The Search for One Vaccine to Rule Them All

Scientists are working on a ‘universal’ vaccine that could protect against a broad range of coronaviruses

The next pandemic was supposed to be influenza. After all, three flu pandemics occurred in the last century alone — the Spanish flu of 1918, Asian influenza in 1957, and the Hong Kong flu of 1968.

With the 21st century came the H5N1 avian flu. First, poultry and wild birds succumbed to it. By the mid-2000s, dozens of people in Southeast Asia fell ill, and around 60% of those who contracted it died. Governments predicted a pandemic and drew up preparedness plans, but it never arrived. Meanwhile, a different strain of flu was bubbling up halfway around the world.

In April 2009, the H1N1 swine flu began infecting people in Mexico and soon spread to the United States. Later that month, the World Health Organization (WHO) declared the first-ever “public health emergency of international concern.” Swine flu spread around the world quickly, and the WHO officially deemed the situation a pandemic in June.

The perpetual threat of an influenza pandemic led researchers like Matthew Memoli, MD, a virologist at the National Institute of Allergy and Infectious Diseases (NIAID), to pursue the idea of a universal flu vaccine — one that would ideally provide broad and long-lasting protection against any new influenza strain people might encounter year after year. His team’s research has shown promising results against seasonal flu.

Now, he’s taking what he’s learned and applying it to a new effort to make a universal vaccine to provide protection against multiple types of coronavirus — the family of viruses to which SARS-CoV-2 belongs.

A multitude of coronaviruses are lurking in bats and other animals, just waiting for the right opportunity to spill over and infect people. It’s not a matter of if but when, and the next outbreak could be even worse. WHO experts have warned that the current Covid-19 pandemic might not be the “big one” that scientists have anticipated.

“It’s clearly the time to start now to develop a universal coronavirus vaccine.”

“What we need to do in order to protect against all of these different potential threats is have a vaccine that offers you some protection, no matter what happens, no matter which virus appears in the population,” Memoli tells Future Human. Last May, Memoli published a commentary urging the scientific community to take up the cause of a universal coronavirus vaccine. The idea is finally gathering steam.

Memoli and his colleagues at NIAID have started work on a universal coronavirus vaccine, and so have other government, academic, and commercial labs. With the speed at which Covid-19 vaccines were developed, some think developing a universal coronavirus vaccine is not only possible but could be accomplished in the next few years.

“Collectively, studies now suggest that developing a universal coronavirus vaccine is scientifically feasible,” wrote Wayne Koff, PhD, CEO of the Human Vaccines Project, and Seth Berkley, MD, CEO of Gavi, the Vaccine Alliance, in a recent editorial in the journal Science.

At the virtual annual meeting of the American Association for the Advancement of Science on February 8, NIAID director Anthony Fauci, MD, underscored the need for such a vaccine. “It’s clearly the time to start now to develop a universal coronavirus vaccine.”

While the world was fixated on the flu, SARS broke out in China in 2003. Before that, coronaviruses were known to cause some cases of the common cold but nothing serious. The new SARS coronavirus was more alarming: Those infected with it developed severe respiratory symptoms. The virus killed nearly 800 people worldwide.

Another novel coronavirus, MERS, was identified in Saudi Arabia in 2012. Like its predecessor, it caused coughing, fever, and shortness of breath. It, too, was deadlier than the common cold, killing just under 900 people. And like SARS-CoV-2, both are believed to have originated in bats.

While many researchers rushed to develop a vaccine for SARS and then MERS, most efforts dwindled when the outbreaks were successfully contained.

But scientists studying coronaviruses have been sounding the alarm about the pandemic potential of a SARS-like coronavirus for years. In 2007, Chinese researchers warned: “The presence of a large reservoir of SARS-CoV-like viruses in horseshoe bats, together with the culture of eating exotic animals in southern China, is a time bomb.”

In 2015, researchers at the University of North Carolina at Chapel Hill led by coronavirus epidemiologist Ralph Baric, PhD, discovered a new SARS-like virus with the ability to jump directly from its bat hosts to humans. In Nature Medicine, they wrote, “Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.”

