A bioengineered pseudovirus nanoparticle displaying SARS‐CoV 2 RBD fully protects mice from mortality and weight loss caused by SARS‐CoV 2 challenge

Abstract

The COVID‐19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) has caused considerable morbidity and mortality worldwide. Although authorized COVID‐19 vaccines have been shown highly effective, their significantly lower efficacy against heterologous variants, and the rapid decrease of vaccine‐elicited immunity raises serious concerns, calling for improved vaccine tactics. To this end, a pseudovirus nanoparticle (PVNP) displaying the receptor binding domains (RBDs) of SARS‐CoV‐2 spike, named S‐RBD, was generated and shown it as a promising COVID‐19 vaccine candidate. The S‐RBD PVNP was produced using both prokaryotic and eukaryotic systems. A 3D structural model of the S‐RBD PVNPs was built based on the known structures of the S60 particle and RBDs, revealing an S60 particle‐based icosahedral symmetry with multiple surface‐displayed RBDs that retain authentic conformations and receptor‐binding functions. The PVNP is highly immunogenic, eliciting high titers of RBD‐specific IgG and neutralizing antibodies in mice. The S‐RBD PVNP demonstrated exceptional protective efficacy, and fully (100%) protected K18‐hACE2 mice from mortality and weight loss after a lethal SARS‐CoV‐2 challenge, supporting the S‐RBD PVNPs as a potent COVID‐19 vaccine candidate. By contrast, a PVNP displaying the N‐terminal domain (NTD) of SARS‐CoV‐2 spike exhibited only 50% protective efficacy. Since the RBD antigens of our PVNP vaccine are adjustable as needed to address the emergence of future variants, and various S‐RBD PVNPs can be combined as a cocktail vaccine for broad efficacy, these non‐replicating PVNPs offer a flexible platform for a safe, effective COVID‐19 vaccine with minimal manufacturing cost and time.

Pseudovirus Nanoparticles Displaying Plasmodium Circumsporozoite Proteins Elicited High Titers of Sporozoite-Binding Antibody

“…The smaller PVNPs observed in this study could potentially be assembled through one or both these two symmetries consisting of 24 and/or 12 S-CSP fusion proteins, respectively. In addition, in our recent studies, we observed impacts on S nanoparticle formation by the displayed antigen [32,35]. In this case, S nanoparticle formation underwent certain changes, making the shell of the S nanoparticle go inward to form a compact particle core with a small center lumen [32,35].…”

“…In addition, in our recent studies, we observed impacts on S nanoparticle formation by the displayed antigen [32,35]. In this case, S nanoparticle formation underwent certain changes, making the shell of the S nanoparticle go inward to form a compact particle core with a small center lumen [32,35]. This could also result in a smaller-sized PVNP.…”

“…UCSF ChimeraX software (version 1.4) [33] was used to model the 3D structures of the S 60 -CSP PVNPs using the cryogenic electronmicroscopy (cryo-EM) density map of the S 60 -VP8* nanoparticle [29] as a template. The two components of the S 60 -CSP PVNP were taken from the crystal structures of the inner shell of 60-valent VLPs of feline calicivirus (FCV) (PDB code: 4PB6) [34] and GII.4 norovirus [35], as well as the predicted structure of P. falciparum CSP (AF-P19597-F1) from the AlphaFold Protein Structure Database (https://alphafold.ebi.ac.uk/, accessed on 26 September 2013). UCSF ChimeraX was also used for the structural analysis of the S-CSP model and the production of the final images.…”

A Viral Protein 4-Based Trivalent Nanoparticle Vaccine Elicited High and Broad Immune Responses and Protective Immunity against the Predominant Rotaviruses

“…Thus, the VP4e on the PVNPs should also form dimers like NoV protrusion (P) dimers . The NoV S domain can assemble into T = 1 and T = 3 icosahedrons after a protein is fused to the C-terminal end of the S domain. , Since the ∼26 nm S 60 -VP8* PVNP is a T = 1 icosahedron, the ∼28 nm S-VP4e PVNPs should be in the same T = 1 icosahedral symmetry consisting of 60 S-VP4e proteins, while the ∼34 nm S-VP4e PVNP should be T = 3 icosahedrons containing 180 S-VP4e proteins.…”

Extraordinary Titer and Broad Anti-SARS-CoV-2 Neutralization Induced by Stabilized RBD Nanoparticles from Strain BA.5

“…Among the approaches to increase breadth and potency, vaccines based on self-assembling nanoparticles appear to be especially promising [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Such nanoparticle vaccines have multiple advantages.…”