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Mice that received a vaccine made from a hybrid spike protein have resisted infection with several coronaviruses, the researchers report.
HHMI scientists are joining many of their colleagues around the world in the fight against the novel coronavirus. They develop diagnostic tests, understand basic virus biology, model epidemiology, and develop potential therapies or vaccines. We will be share stories of some of this work.
Mixing and matching chunks of viral proteins in a single vaccine could offer broader protection against coronaviruses.
Similar to connecting LEGO bricks, scientists can connect different parts of the “spike protein” – the molecule that protrudes from coronaviruses like a pointed crown. A vaccine that contains advanced components of four coronaviruses, including SARS-COV-2, protected mice against the four viruses and other related coronaviruses, David Martinez and colleagues at Howard Hughes Medical Institute Hanna Gray Fellow reported on June 22, 2021, in the journal Science.
The vaccine’s success in mice suggests that a similar strategy in humans could potentially offer protection against future outbreaks, says Martinez, an immunologist at the University of North Carolina at Chapel Hill. Coronaviruses circulate in animals, from bats to cattle, although scientists have yet to determine the extent of their genetic diversity. They know that viruses can sometimes jump into people. In 2003, a coronavirus epidemic caused the SARS epidemic; a related coronavirus sparked the ongoing pandemic. These two viruses are very similar to those that infect bats.
“The fact that we’ve had two coronavirus outbreaks in the past two decades tells us that this is something that can continue to happen,” Martinez said. “We need to find ways to design vaccines that can mitigate the threat of these viruses. “
The findings of Martinez’s team “are an important step towards a vaccine against the coronavirus,” says Melanie Ott, a virologist at the Gladstone Institute of Virology who was not involved in the work. She points out that the researchers’ mix-and-match approach appears to be largely protective against several coronaviruses in mice, providing a level of protection that current vaccines cannot provide.
Future threats
As COVID-19 began to spread around the world in early 2020, the world was waiting for a vaccine that could protect against the coronavirus that caused the disease. Even as safe and effective vaccines became available and vaccinations increased, scientists warned that new variants could break the vaccine’s protection. So far, current coronavirus vaccines appear to resist variants. But researchers around the world are working to make vaccines that could protect against as yet undiscovered coronaviruses.
The vaccines created by Moderna, Pfizer and BioNTech work by giving human cells a strand of messenger RNA. This mRNA serves as a template that cells use to make the SARS-CoV-2 spike protein. On its own, the spike protein is harmless, but it can stimulate the immune system, which begins to make antibodies against it. Later, if a vaccinated person encounters SARS-CoV-2, their body will be ready to fight, as their antibodies are already watching 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 – a protein not found in any virus.
“We took advantage of the fact that the coronavirus spike protein is modular,” says Martinez. Instead of creating a strand of mRNA that encodes an entire spike protein, they created four different mRNAs, each with segments from three different coronavirus spikes. They chose segments of the 2003 SARS virus, the 2019 virus (SARS-CoV-2), and two bat coronaviruses that can infect human cells but have not yet caused an outbreak. The team first published their results on the bioRxiv preprint server 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 parts of proteins from different coronaviruses. Despite the lag, the mouse’s immune system still recognized these rearranged proteins. After inoculating mice with the hybrid spike vaccine, the animals produced effective antibodies against each of the component spike proteins.
The inoculated mice were protected against the coronaviruses whose advanced protein subunits were in the vaccine – and they also resisted two other viruses, including B.1.351 (now known as the ‘beta’ variant). The finding inspires optimism for the team’s strategy, Martinez says, as it suggests that the antibodies generated by the spiked hybrid vaccines could protect against a wide assortment of potential coronaviruses.
Proof of concept
Martinez’s team vaccine used the same mRNA technology that made the Moderna and Pfizer-BioNTech vaccines so successful. Because mRNA is easy to make, once scientists find an optimal peak protein combo, mass production should be straightforward. Before the vaccine goes into human testing, however, Martinez’s team will be conducting studies in larger animals to verify safety and efficacy. These animal studies are still in the planning stage, so human trials could still take months.
Although the inoculated mice were not protected against all types of coronavirus, the vaccine was very effective against “Sarbecoviruses,” the subgroup that includes SARS and SARS-CoV-2. The mice also produced antibodies against more distant coronaviruses, including the MERS virus.
“We are trying to find a way to generate a vaccine that can protect against this subgroup that we know to be at high risk,” Martinez said. “And we’ve shown that, preclinically, this approach can work. “
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DR Martinez et al. “Chimeric spiked mRNA vaccines protect against Sarbecovirus challenge in mice. ” Science. Published online June 22, 2021. doi: 10.1126 / science.abi4506
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