The laborious experiments at Colorado State University are physically and mentally taxing — some people compare the fatigue and exhaustion of working “behind the barrier” of a biosafety level-3 laboratory to a hangover. Ragan gowns up every day of the week, donning two layers of gloves, scrubs, a Tyvek suit and a noisy respirator that purifies the air she breathes. There are no food or water breaks, no texts or checking her phone in idle moments.
Even as vaccine supplies outstrip demand in the United States, the scientific quest for coronavirus shots has scarcely eased. In dozens of academic institutions, government laboratories and companies, the pace of work hasn’t relented. If anything, it feels busier to many scientists working on second-generation vaccines, variant-proof boosters or the ultimate goal — a vaccine that would work against multiple coronaviruses and stop future pandemics.
The world may not need the vaccine Ragan is studying, even if it works. The vaccine’s development path is far less clear. It’s getting harder to run coronavirus vaccine trials as authorized shots become available, shrinking the pool of potential study participants. Most big pharmaceutical partners necessary to turn a promising idea into a product already have made their bets. Any new vaccine must compete against a high bar — first-generation vaccines that were better out of the gate than anyone expected.
People who once peppered Ragan with questions about the virus have, she recently noticed, stopped asking. Why work on a coronavirus vaccine now?
“Friends or family will say, ‘Come out to a barbecue, come on vacation,’ ” Ragan said, her hair still damp after changing and showering after a morning of experiments. “They really don’t understand. They think: We’re good.”
Ragan still remembers the nervous thrill of joining the fight against the virus in February 2020. Her boss, Richard A. Bowen, received a sample of SARS-CoV-2 isolated from a patient in Washington state and grew a stock of the virus in a flask labeled simply, “COVID.”
“It was so exciting. We can partake,” Ragan recalled thinking at the time. “Now, I’m just exhausted.”
The coronavirus vaccine Ragan is working on is more old-fashioned than any authorized in the United States, based on killed viral particles that teach the immune system to rout the live version. It’s similar to vaccines against polio and influenza but produced in a new way. If the shots work, they may provide protection against multiple variants. The technique could be used to make vaccines against other pathogens.
Ragan and her colleagues are driven by the conviction that more tools will probably be needed to quell this pandemic globally. But even if that turns out to be wrong, the work they put in now could become the foundation for responding to the next pathogen, or the one after that.
“There’s a really short-term memory, and people want this to be over,” said Lindsay Hartson, a laboratory manager who suits up to work alongside Ragan. “It’s not.”
Early on, the U.S. government used its financial might to back eight vaccine candidates. Billions of dollars were funneled to a select portfolio of companies, with hope that at least one vaccine would succeed.
The scientific progress and setbacks characterizing the hunt for those vaccines has been followed as closely as the travails of a celebrity romance. So far, in odds and timing almost unheard of in pharmaceutical development, three vaccines have been authorized in the United States, with others on the runway. More than a dozen others have been authorized by at least one country.
Despite such success, many scientists see obstacles ahead. A more menacing variant might emerge. Immunity could taper off over time. This could be a dress rehearsal for an even more catastrophic pandemic. Underlying all of those unknowns is one clear known: More vaccines will be needed.
“It’s always a little naive or human hubris to think, ‘We’re done. We don’t need to develop other interventions,’ ” said John R. Mascola, director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases. “We’re still in the early and mid stages of this.”
Scientists working on vaccines today have a different mind-set from a year ago. The first round of vaccines quelled the virus remarkably well but did not eradicate the threat. They have primarily been used in rich countries. Now, scientists need variant-proof vaccines and enough of them to reach the whole world.
Daniel Hoft, an infectious-diseases specialist at Saint Louis University School of Medicine, is working on a clinical trial of a second-generation vaccine that attempts to trigger a broader scope of immunity.
The authorized vaccines focus the immune system’s firepower on the spike protein that dots the outside of the coronavirus. Targeting the spike turned out to be a powerful way to trigger protective antibodies, an important line of defense. But some scientists worry the strategy comes with a major vulnerability. The coronavirus is evolving, and relatively minor changes to the spike could make it unrecognizable to the disease-blockers. That might enable it to dodge immunity, like a “wanted” poster that depicts only a thief’s nose or eye.
There are other elements of immune protection, including T cells that can clear away infected cells. Hoft is working with the company Gritstone Bio on a vaccine that is specifically designed to trigger those cells, adding a layer of protection that could make it more difficult for the virus to dodge the immune system — in effect, a “wanted” sign that pictures the thief’s whole face.
