Design of a stabilized RBD enables potently neutralizing SARS-CoV-2 single-component nanoparticle vaccines

ABSTRACT

Waning immunity and emerging variants necessitate continued vaccination against SARS-CoV-2. Improvements in vaccine safety, tolerability, and ease of manufacturing would benefit these efforts. Here, we develop a potent and easily manufactured nanoparticle vaccine displaying the spike receptor-binding domain (RBD). Computational design to stabilize the RBD, eliminate glycosylation, and focus the immune response to neutralizing epitopes results in an RBD immunogen that resolves issues hindering the efficient nanoparticle display of the native RBD. This non-glycosylated RBD can be genetically fused to diverse single-component nanoparticle platforms maximizing manufacturing ease and flexibility. All engineered RBD-nanoparticles elicit potently neutralizing antibodies in mice that far exceed monomeric RBD. A 60-copy particle (noNAG-RBD-E2p) also elicits potently neutralizing antibodies in non-human primates. The neutralizing antibody titers elicited by noNAG-RBD-E2p are comparable to a benchmark stabilized spike antigen and reach levels against omicron BA.5 that suggest it would provide protection against emerging variants. Graphical SARS-CoV-2 RBD vaccines are cost-effective but require methods to increase their potency. Dickey et al. use a computational design method to create a stabilized non-glycosylated RBD that it can be fused to a nanoparticle carrier, boosting its potency to levels of a gold-standard spike antigen.