Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2

TLDR

A safe, effective, and scalable vaccine is needed to halt the ongoing SARS‑CoV‑2 pandemic. The study designs self‑assembling protein nanoparticles that elicit potent, protective antibody responses against SARS‑CoV‑2 in mice and initiates cGMP manufacturing to advance the vaccine into clinical trials. The authors use structure‑based design to create self‑assembling protein nanoparticles displaying 60 RBDs that elicit strong antibody responses in mice. The RBD‑nanoparticle vaccines display 60 RBDs, elicit neutralizing titers ten times higher than the prefusion‑stabilized spike at a fifth of the dose, target multiple epitopes with a lower binding‑to‑neutralizing ratio than convalescent sera—potentially reducing enhanced respiratory disease—and their high yield and stability indicate scalable production.

Abstract

A safe, effective, and scalable vaccine is needed to halt the ongoing SARS-CoV-2 pandemic. We describe the structure-based design of self-assembling protein nanoparticle immunogens that elicit potent and protective antibody responses against SARS-CoV-2 in mice. The nanoparticle vaccines display 60 SARS-CoV-2 spike receptor-binding domains (RBDs) in a highly immunogenic array and induce neutralizing antibody titers 10-fold higher than the prefusion-stabilized spike despite a 5-fold lower dose. Antibodies elicited by the RBD nanoparticles target multiple distinct epitopes, suggesting they may not be easily susceptible to escape mutations, and exhibit a lower binding:neutralizing ratio than convalescent human sera, which may minimize the risk of vaccine-associated enhanced respiratory disease. 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.