Multivalent Display of SARS-CoV-2 Spike (RBD Domain) of COVID-19 to Nanomaterial, Protein Ferritin Nanocages

Abstract

SARS-CoV-2, or COVID-19, has a devastating effect on our society, both in terms of quality of life and death rates; hence, there is an urgent need for developing safe and effective therapeutics against SARS-CoV-2. The most promising strategy to fight against this deadly virus is to develop an effective vaccine. Internalization of SARS-CoV-2 into the human host cell mainly occurs through the binding of the coronavirus spike protein (a trimeric surface glycoprotein) to the human angiotensin-converting enzyme 2 (ACE2) receptor. The spike-ACE2 protein–protein interaction is mediated through the receptor-binding domain (RBD) of the spike protein. Mutations in the spike RBD can significantly alter interactions with the ACE2 host receptor. Due to its important role in virus transmission, the spike RBD is considered to be one of the key molecular targets for vaccine development. In this study, a spike RBD-based subunit vaccine was designed by utilizing a ferritin protein nanocage as a scaffold. Several fusion protein constructs were designed in silico by connecting the spike RBD via a synthetic linker (different sizes) to different ferritin subunits (H-ferritin and L-ferritin). The stability and the dynamics of the engineered nanocage constructs were tested by extensive molecular dynamics simulation (MDS). Based on our MDS analysis, a five amino acid-based short linker (S-Linker) was the most effective for displaying the spike RBD over the surface of ferritin. The behavior of the spike RBD binding regions from the designed chimeric nanocages with the ACE2 receptor was highlighted. These data propose an effective multivalent synthetic nanocage, which might form the basis for new vaccine therapeutics designed against viruses such as SARS-CoV-2.

Single‐dose immunisation with a multimerised SARS‐CoV‐2 receptor binding domain (RBD) induces an enhanced and protective response in mice

“…Previous work has shown that protein-based subunit vaccines directed against SARS-CoV-2 deliver high antibody responses in animal models (Tan et al, 2021;Wang et al, 2021). Furthermore, subunit antigens have the potential to deliver a cheaper, boostable and more robust alternative to nucleic-acid based vaccines (Dalvie et al, 2021;Gu et al, 2021;He et al, 2021;Joyce et al, 2021;Kalathiya et al, 2021;Koenig et al, 2021;Ma et al, 2020;Powell et al, 2021;Saunders et al, 2021;Xiang et al, 2020). To explore the development of stable and efficient subunit vaccine candidates, here we covalently linked SARS-CoV-2 proteins expressed in mammalian and bacterial cells with bacterially-expressed Dps from the hyperthermophilic archaeon Sulfolubus islandicus (Gauss et al, 2006).…”

“…1A). Multimerisation has been used for many years to increase the immunogenicity of different antigens through multivalency, and this approach has also been shown recently to work well with SARS-CoV-2 antigens (Dalvie et al, 2021;Kalathiya et al, 2021;Powell et al, 2021;Wang et al, 2021).…”

A Bivalent COVID-19 Vaccine Based on Alpha and Beta Variants Elicits Potent and Broad Immune Responses in Mice against SARS-CoV-2 Variants

“…SARS-CoV-2 virus is composed of nuclear material (RNA genome) surrounded by coat proteins including the spike (S) glycoprotein, which is glycosylated and homotrimeric in nature [ 25 ]. The receptor-binding domain (RBD) is located in the S1 subunit of the spike protein, which binds to the ACE2 receptor and mediates virus entry [ 26 ].…”

Self-Assembled Particles Combining SARS-CoV-2 RBD Protein and RBD DNA Vaccine Induce Synergistic Enhancement of the Humoral Response in Mice

“…An important factor affecting the efficiency of stimulation of the humoral response and neutralizing antibodies is the degree of multimerization of protein viral antigens. It has been shown that immunogens based on dimeric and multimeric derivatives of protein receptors (namely the receptor-binding domain (RBD)) induce a significantly higher titer of neutralizing antibodies [26,27].…”