In January 2020, Caltech biochemist Pamela Bjorkman asked for volunteers to help solve the structures of immune proteins attacking a newly discovered coronavirus. The pathogen had emerged in China and was causing severe pneumonia-like symptoms in the people it infected. Knowing the molecular arrangements of these antibodies would be an important step towards developing drugs to combat the virus.
Christopher Barnes, a postdoc working in Bjorkman’s lab on the structure of HIV and the antibodies that attack it, took the opportunity to solve a new puzzle. “I was like, ‘Oh, I’ll do it!’” says Barnes. At the time he didn’t know how urgent the investigation would become.
Now, we are very familiar with SARS-CoV-2, which causes COVID-19 and has killed more than 6 million people globally. Studies of the structure of the virus and the antibodies that attack it have helped scientists rapidly develop vaccines and treatments that have saved tens of millions of lives. But the virus continues to adapt, making changes to the spike protein it uses to enter cells. That has left researchers scrambling to find new drugs and updated vaccines.
Using high-resolution imaging techniques, Barnes is investigating coronavirus spike proteins and the antibodies that attack them. His goal: to find a persistent weak spot and exploit it to create a vaccine that works against all coronaviruses.
Barnes’ team used cryo-electron microscopy to reveal the structures of eight antibodies that stop the original version of SARS-CoV-2. The technique captures cells, viruses and proteins in the process of being frozen. In this case, the team isolated coronavirus particles laced with proteins from the immune systems of people with COVID-19.
The antibodies had attached to four spots on the spike protein’s receptor-binding domain, or RBD, the team reported in Nature in 2020. This finger-like region anchors the virus to the cell it will infect. When the antibodies bind to the RBD, the virus can no longer connect to the cell.
Barnes’s team also created an antibody classification system based on the location of RBDs where immune system proteins tend to attach. “That’s been really helpful in understanding the kinds of antibody responses that natural infection elicits,” says structural biologist Jason McLellan, who was not involved in the work, and in identifying prime candidates for drug development.
“One of Chris’s main strengths is that he doesn’t limit himself or his research to just one technique,” says McLellan, of the University of Texas at Austin. “He adapts quickly and incorporates new technologies to answer important questions in the field.”
Since opening his own lab at Stanford, Barnes and his colleagues have determined the structures of six antibodies that attack the original SARS-CoV-2 virus and delta Y omicron variants. Those variants are adept at evading antibodies, including lab-made ones that are given to patients to treat COVID-19.
The newly identified antibodies, described in the June 14 Immunity, target the N-terminal domain of the spike protein. The structures of the protein-binding sites are the same in delta and omicron, suggesting that the sites could remain unchanged even in future variants, the team says. Eventually, scientists will be able to mass-produce antibodies that target these sites for use in new therapies.
Barnes has now turned his attention to antibodies that can fend off all coronaviruses, from those that cause the common cold to those found in livestock and other animals that have the potential to spread to people.
Barnes and immunologist Davide Robbiani at the University of Lugano in Switzerland identified classes of antibodies that target variants of all four coronavirus families, blocking the viruses’ ability to fuse with cells.
Also, the structure of one of the binding sites on the spike protein is the same throughout the coronavirus family tree, says Barnes. “This is something you wouldn’t want to mutate as you diversify your viral family because it’s a critical component of how you get into the cell.”
Two independent teams have identified equally broad action on the same classes of antibodies. Taken together, the findings suggest that a universal coronavirus vaccine is possible, says Barnes.
“We’ve all discovered this at the same time,” he says. Teams are now thinking, “Wow, this exists. So let’s try to make a real pan-coronavirus vaccine.”
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