Adaptation‐Proof SARS‐CoV‐2 Vaccine Design

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surface spike glycoprotein-a major antibody target-is critical for virus entry via engagement of human angiotensin-converting enzyme 2 (ACE2) receptor. Despite successes with existing vaccines and therapies that primarily target the receptor binding domain (RBD) of the spike protein, the susceptibility of RBD to mutations provides escape routes for the SARS-CoV-2 from neutralizing antibodies. On the other hand, structural conservation in the spike protein can be targeted to reduce escape mutations and achieve broad protection. Here, candidate stable immunogens are designed that mimic surface features of selected conserved regions of spike protein through "epitope grafting," in which the target epitope topology is presented on diverse heterologous scaffolds that can structurally accommodate the spike epitopes. Structural characterization of the epitope-scaffolds showed stark agreement with computational models and target epitopes. The sera from mice immunized with engineered designs display epitope-scaffolds and spike binding activity. The utility of the designed epitope-scaffolds in diagnostic applications is also demonstrated. Taken all together, this study provides an important methodology for targeting the conserved, non-RBD structural motifs of spike protein for SARS-CoV-2 epitope vaccine design and demonstrates the potential utility of "epitope grafting" in rational vaccine design.

From De Novo Design to Redesign: Harnessing Computational Protein Design for Understanding SARS-CoV-2 Molecular Mechanisms and Developing Therapeutics

“…Vishweshwaraiah et al employed an epitope grafting and scaffold folding approach to develop stable immunogens targeting conserved, non-RBD structural motifs. 119 Detailed analysis of these epitope scaffolds confirmed their structural resemblance to the computational models and the target epitopes. Additionally, when mice were immunized with these engineered designs, their sera exhibited binding activity to both the epitope scaffolds and the spike protein.…”

“…These designed trispecific antibodies exhibited potent and broad neutralization activity. Vishweshwaraiah et al employed an epitope grafting and scaffold folding approach to develop stable immunogens targeting conserved, non-RBD structural motifs . Detailed analysis of these epitope scaffolds confirmed their structural resemblance to the computational models and the target epitopes.…”

“…Additionally, when mice were immunized with these engineered designs, their sera exhibited binding activity to both the epitope scaffolds and the spike protein. 119 ■ DEVELOPMENT OF NOVEL CPD METHODS AND…”

Toehold-Mediated Shape Transition of Nucleic Acid Nanoparticles

“…Nanoparticles can be fabricated from various materials ranging from metal atoms (e.g., gold, silver, and iron oxide nanoparticles), − lipid-based materials (e.g., micelles), and amino acids (e.g., antibodies and vaccines) − to nucleic acids (e.g., nanostructures made of DNA or RNA) or their chemical analogues. , While all these nanomaterials were shown to be effective in synthesis and self-assembly of functional nanoscale-sized objects, nucleic acids offer multiple unique advantages. − The ability of nucleic acids, in particular RNA, to form both canonical (cis-Watson–Crick) and non-canonical base pairs , gives rise to a library of structural motifs with a myriad of architectural differences. − This library is often viewed as modular building blocks to fabricate nucleic acid nanoparticles (NANPs) and nanoscale DNA assemblies in a controlled and pre-programmed fashion. − In addition, the secondary structures of both DNA and RNA can be predicted with high level of accuracy, thus opening possibilities to generate modular NANPs with defined thermodynamic properties and the ability to dynamically respond to the external stimuli. − The intrinsic properties of nucleic acids to form non-covalent interactions with small molecules, metal ions, polypeptides, other nucleic acids, and large proteins enable the possibility to fabricate sophisticated nanodevices using DNA and RNA as building materials. − These unique features expand the possibility of NANPs to serve as highly programmable materials, suitable for applications in synthetic biology, biotechnology, and biosensing.…”

Identify the Virus-like Models for COVID-19 as Bio-Threats: Combining Phage Display, Spectral Detection and Algorithms Analysis

“…And it could be the most severe threat for generations due to its dangerousness and unpredictability [ 1 ]. Great efforts have been made to understand and discover SARS-CoV-2, including its viral structure [ 2 , 3 , 4 ], spread process [ 5 , 6 , 7 , 8 ], pathogenesis mechanism [ 9 , 10 ], diagnostic approach [ 8 ], variants [ 11 , 12 , 13 ], and vaccine immunity [ 13 , 14 , 15 ]. However, there are still significant challenges in the detection of this virus despite all kinds of positive scientific progress have been achieved.…”