There are hundreds of coronaviruses circulating in bats, pigs, camels, and other animals. So far, only seven are known to infect people. But that’s likely just the tip of the iceberg. Under the right circumstances, those viruses could jump from animals to humans, causing a spillover event. And some may have the ability to spread from person to person.

“We can’t wait until it happens to think about what we can do,” says Maria Elena Bottazzi, PhD, associate dean of the National School of Tropical Medicine at Baylor College of Medicine. In 2016, she and her collaborators applied for federal funding to develop a vaccine that would protect against multiple coronaviruses. But by then, the threat of SARS and MERS had already passed. The group didn’t get the funding.

Now, the federal government is taking the threat of another coronavirus pandemic more seriously. The National Institutes of Health recently announced it will fund many projects to advance so-called “pan-coronavirus” vaccines — ones that could provide broad protection against multiple coronavirus strains at the same time.

Biochemist Pamela Björkman, PhD, and her team at the California Institute of Technology are trying to anticipate the next coronavirus spillover. Led by Alex Cohen, a graduate student in Björkman’s lab, they’ve designed a vaccine that targets SARS-CoV-2, as well as seven other coronaviruses found in bats and pangolins that aren’t yet known to infect people — but potentially could.

Vaccines work by training the immune system to recognize a pathogen so that when the body encounters it in the future, it will be primed to fight the invader. Current Covid-19 vaccines do this by spurring the body to make antibodies that target the spike protein. This protein plays a major role in infection by attaching to human cells and allowing SARS-CoV-2 to slip inside.

All coronaviruses have this characteristic spike on their surfaces, but the structure of the spike varies a bit from strain to strain. One approach to a universal vaccine would be to target the various spike proteins of many coronaviruses.

The Caltech team is doing this using a technology first developed at the University of Oxford called a mosaic nanoparticle. Shaped like a soccer ball, the nanoparticle is dotted with protein “tags” that function like pieces of Velcro. Taking fragments of the spike proteins from SARS-CoV-2 plus seven other coronaviruses, the researchers attached them to the tags on the nanoparticle. They then generated enough of these nanoparticles to make a vaccine for mice.

When they injected the mice with this “eight-coronavirus” vaccine, the animals generated antibodies against SARS-CoV-2 and the other coronaviruses, as expected. Much to their surprise though, the mice also made antibodies capable of neutralizing coronavirus strains that weren’t included in the vaccine. The results were published in the journal Science on January 12.

Most antibodies are specific to a certain pathogen, but scientists have found that the body makes some antibodies that are “broadly neutralizing.” In other words, they’re effective against multiple viral strains. That means it may be possible for a single shot to offer protection against a completely new coronavirus, even if the vaccine doesn’t target that exact virus.

“We can’t predict which virus might emerge next,” Björkman says. “But if we could raise these cross-reactive neutralizing antibodies, we think they will work against any new virus.” Though promising, the findings are very preliminary, and scientists don’t yet know how protective such a vaccine will be in people.

And just how “universal” a universal coronavirus vaccine will be is still unclear. A vaccine that’s effective against all coronaviruses is unlikely. They are too many and too diverse. The Caltech team wants to try adding up to 20 SARS-like coronaviruses to their vaccine. The nanoparticle they’re using has 60 Velcro-like tags , so conceivably, they could add even more. But Björkman thinks there’s probably a limit to how many virus strains a single vaccine can target.

“At a certain point, it won’t work as well,” she says. ‘But we don’t know what that point will be,” she says.

They plan to start testing their eight-coronavirus vaccine in larger animals, ideally monkeys. Once the animals are vaccinated, they will be divided into groups and exposed to SARS-CoV-2 and other coronaviruses, allowing researchers to observe how effective the vaccine is against each virus.

Kayvon Modjarrad, MD, PhD, thinks our current way of making vaccines is too reactive. We wait until a pathogen causes an outbreak, then scramble to make a vaccine against it. Once the immediate threat subsides, we abandon those efforts in favor of more pressing health concerns. Modjarrad, director of the Emerging Infectious Diseases Branch at Walter Reed Army Institute of Research in Silver Spring, Maryland, thinks we should be thinking more long term.

“The idea is to be proactive and have a vaccine that targets known variants, known strains, and known species but also anticipates ones we haven’t even seen yet,” he tells Future Human. He jokes that a pan-coronavirus vaccine could be “one vaccine to rule them all.”