“These vaccines are potentially backup as the viruses are still mutating and transmitting widely in many parts of the world,” Hoft said. “It’s very scary to see everyone in the U.S. think, ‘Well, the pandemic is over,’ when the virus is mutating, and if we don’t contribute to helping the rest of the world getting transmission under control, it’s going to come back to haunt us.”
Other scientists are beginning to think about vaccines that could be useful now — but also in preventing future pandemics. The idea that a vaccine could be a Swiss Army knife, effective not against just one virus but a whole family, is tantalizing. A coronavirus has leaped into the human population about once a decade, starting with SARS in 2002-2003 — so even as countries begin to emerge from this pandemic, many experts are beginning to worry about preventing the next one.
At the Duke University School of Medicine, researchers were trying to create a booster shot and discovered, to their surprise, that their vaccine — a bit of the coronavirus spike protein assembled on a submicroscopic scaffold called a ferritin nanoparticle — generated antibodies that could protect against other coronaviruses, including bat viruses and the original SARS.
Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, called the work “an extremely important proof of concept” that a vaccine was possible that protects not only against a known viral threat, but the unknown ones, too.
“We got into this very early on in the epidemic, and we asked the question, ‘What would we do that could help the field and not compete with what the companies were trying to do?’” said Barton Haynes, a Duke immunologist working on the vaccine.
Kayvon Modjarrad at Walter Reed Army Institute of Research spent years working on vaccines against flu, Ebola and another coronavirus before the pandemic. In January 2020, he started rapidly repurposing that work, crafting an experimental vaccine made up of a ferritin nanoparticle studded with coronavirus spike proteins.
Early testing showed little drop-off in the vaccine’s ability to block three variants of concern. Modjarrad’s team is working on tests to see whether there is any decline in effectiveness against the delta variant first detected in India. But it also triggered antibodies against a completely different coronavirus — the original SARS virus.
Scientists working on these vaccines are thinking not just about this pandemic, but also the next one, which could easily be worse. A virus could bedeadlier , such as the Nipah bat virus. It could spread more efficiently, like measles.
“This may just be a shot across the bow, a warning as to what could come potentially,” Modjarrad said. “That’s why we’re working as hard as ever.”
An old-school shot with a twist
The pandemic has been a proving ground for novel technologies, with many hailing a new era in vaccine development. But it has also demonstrated the uncertainty of science. Some tried-and-true technologies flopped or had to go back to the drawing board, while risky new ones succeeded. The opposite might be true in the next pandemic.
Ragan and colleagues at Colorado State are working on one of the oldest vaccine technologies in the book: an inactivated virus. Such vaccines are being used by China and developed by the French company Valneva. But the Colorado researchers are using a different method to turn infectious viruses into inert particles.
Traditional inactivated virus vaccines use chemicals to kill the pathogens. That process may render the end product less potent and effective and may explain why some of the Chinese vaccines haven’t performed well, according to Raymond Goodrich, executive director of Colorado State’s Infectious Disease Research Center.
Goodrich developed a process to use riboflavin, or vitamin B2, and rays of ultraviolet light to do the same thing.
The idea didn’t start with vaccines. During the height of the HIV crisis, Goodrich wanted to find a way to inactivate pathogens in blood products needed for transfusions. But he sought to identify a nontoxic method, because adding chemicals that could kill pathogens would render the blood useless.
Sitting on the bottom of a bookshelf in his office is the blue hardcover book that gave him his eureka moment, “Bioorganic Photochemistry.” A chapter marked with sticky notes was “astounding,” Goodrich said, because it described the unique optical properties of riboflavin. When activated with ultraviolet light, it could cause a chemical reaction that damaged the building blocks of a virus.
The pandemic presented an opportunity to test whether it might be a new way to create an old-school vaccine. Ragan’s experiments this summer will help lay the foundation for potential clinical trials — and help test a technique that could be used for many pathogens.
Goodrich, like all vaccine developers, realizes success is not guaranteed. His technology may not be ready in time for this pandemic. It may not work well enough against this virus to compete with existing options.
The vaccine technologies used so far in the pandemic were not invented overnight. They were ready this time because researchers had spent decades developing them.
“It’s sort of like the end of every pandemic is an opportunity to prepare for the next one,” Goodrich said. “This pandemic has spurred on a tremendous amount of interest into research into ways that we can be better prepared and we can respond more rapidly, not just to the next pandemic, but to other diseases and other agents that have continued to vex human populations over time.”