Genetic immunization with self-assembling SARS-CoV-2 Spike-HBsAg nanoparticles

Abstract As the COVID-19 pandemic continues to pose a great challenge to global health, more effective and durable vaccines are needed owing to the waning protection offered by the current available vaccines. Here we report highly immunogenic self-assembling hepatitis B surface antigen (HBsAg) nanoparticles displaying the ectodomain of SARS-CoV-2 WA1 S6P, the prefusion spike stabilized by six proline substitutions. Three self-assembling nanoparticle constructs with different linkers named CL1, CL2 and CL3 expressed well-formed nanoparticles in mammalian cells. These purified nanoparticles can bind diverse monoclonal antibodies (mAbs) specific to different domains of SARS-CoV-2 spike. Immunization by DNA electroporation of CL2 and CL3 in mice elicited significantly more potent and durable neutralizing antibody responses against diverse SARS-CoV-2 strains than non-nanoparticle forms of stabilized spikes, including SARS-CoV-2 S2P and S6P ectodomain and full-length S2P with its coding sequence matching mRNA-1273. Our data showed that genetic delivery of HBsAg based nanoparticle vaccines displaying SARS-CoV-2 spike can elicit potent and durable neutralizing antibody responses and highlight their potential as next generation genetic vaccine candidates against SARS-CoV-2. NIH Intramural Funding