Even before the first U.S. death from the coronavirus, Drs. Barney Graham and Kizzmekia Corbett at the National Institutes of Health’s Vaccine Research Center were in a race against the clock.
On a Saturday morning in early January 2020, Chinese scientists posted the gene sequence of the rapidly spreading COVID-19 virus online so that other researchers could understand the mysterious, deadly illness that in short order would spread across the globe. By the end of the weekend, Graham and Corbett, aided by years of foundational work, were able to use the genetic information to design the basic structure for the lifesaving COVID-19 vaccines.
This innovation would turn out to be one of the monumental achievements of modern medicine.
“Their names will be in the history books,” said Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases and a 2020 Samuel J. Heyman Service to America Medal recipient. “All the (COVID-19) vaccines that are doing really well are totally dependent on their work.”
Just days after Graham and Corbett supplied the critical information, collaborators at the biotech company Moderna were able to manufacture the first doses of the coronavirus vaccine. The first human trials began just 65 days later. It was, by far, the fastest vaccine development process in history.
“Kizzmekia and Barney have made contributions to human health that few others could claim,” said NIH Director Dr. Francis Collins.
Breaking every speed record for developing a safe and effective vaccine was only possible because of years of work. In 2013, while studying a respiratory syncytial virus, a troubling and sometimes fatal childhood ailment, Graham and his collaborators discovered that a few key mutations to the protein analogous to the spike that sits on the surface of the coronavirus could make them useful for a vaccine. Graham realized that this discovery could unlock a new vaccine design, especially if paired with a rapid manufacturing approach.
Partnering with Moderna, Graham initially planned to use the prototype vaccine for Nipah—a contagious and deadly paramyxovirus transmitted by bats in South and Southeast Asia—as the demonstration project. But when the pandemic began, the decision was quickly made to use COVID-19 for the proof of concept. “We wanted to show the world how fast we could go,” Graham said.
Graham and Corbett’s design ended up forming the backbone of many COVID-19 vaccines in use today, including those made by Moderna, Johnson & Johnson and Novavax. Pfizer’s vaccine, developed separately, relies on a nearly identical design.
Graham, deputy director of the NIH Vaccine Research Center, and Corbett, who leads the coronavirus research team in Graham’s Viral Pathogenesis Laboratory, made versions of a spike protein based on prior work from other coronaviruses. Two specific amino acid substitutions were used to stabilize the protein that sits on the surface of the COVID-19 virus and gives it its distinctive, crown-like appearance, hence the name “coronavirus.”
Their modifications have proven critical. In order to provoke an effective immune response, a vaccine needs to deliver these proteins in their initial active shape, rather than their inactive shape, after interacting with a cell. Graham and Corbett’s mutations met that goal. Jason McClellan’s lab, then at Dartmouth College and now at the University of Texas at Austin, and Andrew Ward’s group at the Scripps Research Institute, also played key roles.
“They could see right away that when the protein was made with their mutations, it looked the way it should,” said Dr. John Mascola, director of the Vaccine Research Center. “When made in the lab without those mutations, it tended to fall apart.”
This modified spike protein can be delivered either by messenger RNA technology, as Moderna’s vaccine does, or by more traditional means.
Corbett, who had previously interned with Graham, returned to NIH after completing her doctoral degree to study coronaviruses, which had been responsible for the troubling outbreaks of SARS in 2003 and MERS in 2012. She took up the mantle, focusing on coronavirus biology, especially spike structure, antibodies and vaccine development.
“I think Barney and Kizzmekia, having seen what happened with SARS, and what happened with MERS, were pretty convinced that we had not seen the last coronavirus,” Collins said. “They wanted to be prepared for that, and that was quite prescient on their part.”
“It’s the culmination of Barney’s life’s work and a validation of his vision of pandemic preparedness,” said Mascola.
Thanks to encouraging data from animal studies and the first human clinical trials, Corbett and Graham had early confidence their vaccine would work. But it wasn’t until Pfizer showed 95% efficacy in its late-stage trial results in November, just ahead of Moderna’s own announcement a week later, that the pair knew just how effective their vaccine design would be.
“It was the first time in 10 months where I was actually able to breathe,” Corbett recalled. “I shed every tear I had wanted to shed over the last year.”
For both, the results were beyond their wildest expectations. “Getting 95% is kind of rare in vaccines. I was expecting 70% and hoping for 80%,” Graham said.
“This moment has transformed virology and vaccinology in a way that no one will be able to ignore,” Corbett said.
Photo credit: Sam Kittner | Marlayna Demond