A 'Universal Vaccine' May Soon Protect Against All Coronaviruses, Including the Common Cold

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Jason S. McLellan, associate professor of molecular biosciences, left, and graduate student Daniel Wrapp, right, work in the McLellan Lab at The University of Texas at Austin in 2020. Vivian Abagiu/College of Natural Sciences at UT Austin

It took Barney Graham, Jason McLellan and their collaborators just a weekend in January 2020 to design a novel vaccine they believed would be capable of protecting people against COVID-19. Their design formed the basis for the vaccines that Moderna, Pfizer and others would eventually use to inoculate millions of Americans a little more than a year later, a pace of development unprecedented in the annals of modern medicine.

By then, however, the two pioneering virologists were already thinking about future pandemics—and how they might get ahead of them.

Graham and McLellan are part of a corps of researchers hoping to take the technology they used on COVID-19 vaccines and apply them to an even more futuristic creation: an arsenal of off-the-shelf premade vaccines that could be easily modified to attack new pathogens as they arise—a kind of "pan" or "universal" coronavirus vaccine capable of protecting against many different strains of the virus at the same time.

Even as scientists race to develop booster shots and tweak existing vaccines to work against new variants to SARS2, they're looking ahead to future pandemics caused by entirely new pathogens from the same coronavirus family, one of just 26 known to infect humans. But SARS-CoV-2 is the third novel, deadly coronavirus to cross over from animals to humans in the last 20 years, and many scientists warn more will inevitably follow. Even though a "universal" vaccine that can protect against any new coronavirus that nature throws at us probably won't be available this year or next, development has become a high priority.

"We want to be proactive rather than reactive to coronaviruses," McLellan says. "The idea is to develop a single vaccine that could protect against all different coronaviruses, including ones that are still in bats and haven't emerged yet."

The idea isn't new. Many scientists were already working on pandemic preparation projects before the coronavirus hit, including several experimental pan-coronavirus vaccines. Approaches that show promise include efforts to identify distinct protein molecules common to all coronaviruses that could attract virus-killing antibodies and custom-made nanoparticles studded with viral fragments from a number of different varieties, to name two. Scientists have also been working for years on a universal influenza vaccine that would do away with the need for a yearly shot that only protects against some common strains.

Scientists have long complained that these efforts—particularly those geared toward coronaviruses—have been hampered by low funding and a lack of urgency. Now that may be changing. Over the last six months, the National Institutes of Health (NIH) issued a notice of "special interest" calling for research labs to apply for funding to develop a universal coronavirus vaccine. Democrats have introduced legislation that would allocate a $1 billion investment for the project, and private foundations and public health officials have promised to contribute, too.

The scientific establishment, meanwhile, has been stepping up its lobbying efforts. In recent months, leading public health officials and scientists have penned editorials in leading scientific journals, including Nature and Science, and begun to make the case for a major investment. Dr. Anthony Fauci, the nation's top infectious disease specialist, has used his platform to argue the case.

"I believe that we have the capability scientifically to develop one that really covers at least all of the SARS-CoV-2 mutations, but also the entire spectrum of the family of coronaviruses," Fauci said at a public event in February. Then, referring to MERS, which killed about one-third of those who caught it, SARS1, which killed up to 10 percent of its victims, and COVID-19, which has so far caused more than 3 million deaths around the world, he warned: "We got hit with three in 18 years that have been either pandemic or pandemic potential, so shame on us if we don't develop the universal coronavirus vaccine."

Humans develop immunity to an invading virus when the body learns to recognize unique shapes formed by the proteins on the pathogen's surface, and then starts producing cellular-level sentinels, known as antibodies, that seek out those specific shapes, glom on to them and keep them in check until other immune cells can arrive to destroy the pathogen they belong to.

