David Veesler and his lab members aren't getting much sleep these days.
In the final weeks of 2021, he and his team worked around the clock to post four coronavirus papers on the preprint server bioRxiv. All delved into the biology of Omicron, the SARS-CoV-2 variant currently driving the explosive growth of cases worldwide. One paper, on the structure of Omicron's spike protein, came out on New Year's Eve.
"We are very tired," Veesler says with a laugh. "We are 16 people working on coronavirus all the time."
In the two years since SARS-CoV-2 blazed across the globe, Veesler and his team at the University of Washington have been in the lab day and night scrutinizing people's immune responses, designing new vaccines, and sharing their insights with colleagues in the US and abroad.
They and others have been racing to piece together a picture of Omicron, a variant that differs drastically from its predecessors. What they're learning could guide the development of new vaccines that offer protection against future pandemics. In the near-term, such vaccines could provide a fresh supply of shots for those still awaiting their first dose – roughly 40 percent of people on the planet.
"The main question is how are we going to make enough doses for everyone?" says Veesler, who was recently selected as a Howard Hughes Medical Institute Investigator. His team feels driven to help. They're part of a fiercely motivated group of scientists working relentlessly to find ways to treat or prevent coronavirus infection, and they're not alone. Scientists around the world are teaming up and buckling down to get a grip on the virus. Their efforts are fast-tracking advances and discoveries, Veesler says, and in the process, they're also transforming science.
Never before have human beings come together to get science done the way it has been done for the past two years."
David Veesler, Howard Hughes Medical Institute
Structural biology at warp speed
Most days of the week, you can find biochemist Lexi Walls in Veesler's lab on the second floor of UW's Health Sciences building. Her desk sits near a window overlooking a small courtyard. Before the pandemic, she could see students and staff hanging out and walking home at night. These days, the building and its surroundings have mostly emptied out, except for Veesler's team and others working on coronavirus. They're hard at it pretty much full time. You might catch a quiet moment at 4:00 a.m. on a Saturday, Walls says, but otherwise, "the lab is constantly buzzing."
She's wearing a black N95 mask, which she'll keep on all day, with short breaks for meals, if she's lucky.
Veesler's team recognizes that they need to eat, sleep, and give their brains a break every now and then to rest, but their pace hasn't always been so dogged.
Walls has been studying coronavirus with Veesler since 2015 when most people had never heard of the microscopic pathogen. Back then, Walls was motivated by a sense of discovery. "At the time, no one else in the world knew much of anything about coronavirus spike proteins."
In 2016, she, Veesler, and their colleagues were the first to image the structure of a coronavirus spike protein, the infection machinery the virus uses to enter cells. When the pandemic began raging in 2020, that published data gave scientists a jumping off point for understanding SARS-CoV-2, which also relies on spike proteins to infect humans.
Four years later – just months after the novel coronavirus emerged in Wuhan – the team described the architecture of the SARS-CoV-2 spike protein in the journal Cell. Last month, Veesler's team continued their structure-solving streak. On New Year's Eve 2021, they reported capturing images of Omicron's spike protein bound to an antibody used in the clinic to treat COVID-19. Called a neutralizing antibody, it blocks the virus's entry into cells and retains activity against Omicron. Around the same time, a handful of other labs also reported efforts to map Omicron's spike structure.
"Structural biology used to move at a slow pace," says Harvard University's Bing Chen, who posted his own team's Omicron work January 12, 2022, on bioRxiv. "Now, it's almost becoming a high-throughput tool." That speed is especially important in a pandemic, he says, because scientists want to generate useful information as quickly as possible.
Scientists already knew that Omicron was strikingly distinct from previous variants. Compared to the original strain, Omicron has dozens of mutations, 37 of which occur in the spike protein. Visualizing where those mutations occur, and how they alter the spike's structure, gives scientists a glimpse of potential weak spots. That could be helpful when designing drugs or antibodies that target the virus, says Matt McCallum, who led the work in Veesler's lab and typed up the manuscript on his flight home from Christmas break.
