The Achilles Heel That Could Lead to Universal Coronavirus Treatments

March 21, 2023 • by Nat Levy

Alone, this target might not be strong enough to directly block infection, but might be used to jump-start or boost an immune response.

A man in white lab coat holds a three dimensional model of a viral protein and an antibody attached

Jason McLellan holds a three dimensional model of a SARS-CoV-2 spike protein with antibody attached. Photo credit: Vivian Abagiu.

Researchers behind discoveries that led to vaccines for the virus that causes COVID-19 have identified a potential Achilles heel that exists in all coronaviruses. These findings, led by researchers at The University of Texas at Austin, could aid the development of improved treatments for COVID-19 and also protect against existing and emerging coronaviruses. 

Most vaccines and antibody-based treatments for COVID-19 neutralize the SARS-CoV-2 virus by disrupting interactions between the protein spike on the virus and the ACE2 receptor on human cells, which the virus hijacks to gain entry. But mutations in the spike protein mean that emerging variants of SARS-CoV-2 can escape the human antibody response, making treatments less effective and leading to vaccinated individuals still experiencing breakthrough infections. The researchers are addressing the issue by focusing on parts of the spike protein that are crucial for the virus’s survival and don’t mutate.

The SARS-CoV-2 spike protein is made up of two subunits – called S1 and S2. The S1 subunit binds to the ACE2 receptor, while the S2 subunit allows the virus to fuse with the membrane of the cell it is gaining access to. Most mutations in the spike protein affect its S1 subunit, but the S2 part is relatively constant across all seven human coronaviruses, making it a prime target for therapeutic antibodies and vaccines.

“We know that S2-directed antibodies are produced following a COVID-19 infection, and similar subunits in flu and HIV are also targeted by the body’s antibodies,” said Rui Silva, a former graduate student in the College of Natural Sciences’ Department of Molecular Biosciences at UT Austin who led the research along with co-first authors Yimin Huang and Annalee Nguyen. “However, we know very little about the antibodies that bind with the S2 subunit.”

Fewer than 5% of the roughly 7,000 known anti-SARS-CoV-2 antibodies target S2, and only two classes of S2-binding antibodies have been characterized in detail. The researchers identified a third class of antibody that targets a part of S2 that is highly similar across coronaviruses.

The researchers found that this class of antibody binds with a hinge in the S2 subunit that plays a crucial role when the subunit changes its shape during the virus’s fusion with the human cell membrane. Further analysis showed that access to the point where the antibody binds to this hinge (called the epitope) depends on the shape-shifting dynamics of the overall spike protein. When the spike binds to the ACE2 receptor, the hinge becomes accessible.  

Although the antibodies did prevent the spike protein’s ability to fuse viral and human cell membranes, they were less potent at neutralizing the virus altogether. However, as well as directly neutralizing viruses, antibodies also indirectly kill virus-infected cells by triggering other processes.

In one experiment, antibodies triggered human natural killer cells to destroy SARS-CoV-2-infected cells. In another, the S2 antibodies caused cells called monocytes to gobble up and destroy the infected cells. This suggests that although S2 antibodies might not be strong enough to directly block infection, they could be used to jump-start or boost an immune response.

“We have identified an epitope in the S2 subunit of SARS-CoV-2 that is constant across all pathogenic coronavirus strains,” said senior author Jennifer Maynard, a professor in the McKetta Department of Chemical Engineering at UT Austin. “Although targeting this epitope alone is unlikely to be potent enough as a treatment or vaccine, therapeutic strategies that can enhance access to this epitope could allow existing human antibodies to more effectively promote viral clearance through other antibody-directed cell-killing processes.”  

Students and faculty members in the College of Natural Sciences and Cockrell School of Engineering led the research, collaborating with personnel from several other institutions. Team members include Jason McLellan, Silva, Yimin Huang, Ching-Lin Hsieh, Amanda Bohanon, Alison Lee and Dzifa Amengor from the College of Natural Sciences; Maynard, Nguyen, Rebecca Wilen, Ahlam Qerqez, Laura Azouz, Kevin Le, Yutong Liu and Andrea DiVenere from the Cockrell School; Kevin Dalby and Tamer Kaoud from the College of Pharmacy at UT Austin; Oladimeji Olaluwoye and Sheena D'Arcy from the Department of Chemistry and Biochemistry at The University of Texas at Dallas; Jun-Gyu Park, Ahmed M. Khalil and Luis Martinez-Sobrido from the Texas Biomedical Research Institute; Shawn Costello, Sophie Shoemaker and Susan Marqusee from University of California, Berkeley; and Eduardo A. Padlan, formerly of the National Institutes of Health.