Exciting advancements in vaccine development have emerged from collaborative research at MIT and Caltech, focusing on a novel experimental vaccine designed to combat emerging variants of SARS-CoV-2, alongside related coronaviruses known as sarbecoviruses, which have the potential to infect humans from animal sources.
Sarbecoviruses encompass the virus responsible for COVID-19 as well as the one that caused the original SARS outbreak in the early 2000s. Variants circulating in bats and other mammals pose future risks for human transmission. Given this context, the new vaccine aims to generate robust immunity against these threats.
The innovative approach involves attaching up to eight different versions of sarbecovirus receptor-binding proteins (RBDs) to nanoparticles. This strategy aims to elicit antibodies that target the conserved regions of RBDs, which largely remain stable across various viral strains, making it difficult for viruses to evolve and evade vaccine-induced immunity.
Arup K. Chakraborty, an esteemed professor at MIT, emphasizes, “This work illustrates how the convergence of computational modeling and immunological research can yield significant breakthroughs.” Chakraborty and Caltech’s Pamela Bjorkman spearheaded the study published today in Cell, with contributions from lead authors Eric Wang, Alexander Cohen, and Luis Caldera from Caltech.
Exploring Mosaic Nanoparticles
This groundbreaking study builds upon earlier initiatives in Bjorkman’s lab, where researchers devised a “mosaic” 60-mer nanoparticle displaying eight different sarbecovirus RBD proteins. The RBD, located within the spike protein of the virus, is crucial for viral entry into host cells and is also the primary target for antibody responses against sarbecoviruses.
Typically, RBDs have variable regions that mutate frequently to escape neutralization by antibodies. Most antibodies generated by conventional vaccines, like mRNA COVID-19 vaccines, tend to target these variable domains, necessitating ongoing updates to maintain vaccine efficacy against new viral strains.
What if a vaccine could focus on inducing antibodies that recognize stable, conserved areas of the RBD? Such a vaccine could provide broader protection not just against SARS-CoV-2 but also against a variety of sarbecoviruses. To achieve this, researchers are aiming to activate B cells that self-generate antibodies targeting these fundamental regions.
The B cell receptors have a dual binding capacity, making them more effectively activated when encountering a structure with multiple antigen copies. The newly developed nanoparticle vaccine, with its array of diverse RBDs, heightens the likelihood that B cells will respond to these vital, conserved regions.
“By presenting various RBDs on the nanoparticle, we can more effectively stimulate B cells that target shared conserved regions,” says Cohen. “This increases the chances of obtaining antibodies that can cross-react with various strains, thus enhancing protective efficacy.”
Animal studies illustrate that this vaccine, identified as mosaic-8, provoked strong immune responses against a wide range of SARS-CoV-2 and other sarbecoviruses, including protection from the original SARS strain.
Harnessing Broadly Neutralizing Antibodies
Following promising results from previous studies, the collaboration with Chakraborty’s lab at MIT propelled efforts to leverage computational strategies for discovering RBD combinations that yield even improved antibody responses. This initiative harnessed two approaches: a massive computational screening of potential RBD mutations and an analysis of naturally occurring RBD variants from zoonotic sarbecoviruses.
In the initial approach, researchers began with the original SARS-CoV-2 strain, generating an array of around 800,000 potential RBD variants by adjusting known antibody-binding sites. These candidates were subsequently screened for stability and solubility to ensure vaccine viability, leading to the selection of the 10 most varied candidates for creating new mosaic nanoparticles.
For the second method, the team sourced natural RBD proteins known for their variation in variable regions while preserving conserved areas. This led to the development of another promising vaccine, mosaic-7COM.
These RBD-nanoparticles underwent evaluation in mice, where researchers administered three doses and analyzed the antibodies’ effectiveness against diverse SARS-CoV-2 variants and additional sarbecoviruses. The results indicated that mosaic-2COM and mosaic-5COM surpassed previous vaccine iterations, with mosaic-7COM demonstrating the most remarkable antibody responses. Antibodies induced by mosaic-7COM displayed effective binding to most tested viruses and inhibited viral entry into cells.
Remarkably, in pre-vaccinated mice—simulating real-world conditions where individuals may have prior COVID-19 exposures—mosaic-7COM consistently produced the highest antibody titers against both SARS-CoV-2 variants and other sarbecoviruses.
The Bjorkman lab has secured funding from the Coalition for Epidemic Preparedness Innovations, aiming to initiate clinical trials for their mosaic-8 RBD-nanoparticle. Future endeavors may direct mosaic-7COM into clinical trials, with ongoing efforts to re-engineer these vaccines for easier mRNA delivery.
This research received funding from several esteemed bodies, including the National Science Foundation, National Institutes of Health, Wellcome Leap, the Bill and Melinda Gates Foundation, and the Coalition for Epidemic Preparedness Innovations.
Photo credit & article inspired by: Massachusetts Institute of Technology
