Single-Component, Self-Assembling, Protein Nanoparticles Presenting the Receptor Binding Domain and Stabilized Spike as SARS-CoV-2 Vaccine Candidates

• See also:
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  Nanomedicine for COVID-19: the role of nanotechnology in the treatment and diagnosis of COVID-19
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• Single-Component, Self-Assembling, Protein Nanoparticles Presenting the Receptor Binding Domain and Stabilized Spike as SARS-CoV-2 Vaccine Candidates
  by LINLING HE HTTPS://ORCID.ORG/0000-0001-8846-5352XIAOHE LINYING WANGCIRIL ABRAHAMCINDY SOUTIMOTHY NGOYI ZHANGIAN A. WILSON HTTPS://ORCID.ORG/0000-0002-6469-2419AND JIANG ZHU HTTPS://ORCID.ORG/0000-0003-0259-7157 , https://www.science.org/journal/sciadv
  Abstract
  Vaccination against SARS-CoV-2 provides an effective tool to combat the COVID-19 pandemic. Here, we combined antigen optimization and nanoparticle display to develop vaccine candidates for SARS-CoV-2. We first displayed the receptor-binding domain (RBD) on three self-assembling protein nanoparticle (SApNP) platforms using the SpyTag/SpyCatcher system. We then identified heptad repeat 2 (HR2) in S2 as the cause of spike metastability, designed an HR2-deleted glycine-capped spike (S2GΔHR2), and displayed S2GΔHR2 on SApNPs. An antibody column specific for the RBD enabled tag-free vaccine purification. In mice, the 24-meric RBD-ferritin SApNP elicited a more potent neutralizing antibody (NAb) response than the RBD alone and the spike with two stabilizing proline mutations in S2 (S2P). S2GΔHR2 elicited twofold higher NAb titers than S2P, while S2GΔHR2 SApNPs derived from multilayered E2p and I3-01v9 60-mers elicited up to 10-fold higher NAb titers. The S2GΔHR2-presenting I3-01v9 SApNP also induced critically needed T cell immunity, thereby providing a promising vaccine candidate.
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  INTRODUCTION
  Three coronaviruses (CoVs) have caused widespread outbreaks in humans, including severe acute respiratory syndrome CoV-1 (SARS-CoV-1), Middle East respiratory syndrome CoV (MERS-CoV), and SARS-CoV-2, which is the causative agent of CoV disease 2019 (COVID-19) (1–3) and has resulted in more than 2.4 million deaths worldwide (4). Enormous efforts are being undertaken to develop effective therapeutics and prophylactics for SARS-CoV-2. Small molecules that can block the host receptor, angiotensin-converting enzyme 2 (ACE2), and the transmembrane protease serine 2 (TMPRSS2) (5), which is required to process the spike protein, are being considered as treatments in addition to other interventions (6). While the immunology underlying COVID-19 is still being intensively studied (6–8), various vaccine candidates are now in clinical development (9–12). Inactivated virus vaccines have exhibited robust neutralizing antibody (NAb) responses in animals (13, 14), whereas viral vector vaccines based on human adenovirus (Ad5 and Ad26) and chimpanzee ChAdOx1 have been evaluated in nonhuman primates and human trials (15–18). Both DNA (19–21) and mRNA (22, 23) vaccines have been rapidly developed, with moderate NAb titers observed for the mRNA vaccine in medium- and high-dose groups (22). A recombinant spike protein adjuvanted with lipid nanoparticles (NPs), NVX-CoV2373, elicited high NAb titers in a human trial that were, on average, fourfold greater than in convalescent patients (24, 25). Efficacy was recently reported for a vector vaccine (AZD1222: 70.4%) (26) and two mRNA vaccines (mRNA-1273: 94.1%; BNT162b2: 95%) (27, 28). In December 2020, the U.S. Food and Drug Administration (FDA) issued the emergency use authorization (EUA) for the two mRNA vaccines.
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