Extraordinary Titer and Broad Anti-SARS-CoV-2 Neutralization Induced by Stabilized RBD Nanoparticles from Strain BA.5

Abstract

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 °C. 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 °C. 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 ID50 and heterologous titers against WA1 of 1767 ID50. 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.

Protein Nanoparticles as Viral Vaccine Platforms

“…Using the EnDS, RBDs of SARS-CoV-2 isolates from WA1 and BA.5 carrying RBDstabilizing mutations were displayed via spyTag/SpyCatcher system to generate individual or mosaic NPs. The NPs were shown to induce significantly higher homologous and heterologous neutralizing titers [115] in mice. Interestingly, the study revealed that these vaccines can also elicit higher neutralizing antibody titers against other β-coronaviruses [115].…”

“…The NPs were shown to induce significantly higher homologous and heterologous neutralizing titers [115] in mice. Interestingly, the study revealed that these vaccines can also elicit higher neutralizing antibody titers against other β-coronaviruses [115].…”

Protein Nanoparticles as Vaccine Platforms for Human and Zoonotic Viruses

“…Using the EnDS, the RBDs of SARS-CoV-2 isolates from WA1 and BA.5 carrying RBD-stabilising mutations were displayed via the spyTag/SpyCatcher system to generate individual or mosaic NPs. The NPs were shown to induce significantly higher homologous and heterologous neutralising titers [ 117 ] in mice. Interestingly, the study revealed that these vaccines can also elicit higher neutralising antibody titers against other β-coronaviruses [ 117 ].…”

“…The NPs were shown to induce significantly higher homologous and heterologous neutralising titers [ 117 ] in mice. Interestingly, the study revealed that these vaccines can also elicit higher neutralising antibody titers against other β-coronaviruses [ 117 ].…”