The team's structural work, McCallum says, also helps explain one of Omicron's hallmarks: an extraordinary ability to sneak past people's immune defenses.
An abysmal drop
Omicron first began its tear around the world late last year. Scientists in South Africa reported the new variant, also known as B.1.1.529, on November 24, 2021. As of January 6, the World Health Organization reports, the highly infectious variant had been detected in 149 countries.
In the United States, Omicron now accounts for more than 99 percent of cases, according to the US Centers for Disease Control and Prevention. This massive surge in infections likely owes to a couple of factors: Omicron is particularly good at latching on to human cells, and it can largely stymie protective antibodies.
After a coronavirus infection, the immune system churns out scads of antibodies to fend off future encounters. These antibodies circulate in the body for weeks and months, some binding directly to the virus to disarm it.
Veesler's team examined immune responses to Omicron using a wide panel of vaccine-elicited neutralizing antibodies as well as monoclonal neutralizing antibodies, possibly the largest panel of its kind, says John Bowen, a research technician in Veesler's lab.
The team looked at antibodies from unvaccinated people and people vaccinated with one of the six major COVID-19 vaccines, and at monoclonal antibody treatments known to target previous coronavirus variants.
Bowen has immersed himself in the latest efforts, like the rest of Veesler's team. Every morning he scans Twitter to catch the latest coronavirus news, eats breakfast, and heads to the lab. Then, it's "work, work, work, take a quick bite to eat, if I can, then back home to bed," he says. The next day, rinse and repeat.
Even on Zoom, the soft-spoken Bowen thrums with excitement. He remembers the day he first observed the different antibody responses to Omicron. It was a Friday afternoon, and he was in constant contact with Veesler by text and phone. "We were on a real time crunch," Veesler says. They were writing a paper on the work with Davide Corti's group at Humabs BioMed, in Switzerland, who had stayed up late to see what Bowen found.
The wait was worth it. Bowen showed that even antibodies from vaccinated people were remarkably ineffective at thwarting Omicron after two doses. People vaccinated with Moderna, Pfizer, or Oxford/AstraZeneca saw a 20- to 40-fold drop in neutralizing antibody activity against Omicron compared to the original viral strain. "That is just abysmal," Veesler says.
Unvaccinated people previously infected with coronavirus – sometimes referred to as "natural infection" – or those vaccinated with the Johnson & Johnson/Jansson, Sputnik V, or Sinopharm vaccines fared even worse. Their activity levels dropped to zero – no neutralizing antibody activity could be detected against Omicron at all.
"I was just blown away," Bowen says. The results, reported in the journal Nature on December 23, 2021, echoed findings from other labs reported at the same time and meant that Omicron could dodge the body's usual defenses. "This is a variant that evades antibody-mediated immunity to a level that's unprecedented," Veesler says.
Bowen's experiments also revealed Omicron's talent for catching hold of ACE2, the receptor protein that ushers coronaviruses into cells. Omicron latched onto ACE2 in humans, and, somewhat surprisingly, in mice. That binding promiscuity suggests the variant might be able to hop from animal to animal, an ability that could lead to so-called spillover events between species.
Veesler cautions that antibody activity levels alone cannot entirely predict how well someone might react to Omicron. Still, more activity is better, he says. Bowen's results seemed to paint a grim picture of how people who received only one or two shots might respond to the new variant.
But parallel experiments Walls was performing generated some hope.
The benefits of boosting
Omicron's meteoric rise came on the heels of Delta, a coronavirus variant that just two months ago was the most infectious scientists had seen. Unlike the variants that came before it, Delta was the first to noticeably sidestep the defenses of vaccinated people.
In October, Walls and Veesler began an in-depth study of how such a breakthrough infection affects a person's immune response. The question has also intrigued scientists in other hard-hit nations. Last year, researchers in South Africa reported that antibody activity was "dramatically boosted" in people infected with coronavirus after receiving the Johnson & Johnson vaccine. Virologist Penny Moore's group at the University of the Witwatersrand in Johannesburg posted the work on the pre-print server medRxiv in November.
