Long before COVID-19 changed everyday life, scientists were aware of the possibility that a coronavirus could make the leap from an animal species to the human population.
How different the past few years would have been if a vaccine that can block the SARS-CoV-2 virus had been administered to workers at the Huanan Market in Wuhan, China — where, scientists suspect, a raccoon dog infected a seller and sparked a pandemic that killed more than 6.3 million people worldwide.
A new type of vaccine developed at Caltech aims to ward off new coronaviruses even before health officials know they exist. When tested on mice and monkeys, it trained the animals’ immune systems to recognize eight viruses at a time — and triggered immunity against viruses they’d never encountered before.
The findings, published Tuesday in the journal Science, could lead to a powerful tool against a virus that mutates too quickly to be contained with current vaccines. An international vaccine foundation has pledged $30 million to begin clinical trials of the experimental vaccine in humans.
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“We’ve had three pandemics or epidemics in the last 20 years: first SARS, then MERS, and then SARS-CoV-2,” said Caltech biochemist Pamela Bjorkman, who led the new work. More outbreaks caused by “spillover events” are inevitable, she said, and “we want to protect ourselves now from the future spillover.”
dr. Anthony Fauci, President Biden’s chief adviser on the COVID-19 pandemic, praised the research as “an important conceptual step toward a pan-coronavirus vaccine.”
“It’s a very, very important proof-of-concept,” he said, noting that it remains to be seen whether it works as well in humans as it does in lab animals. “That’s why you’re doing the experiment.”
The new vaccine does not block all coronaviruses, an ambitious goal that is not yet within the reach of science. Instead, it targets the group known as beta-coronaviruses, which include those that cause COVID-19, severe acute respiratory syndrome, and Middle Eastern respiratory syndrome, among others.
Rather than using a piece of inactivated virus or a lab-made molecule designed to mimic one found in nature, the Caltech researchers created a microscopic piece of matter that they could decorate however they wanted. Their nanoparticle consists of proteins with sticky pieces on their surface, to which researchers can attach even smaller pieces of viruses.
The team tested three versions of the nanoparticle. One was covered with pieces of SARS-CoV-2. A “mosaic” version had SARS-CoV-2 plus samples from seven other coronaviruses, including one that causes MERS and other strains found in bats and pangolins. The latter was bald, to serve as a check.
When looking for bits of viruses to cut and attach, the team focused on a portion of the spike protein called the receptor binding domain, or RBD. This is the portion that is typically targeted by the immune system’s neutralizing antibodies, whether generated in response to a vaccine or previous infection.
Since the RBDs of betacoronaviruses share many traits, the researchers hoped the mosaic version would prompt the immune system to focus on parts common to all eight viruses. They further theorized that if these parts were shared by most or all of the beta-coronaviruses, the vaccine would trigger an immune response when presented to any member of the viral group — even those who weren’t among the samples.
They were right.
When designing their mosaic nanoparticle, they deliberately omitted SARS-CoV, the virus responsible for the severe acute respiratory syndrome. If the vaccine worked as intended, animals vaccinated with the mosaic nanoparticle and then exposed to SARS-CoV would elicit an immune response.
They did. In fact, the vaccinated mice and monkeys had little to no detectable virus in their systems, despite attempts to infect them with SARS-CoV or SARS-CoV-2.
“We are very excited about that,” said Bjorkman.
Such was not the case with the animals injected with the naked nanoparticle – they were unable to fight off viruses and died. The animals that received the vaccine containing only pieces of SARS-CoV-2 were protected against that virus, but had no protection against any other coronavirus, and most of them also died.
If the mosaic vaccine works as well in humans as it does in animals, it could provide protection against the beta-coronaviruses we know, as well as related viruses that have yet to make the leap to humans.
That prospect is promising, but far from certain.
The next step is a Phase 1 clinical trial in humans, the first hurdle to overcome when a new drug or vaccine is brought to market in the US. That will take place at Oxford University, home of Bjorkman’s staff on the project, and will probably take about a year at least.
The Coalition for Epidemic Preparedness Innovations said Tuesday it will foot the bill for the first trial, with the goal of establishing evidence that the vaccine is safe in humans.
“It’s certainly encouraging,” says Dr. Paul Offit, a virologist and immunologist at the University of Pennsylvania. “But these are animal model studies, and as scientists know, mice lie and monkeys exaggerate.”
“It’s hard to make universal vaccines work,” Offit added. “It’s not about lack of money. It is not for lack of desire or effort. It’s just really hard to do.”
This isn’t the only team in the US investigating nanoparticle vaccines for coronaviruses. Researchers at Duke University and the Walter Reed Army Institute of Research are also investigating them.
“These general approaches all use the receptor binding domain to elicit strong antibody responses that can neutralize the virus, so they all hold some promise,” says Dr. Stanley Perlman, a virologist and immunologist at the University of Iowa who specializes in beta-coronaviruses.
“This is a good approach based on what we know,” he said, “and you have to hope that it will be useful for viruses that we haven’t identified yet.”