Since the beginning of the year, one of the biggest challenges across almost all pharmaceutical institutions is developing a vaccine against COVID-19. With more information available on the SARS-CoV-2 virus, its structural proteins, host interactions, and defense mechanisms, various approaches are being employed to design vaccines. In a novel attempt to design nanoparticle vaccines, a team of scientists from the University of Washington, Seattle, and the University of North Carolina, Chapel Hill has observed potent and robust immune response against SARS-CoV-2 using a multivalent nanoparticle, I53-50.
Published in the journal Cell, the report describes a potential nanoparticle-based vaccine which displays around 60 copies of the SARS-CoV-2 receptor-binding domain (RBD) on its surface, in a conformation close to the natural virus. Hence, this nanoparticle vaccine can elicit a robust immune response, as evidenced by a 10-fold higher amount of neutralizing antibodies as compared to the S-2P trimer or monomeric RBD.
I53-50 – Nanoparticle Vaccine for COVID-19
I53-50 is a computationally designed nanoparticle with icosahedral symmetry formed by trimeric and pentameric components that can be used as a platform to display multiple copies of RBD by linking residues 328-531 of the RBD to the trimeric I53-50A particle via linkers containing multiple glycine and serine residues. These recombinant constructs were expressed in mammalian cells (to ensure glycosylation of the RBD) and mixed with the pentameric I53-50B isolated from E. coli. In a molar ratio of 1:1, the two nanoparticle populations assembled into an icosahedral assembly. These nanoparticles were tested for their composition, size, shape, and structure by multiple biophysical methods such as size exclusion chromatography, dynamic light scattering, and negative stain electron microscopy.
By testing the interaction of the nanoparticle with recombinant human ACE2 ectodomain and two monoclonal antibodies against the viral spike protein, the authors found that the binding affinity of the RBD-I53-50 nanoparticle to the receptor ACE2 and SARS-CoV-2 antibodies is comparable to the monomeric RBD, confirming that the nanoparticle displays RBD in its native conformation.
To test the vaccine’s stability, the RBD-I50-53 was subjected to treatment with guanidine hydrochloride (GdnHcl) and stored at different temperatures for over 4 weeks. While the RBD-I50-53 could withstand chemical denaturation by GdnHcl better than S-2P ectodomain trimer and monomeric RBD, the nanoparticle was also stable across 3 temperatures <70°C, 2-8°C and 22-27°C with no apparent unfolding as opposed to the S-2P, which is unstable due to unfolding and aggregation at 2-8°C and 22-27°C. These properties are important for scaled-up manufacture, storage, and distribution of vaccines.
Using the BAL/B mouse model, the authors demonstrated the immunogenicity of the RBD-I53-50 nanoparticles. When injected with the SARS-CoV-2 virus and the RBD nanoparticles, the mice exhibited S-specific antibodies in titers much higher than monomeric RBD and mildly immunogenic S-2P trimer. The antibody levels were equal to/ higher than antibodies in convalescent sera from recovering COVID-19 patients, indicating that the multivalent display of RBD on the nanoparticle can improve S-specific antibody response. The antibodies elicited from the RBD-nanoparticles could neutralize both pseudovirus and live virus in ‘Darwin’ mice. The second dose of RBD-nanoparticles could increase the titer of neutralizing antibodies by 1-2 orders of magnitude, which was drastically better than the second immunization of the S-2P trimer, which had a significantly lower capacity for pseudovirus and live virus neutralization. The authors also established the immune response of the RBD-nanoparticles in a nonhuman primate, the pigtail macaque.
This study shows that the RBD-nanoparticles, while being safe and easy to assemble in vitro, elicit 10-fold higher amounts of S-specific antibodies, 10-fold higher neutralizing activity, and can develop antibodies against multiple epitopes when compared to the S-2P trimer and the non-immunogenic monomeric RBD. The RBD-I53-50 nanoparticles are currently being prepared for clinical trials.
In the face of the current pandemic, high potency and immunogenicity of the vaccine are important to address the high demand for vaccine doses. As proof of concept, nanoparticles may be a good candidate to produce robust vaccines rapidly. Further work on the optimization of expression and display of antigenic epitopes may improve the design further and provide a way for tackling a future outbreak of zoonotic viruses.
By Sahana Shankar, Ph.D. Candidate
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