Cell: Chinese scientists have developed a universal vaccine design strategy for beta coronaviruses, including the new coronavirus

, July 5, 2020 /
BiovalleyBIOON/--- Coronavirus (CoV) is a diverse set of endometriosis that can be further subdivided into four genus: alpha-CoV, beta-CoV, gamma-CoV, and gamma-CoVTo date, seven types of CoV are known to cause human diseaseOf these, two alpha-CoV (hCoV-NL63 and hCoV-229E) and two beta-CoV (HCoV-OC43 and HKU1) cause only self-limiting cold diseasesHowever, the remaining three beta-CoV (SARS-CoV, MERS-CoV and SARS-CoV-2) can be life-threateningSo far, there are no clinically effective drugs to prevent or treat highly pathogenic CoV infections in humans, highlighting the urgency of vaccine developmentin CoV, the stingprotein (S) embedded in the envelope is responsible for identifying the host cell receptor in order to initiate the virus into the cellThe receptor binding domain (RBD) of the S protein is a necessary condition for this receptor dockingSARS-CoV and SARS-CoV-2 use the same functional host cell receptors --- human angiotensin conversion enzyme 2 (hACE2), while MERS-CoV uses human CD26 (also known as human dipeptidease 4, hDPP4)Scientists have previously revealed the structural basis for these CoVs to identify host cell receptorsso far, most of the powerful neutral ized monoclonal antibodies have targeted CoV RBDTherefore, RBD is an attractive vaccine target because it concentrates the immune response on the interference of receptor bindingSo far, there have been reports that a number of RBD-based vaccines are being developed to fight MERS-CoV and SARS-CoVHowever, RBD-based subunit vaccines may face some important challenges, mainly due to their relatively low immunogenicity, so they must be used in combination with appropriate adjures or optimized for appropriate protein sequences, fragment lengths and immunization programmesStrategies to enhance the immunogenicity of the RBD-based vaccine include increasing antigen size, polymerization, or dense display of antigens in particles, however, these strategies inevitably introduce exogenous sequences, complicating their clinical use potentialin a new study, researchers from the Beijing Institute of Life Sciences of the Chinese Academy of Sciences, the Institute of Medical Experimental Animals of the Chinese Academy of Medical Sciences, the Institute of Microbiology of the Chinese Academy of Sciences and the China Center for Disease Control and Prevention described a generic beta-CoV immunogenic design that overcomes the immunogenicity limitations of the RBD-based vaccineCoV RBD dipolymers have been observed before, but their immunogenicity has not yet been testedThey found that the RBD dipolymer form connected by disulfur bonds significantly enhanced the antibody response and neutralizing the antibody titer than the traditional RBD monomer formIn mouse models, it protected the animals from MERS-CoV infection and relieved lung damageThe crystal structure shows that this RBD dipolymer completely exposes the double receptor binding base sequence (receptor binding motif, RBM), which is the main site for neutralizing antibody recognitionpicture from Cell, 2020, doi: 10.1016/j.cell.2020.06.035related findings published online June 28, 2020 in the journal Cell, with the title "A Universal design of betacoronavirus vaccines against ST COVID-19, MERS and SARS"The authors are Lianpan Dai of the Beijing Institute of Life Sciences of the Chinese Academy of Sciences, Professor Chuan Qin, director of the Institute of Medical Experimental Animals of the Chinese Academy of Medical Sciences, Jinghua Yan, a researcher at the Institute of Microbiology of the Chinese Academy of Sciences, and George FGao, director of the Institute of Microbiology of the Chinese Academy of Sciencesin order to improve the stability of this dipolymer, without introducing any external sequence, the immunogen is further designed as a series repeat single-chain dipolymer (tand re-repeat chain dimer, series repeat sc-dimer) version through structural guidance designRBD-sc-dipolymers retain high vaccine efficacy as dipolymers connected by disulfur bondsThis strategy was then further extended to the development of vaccines for two other highly pathogenic beta-CoV --- SARS-CoV-2 and SARS-CoV ---It is worth noting that the RBD-sc-dimmer design significantly increased immunogenicity and neutralizing antibody titer by 10 to 100 times compared to conventional RBD monomers, indicating its feasibility as a general strategy for the design of the beta-CoV vaccinein particular, two doses of RBD-sc-dipolymer-induced neutralizing antibody titer for SARS-CoV-2 infection is as high as about 4096The RBD-sc-dipolymerofs of MERS-CoV and SARS-CoV-2 were further developed for pilot scale production at GMP level productionBoth can be produced at high yield (g/L level) in the industry-standard CHO cell system, indicating the scalability of this strategy and the prospect of further clinical development to control the MERS-CoV and the ongoing COVID-19 pandemic in general, current candidate SPv vaccines fall into two categories: (i) gene-based vaccines, including DNA/mRNA vaccines, recombinant vaccines
