harder to evade, which is important to consider as we think about the design of better therapies and vaccines,” said Elledge.

Authorship, funding, disclosures

Richard Timms of the University of Cambridge and Tomasz Kula of HMS and Brigham and Women’s were co-second authors. Other authors are Elijah Mena, Anthony West Jr., Rui Guo, I-Hsiu Lee, Alexander Cohen, Lindsay McKay, Caihong Bi, Keerti Keerti, Yumei Leng, Eric Fujimura, Richard Horns, Mamie Li, Duane Wesemann, Anthony Griffiths, Benjamin Gewurz, and Pamela Bjorkman.

Elledge and Kula are founders of TSCAN Therapeutics and ImmuneID. Elledge is a founder of MAZE Therapeutics and Mirimus and serves on the scientific advisory board of Homology Medicines, TSCAN Therapeutics, and MAZE Therapeutics, none of which impact this work. Shrock was a consultant for ImmuneID. Elledge and Kula are inventors on a patent application filed by Brigham and Women’s (US20160320406A) that covers the use of the VirScan library to identify pathogen antibodies in blood.

This research was supported by the SARS-CoV-2 Viral Variants Program and the Value of Vaccine Research Network, the Massachusetts Consortium on Pathogen Readiness (MassCPR), National Institutes of Health (1P01AI165072, K99DE031016, AI139538, AI169619, AI170715, and AI170580), National Science Foundation (Graduate Research Fellows Program), Pemberton-Trinity Fellowship, Sir Henry Wellcome Fellowship (201387/Z/16/Z), Jane Coffin Childs Postdoctoral Fellowship, and Burroughs Wellcome Career Award in Medical Sciences. Elledge is an Investigator with the Howard Hughes Medical Institute.

Originally published in Harvard Medical School News and adapted from a Mass General Brigham news release.