Only certain parts of a pathogenic virus are visible to the immune system. Most viruses consist of a piece of genetic material wrapped in a protein and encased in a protective soap-bubble-like membrane. Protruding from this membrane is a grappling hook-like spike used to ensnare and hijack vulnerable host cells. These grappling hooks have distinct shapes, designed to allow them to fit into the protruding target proteins, and bind to them, like a key in a lock. These protruding parts of a virus used to attack the cells are also its Achilles heel

In the early 2010s, Graham, who oversees two dozen scientists focused on developing vaccines for a wide array of respiratory viruses at the NIH's Vaccine Research Center, began collaborating with McLellan, then a post-doctoral researcher in the lab of Peter Kwong, to develop a vaccine that would target a deadly pathogen known as respiratory syncytial virus (RSV). It was difficult to develop a vaccine against this virus, which caused a sometimes fatal respiratory condition in children, because the proteins it used to glom onto cells were capable of shape-shifting—engaging in what one structural biologist describes as a form of "crazy protein yoga" that made it difficult for antibodies to recognize them.

To combat this, McLellan and Graham developed a technique that allowed them to engineer synthetic versions of the grappling-hook-like proteins found on the surface of the respiratory syncytial virus. These synthetic proteins had a few carefully chosen changes to their genes that prevented them from bending and shape-shifting, effectively locking them into a single position so the body had a chance to develop strong antibodies against them. When Graham created a vaccine using the technique and injected it into macaque monkeys, it elicited among the most potent immune responses he had ever seen.

"The body will make antibodies against whatever shape you show it," explains McLellan. "But you need to show it the right shape."

Adds Graham: "We thought we already had potent monoclonal antibodies or neutralizing antibodies for RSV but these ones were 100 to 1000 times more potent."

They two scientists published a paper detailing their success in 2013, showcasing their new technologies and how they could help usher in a new age in vaccine development that involves creating custom-made antibody recipes and turning them into vaccines that can be mass produced. The vaccine entered human Phase III clinical trials in late 2020, and results are expected next year.

By the time the RSV paper was published, Graham, McLellan and their collaborators had already begun modifying their approach to prepare for pandemics. When a virus capable of sparking a deadly new respiratory infection broke out in the Arabian Peninsula, called the Middle East respiratory syndrome (MERS), Graham and McLellan used their new technique to create a vaccine that attacked the spike-like proteins on the MERS virus. It was never approved for human use—MERS had died out before human trials could begin—but it later formed the basis for their work on the COVID-19 vaccine.

After the MERS outbreak, Graham also approached his boss, Dr. Anthony Fauci, who is head of National Institute of Allergy and Infectious Diseases, about developing a blueprint for an arsenal of new tools to protect against future pandemics. His plan—which he officially unveiled in a paper published in the summer of 2019 titled a "Prototype Pathogen Approach for Pandemic Preparedness"—called for the NIH to develop vaccine prototypes and stockpile the materials needed to make them for at least one representative pathogen in each of the 26 viral families known to infect humans—including influenza and coronaviruses. By the time the paper came out, Graham had already begun a collaboration with Moderna to demonstrate the feasibility of a prototype vaccine for coronavirus.

Then the pandemic hit. When Chinese researchers published the genome of COVID-19 in early January, McLellan and Graham quickly pulled out their plans for the MERS vaccine and copied the genetic instructions used to stabilize the virus' grappling-hook protein. Then they incorporated these spike-stiffening genetic tweaks into a vaccine they believed would work against COVID-19 and shipped it off to colleagues at Moderna and some other drug manufacturers. "We started all this before we had the first case in the United States," Graham says.

Graham is hoping the success of the COVID-19 vaccine will create momentum to move ahead with a unified effort to develop prototype vaccines that protect against future pandemics. In the meantime, the battle to keep pace with the current virus, SARS-CoV-2, and prepare for new unrelated coronavirus pathogens has continued. The new tools of structural protein design continue to play a key role.

Last spring, McLellan published a second-generation version of his stabilized spike protein vaccine design which makes even more changes in the structure of the synthetic spikes that makes them even more immobile—and seems to create an even more potent immune response against the COVID-19 virus. The added potency makes it easier to manufacture using the existing infrastructure than developing nations rely upon to make annual flu vaccines, which could help solve the supply bottleneck that has many nations lagging behind the United States in vaccination efforts. Vietnam, Thailand, Brazil and Mexico all have launched clinical trials to test out the new techniques.

