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Mice that received a vaccine made from a hybrid spike protein resisted infection from several coronaviruses, researchers report.
Hanna Gray Fellow, Yale School of Medicine
Mice that received a vaccine made from a hybrid spike protein resisted infection from several coronaviruses, researchers report.

Mixing and matching viral protein pieces into a single vaccine could offer wider protection against coronaviruses.

Like connecting LEGO bricks, scientists can link together different parts of the “spike protein” – the molecule that protrudes from coronaviruses like a pointy crown. A vaccine that contains spike components from four coronaviruses, including SARS-COV-2external link, opens in a new tab, protected mice from the four viruses, and other, related coronaviruses, Howard Hughes Medical Institute Hanna Gray Fellow David Martinez and colleagues reported June 22, 2021, in the journal Science.

The success of the vaccine in mice suggests that a similar strategy in humans could potentially offer protection from future outbreaks, says Martinez, an immunologist at the University of North Carolina at Chapel Hill. Coronaviruses circulate in animals from bats to livestock, though scientists haven’t yet determined the extent of their genetic diversity. They do know the viruses can sometimes make the jump to people. In 2003, a coronavirus outbreak caused the SARS epidemic; a related coronavirus sparked the ongoing pandemic. Both these viruses closely resemble those that infect bats.

“The fact that we’ve had two coronavirus epidemics in the last two decades tells us this is something that can keep happening,” Martinez says. “We need to find ways to devise vaccines that can mitigate the threat from these viruses.”

Martinez’s team’s findings “are an important step towards a pan-coronavirus vaccine,” says Melanie Ott, a virologist at the Gladstone Institute of Virology who was not involved with the work. She points out that the researchers’ “mix-and-match” approach appears to be broadly protective against multiple coronaviruses in mice, offering a level of protection that current vaccines cannot provide.

Future threats

As COVID-19 began to spread worldwide in the early months of 2020, the world awaited a vaccine that could protect against the coronavirus that caused the disease. Even when safe and effective vaccines became available and vaccinations ticked up, however, scientists warned that new variants might break through the vaccine’s protection. So far, current coronavirus vaccines seem to be holding up against the variants. But researchers around the globe are working to make vaccines that could protect against yet undiscovered coronaviruses.

The vaccines created by Moderna and Pfizer and BioNTech work by giving people’s cells a strand of messenger RNA. This mRNA serves as a template that cells use to manufacture the SARS-CoV-2 spike protein. On its own, the spike protein is harmless, but it can rev up the immune system, which starts making antibodies against it. Later, if a vaccinated person encounters SARS-CoV-2, their body will be primed to fight, because their antibodies are already lying in wait for the virus.

To explore the idea that a single vaccine could inoculate against multiple coronaviruses, Martinez and his colleagues created a new spike protein – one that’s not found in any virus.

“We’ve taken advantage of the fact that the spike protein of coronavirus is modular,” Martinez says. Instead of making an mRNA strand that encodes an entire spike protein, they created four different mRNAs, each with segments from three different coronavirus spikes. They chose segments from the 2003 SARS virus, the 2019 virus (SARS-CoV-2), and two bat coronaviruses that can infect human cells but haven’t yet caused epidemics. The team first published their resultsexternal link, opens in a new tab on the preprint server bioRxiv in May. 

Like a LEGO minifigure with the legs of a cowboy, the torso of Spider-Man, and the helmet of an astronaut, each hybrid spike protein contained three protein parts from different coronaviruses. Despite the mismatch, the mouse immune system still recognized these reshuffled proteins. After inoculating mice with the hybrid spike vaccine, the animals produced antibodies effective against each of the component spike proteins.

Inoculated mice were protected from the coronaviruses whose spike protein subunits were in the vaccine – and they also resisted two other viruses, including B.1.351 (now known as the “beta” variant). That finding inspires optimism for the team’s strategy, Martinez says, because it suggests that antibodies generated by hybrid spike vaccines could protect against a broad assortment of potential coronaviruses.

Proof of concept

Martinez’s team’s vaccine used the same mRNA technology that made the Moderna and Pfizer-BioNTech vaccines so successful. Because mRNA is easy to manufacture, once scientists figure out an optimal spike protein combo, mass production should be straight-forward. Before the vaccine moves to human testing, though, Martinez’s team will conduct studies in larger animals to verify safety and efficacy. These animal studies are still in the planning stages, so trials in humans could still be months away.

Though inoculated mice weren’t protected against every kind of coronavirus, the vaccine was highly effective against “Sarbecoviruses,” the subgroup that includes SARS and SARS-CoV-2. The mice also produced antibodies against more distantly related coronaviruses, including the MERS virus.

“We’re trying to find a way to generate a vaccine that can protect against this subgroup that we know is high-risk,” Martinez says. “And we’ve showed that, preclinically, this approach can work.”



D.R. Martinez et al. “Chimeric spike mRNA vaccines protect against Sarbecovirus challenge in miceexternal link, opens in a new tab." Science. Published online June 22, 2021. doi: 10.1126/science.abi4506