A vaccine trains the immune system to recognize a virus in order to counter it. Using imaging technology, structural biologists can intuit the contours of a virus and its proteins, then reproduce those structures to make more effective vaccines. McLellan said of his field, “From the structure, we can determine function—it’s similar to how seeing a car, with four wheels and doors, implies something about its function to transport people.”
The surface of an RSV particle features a protein, designated F. On the top of the protein, a spot called an epitope serves as a landing pad for antibodies, allowing the virus to be neutralized. But something extraordinary happens when the virus invades a cell. The F protein swells like an erection, burying the epitope and effectively hiding it from antibodies. Somehow, McLellan had to keep the F protein from getting an erection.
Until recently, one of the main imaging tools used by vaccinologists, the cryogenic electron microscope, wasn’t powerful enough to visualize viral proteins, which are incredibly tiny. “The whole field was referred to as blobology,” McLellan said. As a work-around, he developed expertise in X-ray crystallography. With this method, a virus, or even just a protein on a virus, is crystallized, then hit with an X-ray beam that creates a scatter pattern, like a shotgun blast; the structure of the crystallized object can be determined from the distribution of electrons. McLellan showed me an “atomistic interpretation” of the F protein on the RSV virus—the visualization looked like a pile of Cheetos. It required a leap of imagination, but inside that murky world Graham and McLellan and their team manipulated the F protein, essentially by cloning it and inserting mutations that kept it strapped down. McLellan said, “There’s a lot of art to it.”
In 2012, the MERS coronavirus emerged in Saudi Arabia. It was extremely dangerous to work with: a third of infected people died. Ominously, it was the second novel coronavirus in ten years. Coronaviruses have been infecting humans for as long as eight centuries, but before SARS and MERS they caused only the common cold. It’s possible that, in the distant past, cold viruses were as deadly as covid, and that humans developed resistance over time.
Like RSV, coronaviruses have a protein that elongates when invading a cell. “It looks like a spike, so we just call it Spike,” Graham said. Spike was large, flexible, and encased in sugars, which made it difficult to crystallize, so X-ray crystallography wasn’t an option. Fortunately, around 2013, what McLellan calls a “resolution revolution” in cryogenic electron microscopy allowed scientists to visualize microbes down to one ten-billionth of a metre. Finally, vaccinologists could truly see what they were doing.
Using these high-powered lenses, Graham and McLellan modified the MERS spike protein, creating a vaccine. It worked well in mice. They were on the way to making a version for humans, but, after MERS had killed hundreds of people, it petered out as an immediate threat to humans—and the research funding petered out, too. Graham was dismayed, realizing that such a reaction was shortsighted, but he knew that his energies hadn’t been wasted. About two dozen virus families are known to infect humans, and the weapon that Graham’s lab had developed to conquer RSV and MERS might be transferrable to many of them.
What was the best way to deliver a modified protein? Graham knew that Moderna, a biotech startup in Cambridge, Massachusetts, had encoded a modified protein on strips of genetic material known as messenger RNA. The company had never brought a vaccine to market, concentrating instead on providing treatments for rare disorders that aren’t profitable enough to interest Big Pharma. But Moderna’s messenger-RNA platform was potent.
In mice, Graham had proved the effectiveness of a structure-based vaccine for MERS and also for Nipah, a particularly fatal virus. In 2017, Graham arranged a demonstration project for pandemic preparedness, with mers and Nipah serving as prototypes for a human vaccine using Moderna’s messenger-RNA platform. Almost three years later, as he was preparing to begin human trials for the Nipah vaccine, he heard the news from Wuhan.
Graham called McLellan, who happened to be in Park City, Utah, getting snowboard boots heat-molded to his feet. McLellan had become a star in structural biology, and was recruited to the University of Texas at Austin, where he had access to cryogenic electron microscopes. It took someone who knew Graham well to detect the urgency in his voice. He suspected that China’s cases of atypical pneumonia were caused by a new coronavirus, and he was trying to obtain the genomic sequence. It was a chance to test their concept in a real-world situation. Would McLellan and his team like to get “back in the saddle” and help him create a vaccine?
“Of course,” McLellan said.
“We got the sequences Friday night, the tenth of January,” Graham told me. They had been posted online by the Chinese. “We woke up on the eleventh and started designing proteins.”
Nine days later, the coronavirus officially arrived in America.
Within a day after Graham and McLellan downloaded the sequence for sars-CoV-2, they had designed the modified proteins. The key accelerating factor was that they already knew how to alter the spike proteins of other coronaviruses. On January 13th, they turned their scheme over to Moderna, for manufacturing. Six weeks later, Moderna began shipping vials of vaccine for clinical trials. The development process was “an all-time record,” Graham told me. Typically, it takes years, if not decades, to go from formulating a vaccine to making a product ready to be tested: the process privileges safety and cost over speed.
Graham had to make several crucial decisions while designing the vaccine, including where to start encoding the spike-protein sequence on the messenger RNA. Making bad choices could render the vaccine less effective—or worthless. He solicited advice from colleagues. Everyone said that the final decisions were up to him—nobody had more experience in designing vaccines. He made his choices. Then, after Moderna had already begun the manufacturing process, the company sent back some preliminary data that made him fear he’d botched the job.
Graham panicked. Given his usual composure, Cynthia, his wife, was alarmed. “It was a crisis of confidence that I just never see in him,” she said. So much depended on the prompt development of a safe and effective vaccine. Graham’s lab was off to a fast start. If his vaccine worked, millions of lives might be spared. If it failed or was delayed, it would be Graham’s fault.
After the vaccine was tested in animals, it became clear that Graham’s design choices had been sound. The first human trial began on March 16th. A week later, Moderna began scaling up production to a million doses per month.
Image: Dr. Barney S. Graham, by Nikola Tamindzic for The New Yorker
[ed. It's all here, the big picture. The most complete accounting of the coronavirus pandemic, from beginning to present.]
