![]() Viral surface proteins are typically presented to the immune system of the host in the form or nanoparticles tens of nm in diameter that present tens of copies of viral proteins. The ability of viral proteins or its domains to induce formation of antibodies depends on the structure and size of antigen. Indeed it has been shown that RBD induces formation of neutralizing antibodies, 9, 15 similar as demonstrated for the related pathogenic coronaviruses 25, 26 and monoclonal antibodies targeting RBD have demonstrated effectiveness in preclinical studies 27, 28. Masking the receptor binding domain by the antibodies can prevent viral binding to the receptor and subsequent infection of target cells. Tertiary structure of the RBD in the complex with the ACE2 receptor has been determined 23, 24. Therefore focusing immune response to the receptor binding domain (RBD) of the Spike protein may increase the probability of inducing neutralizing antibodies. In this case antibodies against diverse surface exposed epitopes of the Spike protein are generated, where some of them may not prevent recognition of the ACE2 receptor or fusion and may even facilitate viral entry through an antibody dependent enhancement mechanism (ADE), as suggested before for SARS CoV and MERS CoV, as a highly undesirable property of a vaccine 20– 22. The majority of vaccines in current clinical trials are based on trimeric full length spike protein or its stabilized devivatives 5, 9, 12– 18, through which the virus attaches to the host cell receptor ACE2 19. Antibodies triggered by a vaccine should preferentially be focused to the domains and epitopes that can prevent viral recognition of the receptor, block viral fusion with cell membrane or interfere with viral replication in other ways. The advantages of DNA plasmid delivery including the speed of adaptation to new targets, cost effective production, stability at ambient temperature without the need for a cold chain make it a potentially attractive vaccination platform, although no DNA plasmid vaccine has been approved for humans so far 10, 11. Different vaccination platforms for the presentation of viral components have been used, including inactivated or attenuated viral particles, purified proteins, mRNA, plasmid DNA, nonreplicating viruses each of them with particular features 4– 9. An effective vaccine should trigger formation of a protective humoral and cell mediated immune response against the viral components that will either inhibit viral entry and replication or kill virus-infected cells. Our results support the advancement of this vaccine platform towards clinical trials.Ĭovid-19 is a pandemic viral disease caused by SARS-CoV-2 that emerged in 2019 and infected >23 millions of people across the world while the number of casualties is approaching 1 million 1– 3 Since we currently lack an effective treatment of the disease and containment of the virus without imposing high cost for the society, vaccination seems to be the best hope to stop the waves of infection that continue to spread throughout the world. The most potent response was observed for the 24-residue β-annulus peptide scaffold that forms large soluble assemblies, that has the advantage of low immunogenicity in comparison to larger scaffolds. Scaffolding strongly augmented the immune response with production of neutralizing antibodies and T cell response including cytotoxic lymphocytes in mice upon immunization with DNA plasmids. Here we prepared and analyzed the response to several DNA vaccines based on genetic fusions of RBD to four different scaffolding domains, namely to the foldon peptide, ferritin, lumazine synthase and β-annulus peptide, presenting from 6 to 60 copies of the RBD on each particle. Small protein antigens typically induce weak immune response while particles measuring tens of nanometers are efficiently presented to B cell follicles and subsequently to follicular germinal center B cells in draining lymph nodes, where B cell proliferation and affinity maturation occurs. The receptor binding domain (RBD) of the surface-exposed spike protein of SARS-CoV-2 represents a suitable target for the induction of neutralizing antibodies upon vaccination. Effective and safe vaccines against SARS-CoV-2 are highly desirable to prevent casualties and societal cost caused by Covid-19 pandemic.
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