Rapid Development of SARS-CoV-2 Spike Protein Receptor-Binding Domain Self-Assembled Nanoparticle Vaccine Candidates

TLDR

The COVID‑19 pandemic, caused by SARS‑CoV‑2, has inflicted global health and economic losses and underscored the urgent need for a stable, easily produced, effective vaccine, with the spike protein receptor‑binding domain (RBD) being an ideal target due to its role in ACE2 binding and membrane fusion. The study designed three RBD‑conjugated nanoparticle vaccine candidates—RBD‑Ferritin (24‑mer), RBD‑mi3 (60‑mer), and RBD‑I53–50 (120‑mer)—using covalent SpyTag‑SpyCatcher conjugation. Immunization of mice with these RBD‑nanoparticles plus AddaVax or Sigma Adjuvant System produced 8‑ to 120‑fold higher neutralizing activity against pseudovirus and authentic virus compared to monomeric RBD, more effectively blocked RBD‑ACE2 binding, and offered a simple, scalable, flexible assembly, establishing them as competitive vaccine candidates and a universal platform.

Abstract

The coronavirus disease pandemic of 2019 (COVID-19) caused by the novel SARS-CoV-2 coronavirus resulted in economic losses and threatened human health worldwide. The pandemic highlights an urgent need for a stable, easily produced, and effective vaccine. SARS-CoV-2 uses the spike protein receptor-binding domain (RBD) to bind its cognate receptor, angiotensin-converting enzyme 2 (ACE2), and initiate membrane fusion. Thus, the RBD is an ideal target for vaccine development. In this study, we designed three different RBD-conjugated nanoparticle vaccine candidates, namely, RBD-Ferritin (24-mer), RBD-mi3 (60-mer), and RBD-I53–50 (120-mer), via covalent conjugation using the SpyTag-SpyCatcher system. When mice were immunized with the RBD-conjugated nanoparticles (NPs) in conjunction with the AddaVax or Sigma Adjuvant System, the resulting antisera exhibited 8- to 120-fold greater neutralizing activity against both a pseudovirus and the authentic virus than those of mice immunized with monomeric RBD. Most importantly, sera from mice immunized with RBD-conjugated NPs more efficiently blocked the binding of RBD to ACE2 in vitro, further corroborating the promising immunization effect. Additionally, the vaccine has distinct advantages in terms of a relatively simple scale-up and flexible assembly. These results illustrate that the SARS-CoV-2 RBD-conjugated nanoparticles developed in this study are a competitive vaccine candidate and that the carrier nanoparticles could be adopted as a universal platform for a future vaccine development.