Meanwhile, western pharmaceutical companies manufacturing vaccines have begun exploring ways to ensure their existing COVID-19 immunizations are effective against newly emergent variants.

Andrea Carfi, head of infectious disease research at Moderna, says the company has been closely monitoring variants. "Among all the variants that we have looked at so far—the variant in California, the variant from New York, the variant from the UK and the South African variant—the one that raises most of the concerns is the one that was identified in South Africa," he says. The South African variant is the one most likely to develop the ability to escape the immune protection of the initial vaccine, due to the way its genetic mutations change the shape of the spike proteins antibodies use to identify it. Moderna currently is testing three different approaches against it: one is to inject subjects with a third dose of the original vaccine in the hope of increasing the number of antibodies in circulation that will neutralize it; a second approach uses a vaccine based on a separate spike structure of South African variant designed to elicit antibodies against its unique shape; the third approach combines the old original vaccine with the South African variant.
In the long run, however, a universal coronavirus vaccine is perhaps the best way to protect against new strains, since it would also work against novel strains.

In his lab, McLellan has identified a portion of the spike protein that appears to be highly conserved in multiple coronaviruses. But he has only just begun experimenting with ways of creating a stable protein structure that will stay in one shape long enough to elicit the desired antibodies.

Researchers in other labs have also identified promising targets. In 2014, a pair of scientists at the University of Dhaka in Bangladesh identified a portion of an enzyme present in all known human coronaviruses. Researchers at the University of Virginia have found a part of the SARS2 spike protein that appears to persist among many of the variants. A vaccine that targets this part was able to protect pigs from both COVID-19 and another coronavirus that gives pigs diarrhea. And researchers at the University of North Carolina, isolated antibodies in the blood of an individual who had survived SARS1 that appeared to offer protection against SARS2, suggesting molecules common to viruses.

One of the most clinically advanced efforts is being developed by VBI Vaccines Inc., a biotechnology firm based in Cambridge, Massachusetts. In recent months it has received tens of millions of dollars in research grants to develop a mechanism of delivering custom-designed proteins to the immune system that closely resemble native pathogens. They are preparing to test new vaccines in humans that would protect against the South African variants and would only require one dose—human trials could begin later this year.

The company has demonstrated in mice that a single vaccine also in development using this technology can provoke an immune response against SARS2, SARS1 and MERS virus and had the added benefit of protecting against a coronavirus that is responsible for 42 percent of common colds. "If you think about those spike proteins as being the three primary colors, red, yellow and blue, we showed that exposing mice to them could also produce neutralizing antibodies of orange," says Jeff Baxter, the company's CEO.

At the NIH, meanwhile, Graham is also working to develop a pan or universal COVID vaccine. For the last five years, he has been collaborating with Neil King, a University of Washington structural protein biologist, who has developed a technique to make custom designed, self-assembling nanoparticles that resemble microscopic soccer balls. Instead of a mosaic of black and white pentagrams, however, their surface displays 20 different varieties of distinctly-shaped, spike-like proteins, which resemble those present on different varieties of coronaviruses. When introduced into the human body through a vaccine, the nanoparticles will hopefully train the immune system to recognize and attack all of the proteins in the mosaic, and many in between. King relies on computational techniques to determine which varieties are most likely to elicit a response that will work against viruses with different shapes on their spikes.

Prior to COVID-19, King and Graham had already begun testing one version in mice, complete with six different varieties of coronavirus spikes—one from SARS, MERS and four other common varieties. The hope is that any new varieties of novel coronaviruses to arise in the years ahead will prove sufficiently similar to at least one of the six different inoculated strains for the body to recognize them as dangerous and attack.

"If this approach works, we'll have made a broadly protective coronavirus vaccine," says King. "We're going to get it. It's just a matter of blood, sweat and tears. And money."

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