Why efforts to make better, more universal coronavirus vaccines are struggling

There’s a new call from the White House to develop vaccines that might protect against future SARS-CoV-2 mutants or even unknown coronaviruses. “The vaccines we have are terrific, but we can do better than terrific,” Ashish Jha, White House COVID-19 response coordinator, said at a vaccine summit yesterday that gathered researchers, companies, and government officials. “Ultimately, we need vaccines that can protect us no matter what Mother Nature throws at us.”

But no specific funding request to Congress was revealed at the summit, or any concrete plans, so vaccine developers and the public shouldn’t expect a second Operation Warp Speed, the U.S. government’s multibillion-dollar crash program to develop the first COVID-19 vaccines. And the scientific, logistical, and regulatory hurdles for any next-generation vaccines are higher.

Operation Warp Speed proved it was possible to race from a newly identified virus to safe and effective immunizations in just 11 months—many times faster than ever before. Today, there are a few dozen fledgling efforts to create vaccines that protect against future SARS-CoV-2 mutants or take an even more “pan” approach in order to thwart unknown coronaviruses that have yet to jump into humans. But only a single candidate, developed by the U.S. Army, has made it into a phase 1 clinical trial.

“We want to start clinical trials tomorrow, but there are lots of barriers to getting there,” says Yale University immunologist Akiko Iwasaki, a panelist at the White House summit who has a vaccine candidate that’s administered as a nasal spray. For starters, funding remains far tighter than in the Warp Speed days: The Coalition for Preparedness Innovations (CEPI) has invested a more modest $200 million in 11 efforts run by small companies and academics, and the U.S. National Institute of Allergy and Infectious Diseases (NIAID) has committed just $43 million in four pancoronavirus vaccine programs. And efforts also face a dearth of materials needed to make vaccines, a shortage of nonhuman primates on which to test candidates, and uncertainty about how to assess new products in populations that already have immune response to SARS-CoV-2.

White House summits aside, some scientists contend there’s a deeper barrier. “The sense of urgency is completely gone,” says Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai who is developing both pan–COVID-19 and panflu vaccines.

That’s understandable, says Moncef Slaoui, the scientific leader of Operation Warp Speed and a veteran vaccine developer. Even though new SARS-CoV-2 variants are eroding the ability of today’s COVID-19 vaccines to block infection and prevent symptomatic disease, those vaccines are still preventing severe illness and death. “Current vaccines are effectively able to deal with the pandemic, because the number one priority is mortality and morbidity,” Slaoui says. “Pancoronavirus vaccines, whatever definition you use for them, are about preparedness, rather than dealing with the actual pandemic.”

The “pan” in potential next generation vaccines is often in the eyes of the beholder, as the projects underway have a variety of aims. The most modest, but still ambitious, goal is to avoid racing to create specific boosters that play catch-up with the latest SARS-CoV-2 variant and instead to develop vaccines that can reliably ward off severe disease from any future mutants of the pandemic coronavirus.

person gets an injection
The U.S. Army has a phase 1 trial of a pan coronavirus vaccine underway. Mike Walters/Walter Reed Army Institute of Research

Lawrence Corey of the Fred Hutchinson Cancer Research Center, who co-led the clinical trials network for Operation Warp Speed, is most interested in COVID-19 vaccines that set their sights higher still and promise to reduce the risk of infection and transmission of all SARS-CoV-2 spinoffs. “Do we really want to have 90,000 COVID deaths [in the United States] a year?” Corey asks. And he calls for more government backing so as to not squander the momentum of the field. “There are plenty of ideas,” he says. “What’s not forthcoming is the commitment.”

The next level of vaccines shoots for protection against sarbecoviruses, the grouping that includes SARS-CoV-2 and SARS-CoV-1—the cause of the outbreak of sudden acute respiratory syndrome (SARS) 20 years ago—and viral relatives in bats and pangolins that could spark the next human outbreak. A vaccine with even more “breadth” would thwart the beta genus of coronavirus, which includes sarbecoviruses, merbecoviruses like the one that causes Middle East respiratory syndrome, and two that now trigger the common cold. The ultimate vaccine would work against all four genera in the coronavirus family.

All of the work in this area is “really quite early,” says Melanie Saville, who heads vaccine R&D at CEPI. “I would classify this as high-risk, high-reward research,” she says. “We have to manage people's expectations here.”

Kayvon Modjarrad and colleagues at the Walter Reed Army Institute of Research (WRAIR) have the only pancoronavirus vaccine candidate to reach clinical testing so far. To trigger immune responses the vaccine uses the same coronavirus surface protein, spike, as many existing shots but tries to improve the way it is presented to the immune system. The WRAIR candidate contains several copies of spike bound to ferritin, a protein that normally carries iron around the blood. Receptors on the surface of antibody-making B cells can then “cross link” to these closely arrayed spikes, which theoretically leads to production of more powerful antibodies. In test tube studies, the vaccine “neutralized” a broad range of SARS-CoV-2 variants. WRAIR plans to publish data soon from its phase 1 study, but declined Science ’s request to interview investigators.