Modjarrad’s lab is working on a nanoparticle-based vaccine that targets SARS, as well as several known variants of SARS-CoV-2. He says the experimental vaccine has shown encouraging results in monkeys, and a major company is interested in partnering with the Army on developing it. His team is preparing the data for publication.

Before Covid-19, a vaccine to protect against hypothetical threats didn’t get much traction outside of government and academic labs. For Big Pharma, there’s little incentive to manufacture a vaccine that may never be needed. Developing new vaccines is incredibly expensive compared to tweaking existing ones.

A major challenge for creating a universal flu vaccine has been that the virus constantly mutates — far more than coronaviruses do. And the parts of the flu virus that remain stable from year to year have proven more difficult to target with a vaccine. Despite decades of research, a universal flu vaccine doesn’t exist yet.

Complicating an already complex problem, researchers from Scripps Research Institute found that some common strains of influenza can mutate to evade broadly neutralizing antibodies thought to be able to block all flu strains. SARS-CoV-2 variants pose a similar conundrum to vaccine makers. If the spike protein changes too much, it could render our current Covid-19 vaccines ineffective. Already, our vaccines appear less effective against the more transmissible South African variant.

Some scientists think we can evade this problem by targeting sites of the virus other than the spike protein. The tricky part is identifying these sites across many types of coronavirus. One biotech company, Gritstone Oncology of Emeryville, California, is developing a Covid-19 vaccine that uses protein fragments from various coronaviruses to spur the production of antibodies, as well as virus-killing T cells — another type of immune cell. The approach could protect against new variants of SARS-CoV-2 and possibly other coronaviruses.

“Not all parts of the virus are going to be mutating,” Gigi Gronvall, PhD, an immunologist and senior scholar at the Johns Hopkins Center for Health Security, explained to reporters in a February 18 briefing. “There may be parts of the virus that are more stable.”

A universal coronavirus vaccine may depend on it.

Researchers working on a universal coronavirus vaccine imagine a future in which doses could be widely distributed across the globe and stockpiled by governments so that a vaccine would be immediately available in the event of a new outbreak. One way to ensure that is to formulate doses in ways that could be distributed more easily.

Baozhong Wang, PhD, a professor at the Institute for Biomedical Sciences at Georgia State University, is working on a micro-needle patch to administer a universal coronavirus vaccine. The patch works like putting a small Band-Aid on the skin. Its tiny needles prick into the skin painlessly and quickly dissolve, releasing the vaccine. It could be self-administered and wouldn’t require syringes or glass vials.

“The reward of abolishing the specters of these pandemics is of incalculable worth for humanity.”

Björkman says her team’s vaccine could be freeze-dried as a powder and stored at room temperature. That could make it easier to transport a vaccine to rural areas without reliable refrigeration. It could also allow countries to stockpile a universal vaccine — potentially for several years—without it spoiling.

Another benefit to the nanoparticle approach is that it’s a “plug and play” platform, says Cohen. “You can put any strain on this nanoparticle and mix and match for whatever you want.” So, if a new coronavirus becomes a threat in the future, it could be swapped out on the nanoparticle without the need to design an entirely new vaccine.

Tillman Gerngross, PhD, co-founder and CEO of New Hampshire-based biotech company Adimab, which is developing pan-coronavirus antibody drugs, thinks a universal coronavirus vaccine could be made quickly if there’s enough investment. “It used to take five to 10 years to develop a vaccine, and we’ve seen you can actually do it in less than a year,” he tells Future Human. “I would say something like that is possible within a year or two.”

Such an undertaking would likely require international collaboration among scientists and considerable investment from governments, industry, and philanthropy. In a commentary in the journal Nature earlier this month, Scripps researchers estimated that it would cost around $100 million to $200 million. The government has already spent more than $12 billion to bring Covid-19 vaccines to the public.

The payoff of such an effort could be immense, Wang says. “The reward of abolishing the specters of these pandemics is of incalculable worth for humanity.”

Former staff writer at Medium, where I covered biotech, genetics, and Covid-19 for OneZero, Future Human, Elemental, and the Coronavirus Blog.

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