A new experimental vaccine developed by researchers at MIT and Caltech could offer protection against emerging variants of SARS-CoV-2, as well as related coronaviruses, known as sarbecoviruses, that could spill over from animals to humans.
In addition to SARS-CoV-2, the virus that causes COVID-19, sarbecoviruses - a subgenus of coronaviruses - include the virus that led to the outbreak of the original SARS in the early 2000s. Sarbecoviruses that currently circulate in bats and other mammals may also hold the potential to spread to humans in the future.
By attaching up to eight different versions of sarbecovirus receptor-binding proteins (RBDs) to nanoparticles, the researchers created a vaccine that generates antibodies that recognize regions of RBDs that tend to remain unchanged across all strains of the viruses. That makes it much more difficult for viruses to evolve to escape vaccine-induced antibodies.
"This work is an example of how bringing together computation and immunological experiments can be fruitful," says Arup K. Chakraborty, the John M. Deutch Institute Professor at MIT and a member of MIT's Institute for Medical Engineering and Science and the Ragon Institute of MIT, MGH and Harvard University.
Chakraborty and Pamela Bjorkman, a professor of biology and biological engineering at Caltech, are the senior authors of the study, which appears today in Cell . The paper's lead authors are Eric Wang PhD '24, Caltech postdoc Alexander Cohen, and Caltech graduate student Luis Caldera.
Mosaic nanoparticles
The new study builds on a project begun in Bjorkman's lab, in which she and Cohen created a "mosaic" 60-mer nanoparticle that presents eight different sarbecovirus RBD proteins. The RBD is the part of the viral spike protein that helps the virus get into host cells. It is also the region of the coronavirus spike protein that is usually targeted by antibodies against sarbecoviruses.
RBDs contain some regions that are variable and can easily mutate to escape antibodies. Most of the antibodies generated by mRNA COVID-19 vaccines target those variable regions because they are more easily accessible. That is one reason why mRNA vaccines need to be updated to keep up with the emergence of new strains.
If researchers could create a vaccine that stimulates production of antibodies that target RBD regions that can't easily change and are shared across viral strains, it could offer broader protection against a variety of sarbecoviruses.
Such a vaccine would have to stimulate B cells that have receptors (which then become antibodies) that target those shared, or "conserved," regions. When B cells circulating in the body encounter a vaccine or other antigen, their B cell receptors, each of which have two "arms," are more effectively activated if two copies of the antigen are available for binding to each arm. The conserved regions tend to be less accessible to B cell receptors, so if a nanoparticle vaccine presents just one type of RBD, B cells with receptors that bind to the more accessible variable regions, are most likely to be activated.
To overcome this, the Caltech researchers designed a nanoparticle vaccine that includes 60 copies of RBDs from eight different related sarbecoviruses, which have different variable regions but similar conserved regions. Because eight different RBDs are displayed on each nanoparticle, it's unlikely that two identical RBDs will end up next to each other. Therefore, when a B cell receptor encounters the nanoparticle immunogen, the B cell is more likely to become activated if its receptor can recognize the conserved regions of the RBD.
"The concept behind the vaccine is that by co-displaying all these different RBDs on the nanoparticle, you are selecting for B cells that recognize the conserved regions that are shared between them," Cohen says. "As a result, you're selecting for B cells that are more cross-reactive. Therefore, the antibody response would be more cross-reactive and you could potentially get broader protection."
In studies conducted in animals, the researchers showed that this vaccine, known as mosaic-8, produced strong antibody responses against diverse strains of SARS-CoV-2 and other sarbecoviruses and protected from challenges by both SARS-CoV-2 and SARS-CoV (original SARS).
Broadly neutralizing antibodies
After these studies were published in 2021 and 2022, the Caltech researchers teamed up with Chakraborty's lab at MIT to pursue computational strategies that could allow them to identify RBD combinations that would generate even better antibody responses against a wider variety of sarbecoviruses.
Led by Wang, the MIT researchers pursued two different strategies - first, a large-scale computational screen of many possible mutations to the RBD of SARS-CoV-2, and second, an analysis of naturally occurring RBD proteins from zoonotic sarbecoviruses.
For the first approach, the researchers began with the original strain of SARS-CoV-2 and generated sequences of about 800,000 RBD candidates by making substitutions in locations that are known to affect antibody binding to variable portions of the RBD. Then, they screened those candidates for their stability and solubility, to make sure they could withstand attachment to the nanoparticle and injection as a vaccine.
From the remaining candidates, the researchers chose 10 based on how different their variable regions were. They then used these to create mosaic nanoparticles coated with either two or five different RBD proteins (mosaic-2COM and mosaic-5COM).
In their second approach, instead of mutating the RBD sequences, the researchers chose seven naturally occurring RBD proteins, using computational techniques to select RBDs that were different from each other in regions that are variable, but retained their conserved regions. They used these to create another vaccine, mosaic-7COM.
Once the researchers produced the RBD-nanoparticles, they evaluated each one in mice. After each mouse received three doses of one of the vaccines, the researchers analyzed how well the resulting antibodies bound to and neutralized seven variants of SARS-CoV-2 and four other sarbecoviruses.
They also compared the mosaic nanoparticle vaccines to a nanoparticle with only one type of RBD displayed, and to the original mosaic-8 particle from their 2021, 2022, and 2024 studies. They found that mosaic-2COM and mosaic-5COM outperformed both of those vaccines, and mosaic-7COM showed the best responses of all. Mosaic-7COM elicited antibodies with binding to most of the viruses tested, and these antibodies were also able to prevent the viruses from entering cells.
The researchers saw similar results when they tested the new vaccines in mice that were previously vaccinated with a bivalent mRNA COVID-19 vaccine.
"We wanted to simulate the fact that people have already been infected and/or vaccinated against SARS-CoV-2," Wang says. "In pre-vaccinated mice, mosaic-7COM is consistently giving the highest binding titers for both SARS-CoV-2 variants and other sarbecoviruses."
Bjorkman's lab has received funding from the Coalition for Epidemic Preparedness Innovations to do a clinical trial of the mosaic-8 RBD-nanoparticle. They also hope to move mosaic-7COM, which performed better in the current study, into clinical trials. The researchers plan to work on redesigning the vaccines so that they could be delivered as mRNA, which would make them easier to manufacture.
The research was funded by a National Science Foundation Graduate Research Fellowship, the National Institutes of Health, Wellcome Leap, the Bill and Melinda Gates Foundation, the Coalition for Epidemic Preparedness Innovations, and the Caltech Merkin Institute for Translational Research.
