Publication date: Dec 28, 2023
The receptor-binding domain (RBD) of the SARS-CoV-2 spike is a primary target of neutralizing antibodies and a key component of licensed vaccines. Substantial mutations in RBD, however, enable current variants to escape immunogenicity generated by vaccination with the ancestral (WA1) strain. Here, we produce and assess self-assembling nanoparticles displaying RBDs from WA1 and BA. 5 strains by using the SpyTag:SpyCatcher system for coupling. We observed both WA1- and BA. 5-RBD nanoparticles to degrade substantially after a few days at 37 ^0C. Incorporation of nine RBD-stabilizing mutations, however, increased yield ~five-fold and stability such that more than 50% of either the WA1- or BA. 5-RBD nanoparticle was retained after one week at 37 ^0C. Murine immunizations revealed that the stabilized RBD-nanoparticles induced ~100-fold higher autologous neutralization titers than the prefusion-stabilized (S2P) spike at a 2 μg dose. Even at a 25-fold lower dose where S2P-induced neutralization titers were below the detection limit, the stabilized BA. 5-RBD nanoparticle induced homologous titers of 12,795 ID and heterologous titers against WA1 of 1767 ID. Assessment against a panel of β-coronavirus variants revealed both the stabilized BA. 5-RBD nanoparticle and the stabilized WA1-BA. 5-(mosaic)-RBD nanoparticle to elicit much higher neutralization breadth than the stabilized WA1-RBD nanoparticle. The extraordinary titer and high neutralization breadth elicited by stabilized RBD nanoparticles from strain BA. 5 make them strong candidates for next-generation COVID-19 vaccines.
Open Access PDF