Protein engineering responses to the COVID-19 pandemic

Abstract

Antigen design guided by high-resolution viral glycoprotein structures has successfully generated diverse vaccine candidates for COVID-19. Using conjugation systems to combine antigen design with computationally optimized nanoparticles, researchers have been able to display multivalent antigens with beneficial substitutions that elicited robust humoral immunity with enhanced neutralization potency and breadth. Here, we discuss strategies that have been used for structure-based design and nanoparticle display to develop COVID-19 vaccine candidates as well as potential next-generation vaccine candidates to protect against SARS-CoV-2 variants and other coronaviruses that emerge into the human population.

Figure 1

Examples of structure-based design and nanoparticle display of SARS-CoV-2 spike-based antigens. Schematic representation of monomeric, dimeric, trimeric RBDs, stem-helix trimer, S2-only antigen (top row), engineered trimeric spikes in the prefusion conformation (middle) and nanoparticles displaying 60 RBDs or 20 spikes (bottom). RBD monomer is depicted as a ribbon diagram with stabilizing substitutions [19,20] highlighted as spheres. RBD dimer, RBD trimer, stem helix trimer [58] and S2-only antigen are shown as molecular surfaces. For the RBD dimer [23], ACE2-binding sites (or receptor-binding motifs) are colored dark blue. All spike ectodomains are shown as molecular surfaces with proline substitutions [47], inter-protomer disulfide bond [49], inter-subunit disulfide bond [50,51,52] highlighted as spheres. The molecular clamp [59] derived from HIV gp41 HR1-HR2 (PDB ID: 1SZT) is depicted as a red molecular surface. The example of a chimeric spike [61] shown here comprises an NTD from HKU3-1 (green), an RBD from SARS-CoV (dark blue) and an S2 subunit from SARS-CoV-2 (light blue). One example of nanoparticles shown here is RBD-mi3 [72] (PDB ID: 7B3Y), wherein 20 copies of engineered 2-keto-3-deoxy-phosphogluconate (KDPG) aldolase trimer (ribbons) self-assemble to form a nanoparticle. 60 RBDs are conjugated to the mi3 surface via SpyTag:SpyCatcher system. The other example of nanoparticle display is I53-dn5 [77] (PDB ID: 6VFJ), wherein 20 copies of the trimeric component (light red) are used to display trimeric spikes.