Using Structural Biology to Drive Pandemic Preparedness Webinar
Safe, effective, and scalable vaccines and therapeutics are needed to halt the ongoing SARS-CoV-2 pandemic. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 convlescent sera. To further understand this point, we structurally defined an RBD antigenic map using cryo-electron microscopy, ELISA, and BLI. We show that there are many distinct neutralizing epitopes present on the receptor binding domain, that not all of these neutralizing antibodies directly block the receptor (ACE2) interaction, and that some have breadth against other related sarbecoviruses. We used this to design a self-assembling protein nanoparticle made of RBD immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice and NHPs. Antibodies elicited by the RBD nanoparticles target multiple distinct epitopes, suggesting they may not be as easily susceptible to escape mutations present in the variants of concern. The high yield and stability of the assembled nanoparticles suggest that manufacture of the nanoparticle vaccines will be highly scalable. These results highlight the utility of robust antigen display platforms and have launched cGMP manufacturing efforts to advance the SARS-CoV-2-RBD nanoparticle vaccine into the clinic.