vector and live virus vaccines, which produce antigens in host cells; Protein subunit vaccines have traditionally been used in vaccine development and have good safety and efficacy in preventing diseases such as hepatitis B and shingles In this new study, the researchers report on the design of CoV RBD-sc-dimas as a protein subunit vaccine, representing a promising path to CoV vaccine development Antigen design, guided by structure, is an important tool for the rapid and accurate manufacture of vaccines The full-length S protein is another common option as a CoV antigen subunit vaccine The full-length tripolymer S protein usually has a high immunity, most likely because it has a larger size (approximately 600kDa) It contains not only RBD, the main target for powerful neutralizing antibodies, but also non-RBD regions that can also induce neutralizing antibodies or protective antibodies, such as the N-end domain A common strategy for maintaining the efficacy of the CoV vaccine based on the full-length S protein has previously been reported to maintain the pre-conformation already infusion of MERS-CoV S proteins through structure-based antigen design However, since antibody-dependent enhancement (ADE) has been reported against CoV immune response, effective immunogens have been sought to minimize In addition, THE RBD OF THE COV S protein has been considered an attractive vaccine target because of its advantages in immune focus, but may require effective adjorring and multiple doses to produce sufficient immunogenicity the researchers identified the RBD dipolymer, which is connected by the disulfur bond, as an immunogenigenic: its immunogenicity is significantly higher than that of a conventional RBD monomer, as evidenced by neutralizing antibody titer Through structural guided design, this RBD dipolymer has been further modified to become a series repeat sc-dipolymer, which can be a common strategy for beta-CoV vaccine design In fact, two immunitys to mice using RBD-sc-dipolymers were sufficient to achieve a high level of antibody response to all test vaccines for MERS, COVID-19, and SARS Accordingly, two doses of vaccination programmes will be used to assess the protective effect of the RBD-sc-dipolymer-based CoV vaccine in animal models and humans It is worth noting that after three immunizations, the immunogenicity of the RBD monomer is similar to that of two sc-dimmer vaccines In particular, for the SARS-CoV vaccine, RBD-sc-dipolymers showed only slightly higher antibody responses after three immunitys (?P 0.01) and neutralizing antibody titer (?P 0.05) the reason for the increase in the immune progeny of the RBD-sc-dipolymer is: (i) antigen molecular weight from about 30k Da doubles to about 60kDa; (ii) The dipolymer double-valent effect, which may allow B-cell receptors in B cells to cross-link for better stimulation; in summary, the researchers provided a common strategy for designing the beta-CoV vaccine and confirmed the concept in the development of vaccines for MERS, COVID-19 and SARS The resulting immunogens can be applied to other expression systems, such as yeast , insect cells, or to other vaccine platforms such as DNA, messenger RNA, and vaccine carrier The modified RBD-sc-dipolymer does not introduce any exogenous sequences, highlighting the feasibility of clinical development of this RBD-sc-dipolymer-based CoV vaccine The COVID-19 and MERS candidate vaccines described in this study are promising further progress from the experimental table to the clinic G/L level antigen production highlights the expansion of production capacity to meet urgent global needs, particularly for pandemic COVID-19 the limitations of this study CoV RBD is known to be the main target of neutralizing antibody interference viral receptorbindings, and these researchers are concerned about the body fluid reaction induced by RBD-based vaccines Extended studies, such as passive transfer experiments, should also be carried out to further confirm whether this body fluid reaction is sufficient to withstand the challenge of CoV, although recent studies have confirmed the existence of passive protection through the use of human-derived monoclonal antibodies In addition, while phosphate buffers (PBS) and PBS add-ons are widely used as placebos in recombinant protein-type vaccine studies, using a control group given an unrelated protein plus adjuvant would be a better negative control option (Bio Valley Bioon.com) References: Lianpan Dai et al.
A universal design of betacoronavirus vaccines against COVID-19, MERS and SARS Cell, 2020, doi:10.1016/j.cell.2020.06.035.