While Veesler's lab was analyzing its breakthrough infection data, booster shots became readily available in the US, and Omicron began circulating globally. So, the team expanded its investigation in real time, examining antibodies of those who had been boosted.
People who received three doses of the Pfizer-BioNTech mRNA vaccine had neutralizing antibodies that were both potent and broadly effective, the scientists reported January 19, 2022, in the journal Cell. The antibodies could efficiently target several coronavirus variants, including Omicron. Because booster shots are relatively new, his lab is still tracking how long the immune jolt lasts.
The results are part of a larger pattern the team uncovered, wherein multiple exposures to coronavirus ratchet up neutralizing antibody activity. The bottom line is, the more times a person's immune system encounters SARS-CoV-2, the stronger their antibody response is likely to be, Walls says. "The more exposures you've had, the better you're going to fare against Omicron – that's the biggest takeaway. If you have been vaccinated twice, you should get boosted."
Moore, who was not involved in Veesler's team's work, cautions that vaccinated individuals should not seek out coronavirus exposure. "This is not at all an encouragement for people to go and get infected. We can get very high antibody levels simply by vaccinating people," she says, "and this comes with almost no risk."
When the mRNA vaccines first became available in 2021, Veesler remembers explaining to his grandmother, who lives in France, why she should get the shot. "She listened to her grandson," he says with a smile.
Now, he's got his eye on designing the next generation of coronavirus vaccines. One of his team's approaches relies on nanoparticles decorated with spike protein snippets, like an ornament rolled in glitter. To trigger a response, current vaccines show the immune system the virus's entire spike protein. Veesler's team's nanoparticle vaccines are different – they showcase just a tiny section. Known as the receptor-binding domain, this section is the spike protein's Achilles' heel, Walls says.
Recent work by Bowen, Walls, and others in Veesler's lab is helping to refine just what portion – and conformation – of the spike to use. Some coronavirus vaccines, for example, include mutations in the spike protein that lock it into a specific shape. These vaccines elicit greater titers of neutralizing antibodies than those without these modifications, the team reported on bioRxiv on December 21, 2021.
Even as current reports indicate that Omicron might be less severe than Delta, and case counts may be peaking in places, other variants could be lurking in the wings. By homing in on the viral section most likely to rev up the immune system, Veesler's team hopes to create vaccines that generate broad, long-lasting protection – so when the next wave of coronavirus or one of its relatives hits, humankind will be ready.
One nanoparticle vaccine candidate Veesler's team developed with UW's Neil King, along with the South Korean vaccine developer SK bioscience, is nearing the end of a Phase 3 clinical trial that will assess the vaccine's efficacy. The work is supported, in part, by the Coalition for Epidemic Preparedness Initiatives, an organization funding several vaccine candidates with an eye toward stopping future epidemics.
The goal is to distribute safe, effective vaccines to countries lacking access. "In the US, we have an excess of vaccine – we can just go to CVS and get a dose," Veesler says. "Elsewhere, they have none." He hopes the coronavirus vaccines his team is working on will ultimately expand global supplies. The team expects to have clinical trial results for their first candidate within the next few months.
It's a time of excitement for Veesler's lab, and unparalleled teamwork. Among academic and industry labs world-wide, Walls says, there's much more willingness to collaborate. Still, the one thing they could all use more of, is time. "Our team has ideas and aspirations that are way bigger than we can address right now," she says. "There are so many things we want to do."
Until then, the lab remains united by a common purpose, Bowen adds. "Every single day we're doing research that directly impacts people's lives.
Walls, A. C., et al. (2022) SARS-CoV-2 breakthrough infections elicit potent, broad and durable neutralizing antibody responses. Cell. doi.org/10.1016/j.cell.2022.01.011.