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Development toward Vaccines design against COVID-19, MERS, and SARS

Present CoV vaccine candidates can generally be categorised into two categories: gene-based vaccines, including DNA/messenger RNA vaccines, recombinant vaccine vectors and live-virus vaccines, and second is protein-based vaccines producing in vitro antigens, including inactivated whole virus and protein subunit vaccines. Traditionally, protein subunit vaccines have been used for the production of vaccines and such vaccines have strong protection and efficacy profiles in the prevention of diseases such as hepatitis B and herpes zoster. The design of CoV RBD-scdimer as a protein subunit vaccine was stated here, representing a promising CoV vaccine production pathway.

The current study was publish in Cell under title "A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS".

A significant tool for making vaccines with speed and precision is structure-guided antigen design. Another common option is the full-length S protein as a subunit of CoV antigen. Full-length trimeric S protein is usually highly immunogenic due likely to its large size (~600 kDa). It contains not only RBD, the key target for potent neutralising antibodies, but also non-RBD regions that for instance, the N-terminal domain, can also induce neutralising or defensive antibodies.

A generalised strategy was reported to stabilise MERS-CoV S protein pre-fusion conformation through structure-based antigen design that improved the efficacy of the CoV vaccine based on fulllength S protein. However since the CoV immune response has been documented for antibody-dependent enhancement (ADE), minimised effective immunogens are pursued. Alternatively, because of its immune focusing benefits, the RBD of CoV S protein has been recognised as an attractive vaccine target, but may require effective adjuvant and multiple doses.

The disulfide-linked RBD-dimer was identified as an immunogen which significantly improved immunogenicity as compared to the conventional monomer.

The RBD-dimer has been further developed through a structure-guided design as a tandem repeat sc-dimer, which can be a generalizable beta-CoV vaccine design strategy. In fact two RBD-sc-dimer immunizations have already been sufficient to optimise high levels of antibody responses for all MERS, COVID-19, and SARS vaccines tested. A two-dose vaccination regimen will therefore be applied to determine the protective efficacy of the RBD-sc-dimer-based CoV vaccines in animal models and humans. Of note, monomeric RBD is identical in terms of immunogenicity to two sc-dimer vaccines after three immunizations. Specifically, for

After three immunizations, the SARS-CoV vaccine, RBD-sc-dimer, showed only a slightly higher antibody response (p<0.01) and NAb titer (p<0.05).

The enhanced immunogenicity of the RBD-sc-dimer could be explained by (1) doubling the antigen's molecular weight from ~30 kDa to ~60 kDa, (2) dual RBMs, by which the dimer functions bivalently, which can cross-link B cell receptors in B cells for better stimulation, (3) occlusion of non-RBM epitopes on the RBD dimer interface to further improve immune focus, and (4) exposure of immunodominated cells to better stimulation.

The authors explain "We provided a universal strategy for the design of beta-CoV vaccines and demonstrated the principle of MERS, COVID-19, and SARS vaccine production. Other expression mechanisms, such as yeast and insect cells, and even other vaccine platforms, such as DNA, messenger RNA, and vaccine vectors, may be added to the resulting immunogens".

RBD-sc-dimer engineered without any exogenous sequence introduction illustrated the viability of RBD-sc-dimer-based CoV vaccines for clinical production. For further development from bench to clinic, the COVID-19 and MERS vaccine candidates mentioned here are of promise. The g/L level antigen yields highlight the scale-up production ability to meet the urgent global demands, particularly for the COVID-19 pandemic.

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