
The rapidity of SARS-CoV-2 evolution and ongoing threat posed by homologous coronaviruses have underpinned a necessity for a more effective and pan-corona vaccine platform. An experimental new vaccine, designed at MIT and Caltech, employs nanoparticles to produce immune responses capable of neutralizing not only a variety of SARS-CoV-2 variants but a variety of additional sarbecoviruses—coronaviruses with spillover potential in humans. The new technology could transform pandemic preparedness, with reduced need for ongoing updating of vaccines and extended protection for new and emerging threats.
Understanding Sarbecoviruses and the Need for Wider Protection
Sarbecoviruses, a family of coronaviruses, encompass SARS virus, causative of an early 2000s epidemic, SARS-CoV-2, and a variety of similar viruses in circulation in bats and animals at present. With zoonotic spillover events increasingly a concern, development of vaccines effective for protection against a variety of sarbecoviruses is a key first step in pandemic preparedness.
Traditional mRNA-based vaccines, such as those developed by Pfizer-BioNTech and Moderna, have been effective at preventing severe SARS-CoV-2 infection but cause antibody responses that target variable parts of the virus’s receptor-binding domain (RBD), parts that frequently change with new variants. With new variants, vaccine-evoked immunity wanes, and booster shots and reformulation become a necessity. The new nanoparticle-based vaccine aims to circumvent such an issue through an immune reaction elicited in parts of the RBD that are conserved in alternative strains.
Mosaic Nanoparticles: NextGen Vaccine Formulation
The new vaccine is based on a “mosaic” nanoparticle strategy, where up to eight different sarbecovirus RBDs are attached to a 60-mer nanoparticle scaffold. This design is crucial for eliciting a broad immune response.
B cells, which produce antibodies, respond best when stimulated with a several-copy form of an antigen. Conventional vaccines, with a single shape of an RBD, will most likely enable dominant antibody-producing B cells to bind to regions that can vary a lot, such as in a high-mutation region. In contrast, the mosaic nanoparticle vaccine maximizes opportunity for antibody-producing B cells that bind to regions shared between numerous sarbecoviruses to become stimulated. That mechanism generates broadly neutralizing antibodies that can defend a range of coronaviruses, including ones not yet in humans.
Preclinical Success and Possibility for a Human Trial
In preclinical studies, the mosaic nanoscale vaccine fared remarkably well in trials in animals. In testing a variety of variants of the vaccine, including an early 2021-2022 model, mosaic-8, and newer variants, including newer variants such as mosaic-2COM, mosaic-5COM, and mosaic-7COM, a variety of newer variants incorporated computationally optimized and naturally derived RBD sequences in an effort to maximize stimulation of the immune system.
When tested in a murine model, both mosaicked nanoparticle vaccines elicited strong antibody activity in a range of SARS-CoV-2 variants and other sarbecoviruses. As for compositions, most and most broadly effective immune activity elicited, mosaicked-7COM potently neutralized a range of SARS-CoV-2 strains and similar viruses. To simulate real-life scenarios with a background level of immunity through infection and/or vaccination, even in mice, the vaccines have been evaluated in animals with a background of a preceding bivalent mRNA COVID-19 vaccine. In such animals, in each case, the mosaic-7COM preparation elicited a high level of cross-reactive antibody, and it is hoped that it will serve as an effective booster in subjects with a background of SARS-CoV-2 immunization.
Computational Insights for Vaccine Optimisation
A key aspect of such a study included use of computational modeling for determination of most effective RBD combinations. Two computational methodologies, in a study at MIT under Arup K. Chakraborty,
Large-Scale Mutation Analysis: The group generated over 800,000 possible RBD sequences via substitution in epitope regions that have been previously characterized. They then assayed candidates for solubility and stability and selected 10 variants that optimized diversity in immune response.
Natural RBD selection: In contrast to artificial mutations, computational methodologies were used in the group to identify seven naturally arising sarbecovirus RBDs with variable site diversity and regions of conservation.
These computational observations guided the selection of RBDs included in the mosaic nanoparticle vaccines and, in a significant manner, amplified their breadth of protection.
Clinical and Manufacturing Hopes
The promising early stage trials have paved the way for trials in humans. The Bjorkman laboratory at Caltech received funding for its mosaic-8 nanoparticle vaccine for trials in humans through a grant with the Coalition for Epidemic Preparedness Innovations (CEPI). Due to its high success in early stage trials, researchers have hoped to transition its version, mosaic-7COM, for trials in humans, as well.
Another crucial advantage of such a platform is its suitability for use with mRNA vaccine technology. Present types of the nanoparticle vaccine have to rely on protein-based production, but encoding for an mRNA vaccine in terms of encoding for the mosaic RBDs is starting to be researched. With success, it could enable high-volume production and rapid distribution, such as with present-day COVID-19 mRNA vaccines.
Implications for future pandemic preparedness
The development of a broadly protective sarbecovirus vaccine has important implications for global health security. By actively vaccinating a range of coronaviruses, such an intervention could:
Reduce the constant need for updating vaccines: Unlike strain-specific mRNA vaccines, in which new strains require new updates, mosaic nanoparticle vaccines can grant long-term protection for numerous strains of virus.
Prevent future pandemics: By vaccinating for yet uninfected sarbecoviruses, such a vaccine strategy could prophylactically shut down zoonotic spillover events.
Enhance booster strategies: With its efficacy in subjects with a vaccination background, a mosaic nanoparticle vaccine can act as a booster for a general boost in immunity for future and present coronaviruses.
Conclusion
The nanoparticle-based vaccine developed at MIT and Caltech is a breakthrough in SARS-CoV-2 and beta-coronavirus immunology with a long-term protective mechanism through broadly neutralizing antibodies, elicited with mosaic nanoparticles. With trials ongoing, such an unprecedented vaccine could become an important tool in ending current and future occurrences of the pandemic. If successful, such technology could redefine not only vaccine development for coronaviruses, but for a range of emerging pathogens with high evolutionary capabilities posing a threat to worldwide health.
Dr. Prahlada N.B
MBBS (JJMMC), MS (PGIMER, Chandigarh).
MBA in Healthcare & Hospital Management (BITS, Pilani),
Postgraduate Certificate in Technology Leadership and Innovation (MIT, USA)
Executive Programme in Strategic Management (IIM, Lucknow)
Senior Management Programme in Healthcare Management (IIM, Kozhikode)
Advanced Certificate in AI for Digital Health and Imaging Program (IISc, Bengaluru).
Senior Professor and former Head,
Department of ENT-Head & Neck Surgery, Skull Base Surgery, Cochlear Implant Surgery.
Basaveshwara Medical College & Hospital, Chitradurga, Karnataka, India.
My Vision: I don’t want to be a genius. I want to be a person with a bundle of experience.
My Mission: Help others achieve their life’s objectives in my presence or absence!
My Values: Creating value for others.
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