A new experimental vaccine developed by researchers at MIT and the California Institute of Technology may be able to protect against emerging variants of SARS-CoV-2 that can jump from animals to humans, as well as related coronaviruses called sarbecoviruses.
In addition to SARS-CoV-2, the virus that causes COVID-19, the sarbecoviruses, a subgenus of coronaviruses, include the virus that caused the first SARS outbreak in the early 2000s. Sarbecoviruses that are currently circulating in bats and other mammals may also spread to humans in the future.
By attaching up to eight different sarbecovirus receptor-binding proteins (RBDs) to nanoparticles, the researchers created a vaccine that generates antibodies that recognize regions of the RBDs that tend to be constant across all virus strains, making it much more difficult for the virus to evolve to evade the antibodies generated by the vaccine.
“This work is an example of how powerful it can be to combine computational and immunological experiments,” said Arup K. Chakraborty, the John M. Deutch Institute Professor at MIT and a member of the MIT Institute for Medical Engineering and Science and the Ragon Institute at MIT, MGH and Harvard.
Chakraborty and Pamela Bjorkman, professor of biology and bioengineering at Caltech, are lead authors of the study, which was published today in the journal Cell . Lead authors of the paper are Dr. Eric Wang (Class of ’24), Caltech graduate student Alexander Cohen, and Caltech graduate student Luis Caldera.
Mosaic Nanoparticles
The new work builds on a project initiated in Bjorkman’s lab, in which he and Cohen created “mosaic” 60-mer nanoparticles expressing eight different sarbecovirus RBD proteins. The RBD is part of the viral spike protein that helps the virus enter host cells. It is also the region of the coronavirus spike protein that is often targeted by antibodies against sarbecoviruses.
The RBD contains multiple variable regions that can easily mutate to circumvent antibody resistance. Most of the antibodies generated by mRNA COVID-19 vaccines target these variable regions because they are more accessible. This is one of the reasons why mRNA vaccines need to be updated to keep up with the emergence of new strains.
If researchers can develop a vaccine that stimulates antibody production that targets the RBD region, which does not change easily and is shared among virus strains, it could provide broader protection against different sarbecoviruses.
Such vaccines must stimulate B cells with receptors (which then become antibodies) that target shared or “conserved” regions. When B cells circulating in the body encounter a vaccine or other antigen, B cell receptors, each with two “arms,” are activated more efficiently if there are two copies of the antigen that can bind to each arm. Conserved regions tend to be less accessible to B cell receptors, so if a nanoparticle vaccine expresses only one type of RBD, B cells whose receptors bind to the more accessible variable regions are most likely to be activated.
To overcome this, researchers at Caltech designed a nanoparticle vaccine consisting of 60 copies of the RBDs of eight related sarbecoviruses that have different variable regions but similar conserved regions. Because each nanoparticle displays eight different RBDs, it is highly unlikely that two identical RBDs will be placed next to each other. Thus, when a B cell receptor encounters the nanomolecule immune molecule, if that receptor can recognize a conserved region of the RBD, the B cell is more likely to be activated.
“The idea behind this vaccine is that by displaying all these different RBDs simultaneously on a nanoparticle, you’re selecting for B cells that recognize the conserved regions that are shared between them,” Cohen said. “As a result, you’re selecting for B cells that are more cross-reactive. So your antibody response will be more cross-reactive and you’re more likely to get broader protection.”
In animal studies, the researchers showed that the vaccine, called Mosaic 8, generated strong antibody responses against multiple strains of SARS-CoV-2 and other sarbecoviruses and protected against infection from both SARS-CoV-2 and SARS-CoV (the original SARS).
Broadly neutralizing antibodies
Following the publication of these studies in 2021 and 2022, Caltech researchers collaborated with the Chakraborty lab at MIT to pursue computational strategies that could identify RBD combinations that could elicit better antibody responses against a broader range of sarbecoviruses.
Under Wang’s direction, the MIT researchers pursued two distinct strategies: first, a large-scale computational screening of many possible mutations in the SARS-CoV-2 RBD, and second, an analysis of the native RBD proteins of zoonotic sarbecoviruses.
In the first approach, the researchers started with the original SARS-CoV-2 strain and generated sequences of about 800,000 RBD candidates by making substitutions at positions known to affect the ability of antibodies to bind to different parts of the RBD. They then tested the stability and solubility of those candidates to ensure they could withstand attachment to nanoparticles and injection as a vaccine.
From the remaining candidates, the researchers selected 10 based on the degree of difference in their variable regions, and then used them to create mosaic nanoparticles coated with either two or five different RBD proteins (mosaic-2 COM and mosaic-5 COM
In the second approach, instead of mutating the RBD sequence, the researchers used computational techniques to select RBDs that differed in variable regions but left the conserved regions intact, selecting seven naturally occurring RBD proteins, which they used to create another vaccine, mosaic-7 COM .
After creating the RBD nanoparticles, the researchers evaluated each in mice. After administering three doses of the vaccine to each mouse, the researchers analyzed antibody binding and neutralization levels against seven SARS-CoV-2 variants and four other sarbecoviruses.
The researchers also compared the Mosaic nanoparticle vaccine to nanoparticles displaying only one type of RBD, as well as the original Mosaic 8 particles from studies in 2021, 2022, and 2024. They found that Mosaic-2 COM and Mosaic-5 COM performed better than both vaccines, while Mosaic-7 COM produced the best response of all vaccines. Mosaic-7 COM produced antibodies that bound to most of the viruses tested, and these antibodies were also able to block the viruses from entering cells.
The researchers saw similar results when they tested the new vaccine in mice that had previously been given a bivalent mRNA COVID-19 vaccine.
“We wanted to simulate the reality of people being infected with or vaccinated against SARS-CoV-2,” Wang said. “In pre-vaccinated mice, mosaic 7 COM consistently showed the highest levels of binding to both SARS-CoV-2 mutants and other sarbecoviruses.”
Bjorkman’s lab has received funding from the Coalition for Epidemic Preparedness Innovations to conduct clinical trials of the Mosaic 8 RBD nanoparticles. They also hope to bring Mosaic 7 COM , which showed better results in the current study, into clinical trials. The researchers plan to redesign the vaccine so it can be administered as mRNA, making it easier to manufacture.
The research was funded by a National Science Foundation Graduate Research Fellowship, the National Institutes of Health, Wellcome Leap, the Bill & Melinda Gates Foundation, the Coalition for Epidemic Preparedness Innovations and the Caltech Merkin Institute for Translational Research.
