A novel trial vaccine created by scientists at MIT and Caltech may provide defense against newly arising variants of SARS-CoV-2, in addition to related coronaviruses, termed sarbecoviruses, which might transition from animals to humans.

Apart from SARS-CoV-2, the pathogen responsible for COVID-19, sarbecoviruses—a subgroup of coronaviruses—encompass the virus that caused the original SARS outbreak in the early 2000s. Currently circulating sarbecoviruses in bats and other mammals might also have the capacity to infect humans in the time to come.

By attaching as many as eight distinct forms of sarbecovirus receptor-binding proteins (RBDs) to nanoparticles, the investigators developed a vaccine that produces antibodies recognizing areas of RBDs that generally remain stable across all viral strains. This significantly complicates the ability of viruses to mutate and evade antibodies induced by the vaccine.

“This research illustrates how the combination of computational methods and immunological trials can yield productive outcomes,” states Arup K. Chakraborty, the John M. Deutch Institute Professor at MIT and a member of MIT’s Institute for Medical Engineering and Science, along with the Ragon Institute of MIT, MGH, and Harvard University.

Chakraborty, along with Pamela Bjorkman, a biology and biological engineering professor at Caltech, are the principal authors of the investigation, which is published today in Cell. The leading authors of the paper include Eric Wang PhD ’24, Caltech postdoc Alexander Cohen, and Caltech graduate student Luis Caldera.

Mosaic nanoparticles

The recent study expands upon a project initiated in Bjorkman’s lab, where she and Cohen designed a “mosaic” 60-mer nanoparticle that displays eight different sarbecovirus RBD proteins. The RBD is a section of the viral spike protein crucial for the virus’s entry into host cells and is typically the target for antibodies against sarbecoviruses.

RBDs encompass regions that are subject to variability and can mutate easily to avoid antibodies. The majority of antibodies from mRNA COVID-19 vaccines focus on these variable areas because they are more readily accessible. This presents one reason why mRNA vaccines require updates to address the emergence of new strains.

If scientists could develop a vaccine that encourages the production of antibodies targeting RBD regions resistant to easy changes and shared across various viral strains, it could deliver broader defense against multiple sarbecoviruses.

Such a vaccine would need to provoke B cells that possess receptors (which later form antibodies) aimed at these shared, or “conserved,” areas. When B cells circulating throughout the body encounter a vaccine or other antigen, their B cell receptors—each featuring two “arms”—are activated more efficiently if two antigen copies are available for binding to each arm. The conserved areas are generally less accessible to B cell receptors, meaning that if a nanoparticle vaccine presents solely one form of RBD, B cells with receptors targeting the more accessible variable regions are more likely to be activated.

To tackle this challenge, the Caltech researchers devised a nanoparticle vaccine exhibiting 60 copies of RBDs from eight related sarbecoviruses that exhibit different variable areas but similar conserved aspects. Given that eight distinct RBDs are presented on each nanoparticle, it’s improbable for any two identical RBDs to be adjacent. Thus, when a B cell receptor encounters the nanoparticle immunogen, the likelihood of activation increases if its receptor recognizes the conserved regions of the RBD.

“The principle behind the vaccine is that by simultaneously presenting all these different RBDs on the nanoparticle, you are favoring B cells that recognize the conserved regions they share,” explains Cohen. “As a result, you’re promoting B cells that are more cross-reactive. Consequently, the antibody response would be more broadly reactive, potentially leading to broader protection.”

In animal studies, the researchers demonstrated that this vaccine, termed mosaic-8, produced robust antibody responses against diverse variants of SARS-CoV-2 and other sarbecoviruses, providing protection from challenges posed by both SARS-CoV-2 and SARS-CoV (original SARS).

Broadly neutralizing antibodies

Following the publication of these studies in 2021 and 2022, the Caltech researchers collaborated with Chakraborty’s lab at MIT to explore computational techniques that could help them identify RBD combinations yielding even stronger antibody responses against a broader range of sarbecoviruses.

Under Wang’s leadership, the MIT team pursued two distinct strategies—first, undertaking a large-scale computational evaluation of numerous possible mutations to the RBD of SARS-CoV-2, and secondly, analyzing naturally occurring RBD proteins from zoonotic sarbecoviruses.

For the initial method, the researchers started with the original SARS-CoV-2 strain and generated sequences of around 800,000 RBD candidates by substituting at locations that are known to influence antibody binding to variable sections of the RBD. They then evaluated those candidates for stability and solubility to ensure they could endure attachment to the nanoparticle and be administered as a vaccine.

Out of the remaining candidates, the researchers selected 10 based on the variance of their variable regions. They subsequently utilized these to produce mosaic nanoparticles coated with either two or five different RBD proteins (designated mosaic-2_COM and mosaic-5_COM).

In their second method, instead of altering the RBD sequences, the team chose seven naturally occurring RBD proteins, employing computational approaches to select those RBDs differing in their variable areas while preserving their conserved features. They utilized these to create another vaccine, mosaic-7_COM.

Once the researchers fabricated the RBD-nanoparticles, they assessed each in mice. After three doses of one of the vaccines were administered to every mouse, the team analyzed the efficacy of the resulting antibodies in binding to and neutralizing seven variants of SARS-CoV-2 as well as four other sarbecoviruses.

They also made comparisons between the mosaic nanoparticle vaccines and a nanoparticle displaying a single type of RBD, along with the original mosaic-8 particle from their prior studies in 2021, 2022, and 2024. They discovered that mosaic-2_COM and mosaic-5_COM surpassed the performance of both earlier vaccines, while mosaic-7_COM exhibited the best responses overall. Mosaic-7_COM prompted antibodies that bound effectively to most of the viruses examined, with those antibodies also able to inhibit viral entry into cells.

The researchers noted similar outcomes when they evaluated the novel vaccines in mice previously vaccinated with a bivalent mRNA COVID-19 vaccine.

“We aimed to replicate the scenario where individuals have already been infected and/or vaccinated against SARS-CoV-2,” Wang explains. “In pre-vaccinated mice, mosaic-7_COM consistently generated the highest binding titers for both SARS-CoV-2 variants and other sarbecoviruses.”

Bjorkman’s laboratory has received support from the Coalition for Epidemic Preparedness Innovations to conduct a clinical trial of the mosaic-8 RBD-nanoparticle. They also aspire to advance mosaic-7_COM, which performed better in the current investigation, into clinical testing. The researchers plan to focus on reengineering the vaccines for administration as mRNA, facilitating their production.

This research received funding from 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.