Abstract Background The zoonotic emergence of SARS-CoV-2 quickly developed into a global pandemic. Multiple vaccine platforms have been advanced to clinical trials and emergency use authorization. The recent emergence of SARS-CoV-2 virus variants with Spike receptor-binding domain (RBD) and N-terminal domain (NTD) mutations, highlights the need for next-generation vaccines that can elicit immune responses that are resilient against Spike mutations. Methods Using a structure-based vaccine design approach, we developed multiple optimized SARS-CoV-2 nanoparticle immunogens that recapitulate the structural and antigenic profile of the SARS-CoV-2 prefusion spike. We assessed these immunogens in murine immunogenicity studies and in a K18-hACE2 transgenic mouse model with a SARS-CoV-2 challenge. Immune sera from vaccinated mice were assessed for SARS-CoV-2 binding, and neutralization against SARS-CoV-2, variants of concern, and the heterologous SARS-CoV-1 virus. Results In combination with a liposomal-saponin based adjuvant (ALFQ), these immunogens induced robust binding, ACE2-inhibition, and authentic virus and pseudovirus neutralization. A Spike-Ferritin nanoparticle (SpFN) vaccine elicited neutralizing ID50 titers >10,000 after a single immunization, while RBD-Ferritin (RFN) nanoparticle immunogens elicited ID50 titer values >10,000 values after two immunizations. Purified antibody from SpFN- or RFN-immunized mice was transfused into K18-ACE2 transgenic mice and challenged with a high-dose SARS-CoV-2 virus stock. In order to understand the breadth of vaccine-elicited antibody responses, we analyzed SpFN- and RBD-FN-immunized animal sera against a set of heterologous SARS-CoV-2 RBD variants and SARS-CoV RBD. High binding titers with ACE2-blocking activity were observed against SARS-CoV-2 variants and the heterologous SARS-CoV-1 RBD. Furthermore, both SpFN- and RFN-immunized animal sera showed SARS-CoV-1 neutralizing ID50 titers of >2000. Conclusion These observations highlight the importance of SARS-CoV-2 neutralizing antibody levels in providing protection against emerging SARS-like coronaviruses and provide a robust platform for pandemic preparedness. Structure-based design enables development of a SARS-CoV-2 nanoparticle immunogen. Disclosures All Authors : No reported disclosures
【초록키워드】 SARS-CoV-2, Vaccine, immune response, clinical trial, pandemic, spike, antibody, neutralization, Vaccine design, mutations, variant, SARS-CoV-2 variant, variants of concern, SARS-CoV-2 virus, virus, SARS-CoV-1, Emergency use authorization, immunization, global pandemic, pseudovirus, mice, RBD, immunogen, sera, zoonotic, Neutralizing, NTD, vaccine platform, platform, Heterologous, SARS-CoV-2 neutralizing antibody, binding, breadth, K18-hACE2, N-terminal domain, Combination, SARS-CoV-2 RBD, observation, High-dose, antigenic, domain, transgenic mice, prefusion, Multiple, SARS-CoV RBD, murine, responses, SARS-CoV-2 virus variant, approach, Transgenic mouse, SARS-CoV-1 RBD, SARS-CoV-1 virus, highlight, robust, K18-ACE2, Result, analyzed, reported, elicit, SARS-like coronavirus, elicited, the SARS-CoV-2, transfused, were assessed, 【제목키워드】 SARS-CoV-2, immunogenicity, nanoparticle,