The limited availability of animals to test experimental vaccines on has stalled other projects. Andrew Ward, a structural biologist at Scripps Research who began working on coronavirus vaccines 5 years before the pandemic surfaced, says there is “enormous competition” for monkeys and the best mouse model systems. Operation Warp Speed allocated research animals to the most promising vaccine candidates, but now efforts have just become a free for all, not a coordinated Manhattan Project,” says Ward, who, as a result, has turned most of his attention to paninfluenza vaccines.

Iwasaki, who contends a nasal spray might be able to broaden protection by stimulating production of mucosal antibodies that have twice as many arms to bind viruses as the Y-shaped ones triggered by injection, also has had difficulty obtaining monkeys for studies. “If there was a government organized effort to help us, it would have gone much faster,” she says.

NIAID only funds two investigator-initiated grants for pancoronavirus vaccine research. One went to Lbashir BenMohamed, an immunologist at the University of California, Irvine, who has a 5-year, $3.6 million grant and had hoped to enter clinical trials this year. But his team, too, has had to wait for access to animal models, which it needs to select the most promising vaccine candidate. He now is looking at 2023—if his team can overcome another challenge.

Working with TechImmune, a startup company, BenMohamed’s team designed its vaccine candidate by first analyzing sarbecoviruses that have infected humans, camels, bats, minks, and pangolins for shared genetic sequences. They then make proteins that reflect these conserved regions and link them together. Like the existing Moderna and Pfizer-BioNTech vaccines, their vaccine encodes these conserved proteins in messenger RNA and relies on the body to turn that code back into protein. But a shortage of the lipid shells needed to enclose and protect the RNA has slowed progress. “We are bumping up against having to get into the queue for a lot of these things,” says Jeffrey Ulmer, TechImmune’s president. “Demand way outstrips supply.”

Biochemist Pamela Bjorkman of the California Institute of Technology says her team’s promising pan-sarbecovirus vaccine likely won’t enter the clinic until even later, perhaps 2024. That team has plucked a critical portion of spike from eight different sarbecoviruses—the so-called receptor binding domain—and stitched them together into a “mosaic.” Her team has faced manufacturing challenges, and only received substantial support recently, with CEPI announcing on 5 July a grant of up to $30 million to take the candidate through phase 1 trials. “This is taking longer than we’d hoped,” Bjorkman says.

Challenging proving ground

To prove their worth, pancoronavirus vaccines will have to travel a much rougher road than the first COVID-19 shots. The people in trials of the first COVID-19 vaccines had no specific immunity to SARS-CoV-2, making it straightforward to assess whether the shots provided protection. Today, most everyone has been vaccinated, infected with the virus, or both. Even the lowest hurdle for a pancoronavirus vaccine—proof of protection against all known SARS-CoV-2 variants—will be difficult to establish, predicts NIAID’s Barney Graham, who long worked on pancoronavirus vaccines at NIAID and helped Moderna develop its COVID-19 shot.

Graham, who now is at Morehouse College, also notes that the immune response to any new SARS-CoV-2 vaccine will be skewed by the immune system’s memory of the first viral proteins it encountered, whether through vaccination or infection with one of the many variants that have circulated. So assessing the new vaccines’ ability to provide broader protection may require trials in people who have “no competition in the immune system”—which in many countries would now mean infants. “There are a lot of fundamental biological and immunology questions to answer,” Graham says. “It's not going to go as fast as before.”

Exactly how these vaccines would be used—as periodic boosters that top up existing SARS-CoV-2 immunity and add breadth or only immediately after a new coronavirus surfaces—also remains a big question. And developing a panvaccine as insurance is a risky proposition, Graham says. A candidate vetted in clinical trials and sitting on the shelf might only have limited efficacy against, say, a SARS-CoV-3. At best, it would buy developers time to produce a vaccine specific to the newly emerged pathogen.

Graham says if he had to make a choice with limited resources, he’d prefer investing in having “knowledge on the shelf” to quickly make a vaccine rather than paying to have a panvaccine at the ready that could only “hold the fort until you get the real thing a few months later.”

Slaoui see the importance of pancoronavirus vaccine research, and says if we “disrupt the economic model” for R&D and take a Warp Speed approach, development could be “up to 10 times faster.” But he thinks the best bang for buck, especially when it comes to thwarting an entirely novel coronavirus, will come from investing heavily in building vaccine manufacturing plants that can quickly make vetted candidates against a new threat. “The day somebody comes up with a panvaccine that actually works, we should celebrate it,” Slaoui says. “But we will only know that when another pandemic comes and we try it.”