The key to battling the COVID-19 pandemic and its potential aftermath is to develop a variety
of vaccines that are efficacious and safe, elicit lasting immunity, and cover a range of
SARS-CoV-2 variants. Recombinant viral receptor-binding domains (RBDs) are safe vaccine
candidates but often have limited efficacy due to the lack of virus-like immunogen display
pattern. Here we have developed a novel virus-like nanoparticle (VLP) vaccine that
displays 120 copies of SARS-CoV-2 RBD on its surface. This VLP-RBD vaccine mimics
virus-based vaccines in immunogen display, which boosts its efficacy, while maintaining the
safety of protein-based subunit vaccines. Compared to the RBD vaccine, the VLP-RBD vaccine
induced five times more neutralizing antibodies in mice that efficiently blocked SARSCoV-
2 from attaching to its host receptor and potently neutralized the cell entry of variant
SARS-CoV-2 strains, SARS-CoV-1, and SARS-CoV-1-related bat coronavirus. These neutralizing
immune responses induced by the VLP-RBD vaccine did not wane during the twomonth
study period. Furthermore, the VLP-RBD vaccine effectively protected mice from
SARS-CoV-2 challenge, dramatically reducing the development of clinical signs and pathological
changes in immunized mice. The VLP-RBD vaccine provides one potentially effective
solution to controlling the spread of SARS-CoV-2
