A novel receptor-binding domain (RBD)-based mRNA vaccine against SARS-CoV-2.
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ABSTRACT:
SUBMITTER: Tai W
PROVIDER: S-EPMC7403570 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:There are currently approximately 4,000 mutations in the SARS-CoV-2 S protein gene and emerging SARS-CoV-2 variants continue to spread rapidly worldwide. Universal vaccines with high efficacy and safety urgently need to be developed to prevent SARS-CoV-2 variants pandemic. Here, we described a novel self-assembling universal mRNA vaccine containing a heterologous receptor-binding domain (HRBD)-based dodecamer (HRBDdodecamer) against SARS-CoV-2 variants, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (B.1.1.28.1), Delta (B.1.617.2) and Omicron (B.1.1.529). HRBD containing four heterologous RBD (Delta, Beta, Gamma, and Wild-type) can form a stable dodecameric conformation under T4 trimerization tag (Flodon, FD). The HRBDdodecamer -encoding mRNA was then encapsulated into the newly-constructed LNPs consisting of a novel ionizable lipid (4N4T). The obtained universal mRNA vaccine (4N4T-HRBDdodecamer) presented higher efficiency in mRNA transfection and expression than the approved ALC-0315 LNPs, initiating potent immune protection against the immune escape of SARS-CoV-2 caused by evolutionary mutation. These findings demonstrated the first evidence that structure-based antigen design and mRNA delivery carrier optimization may facilitate the development of effective universal mRNA vaccines to tackle SARS-CoV-2 variants pandemic.
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Project description:The receptor-binding domain (RBD) of SARS-CoV-2 S protein is proved to be the major target of neutralizing antibodies. However, on the S protein, only a portion of epitopes in RBD can be effectively displayed with dynamic changes in spatial conformations. Using RBD fragment as antigen can better expose the neutralizing epitopes, but the immunogenicity of RBD monomer is suboptimal. Multimeric display of RBD molecules is a feasible strategy to optimize RBD-based vaccines. In this study, RBD single-chain dimer derived from Wuhan-Hu-1 was fused with a trimerization motif, and a cysteine was also introduced at the C-terminus. The resultant recombinant protein 2RBDpLC was expressed in Sf9 cells using a baculovirus expression system. Reducing/non-reducing PAGE, size-exclusion chromatography and in silico structure prediction indicated that 2RBDpLC polymerized and possibly formed RBD dodecamers through trimerization motif and intermolecular disulfide bonds. In mice, 2RBDpLC induced higher levels of RBD-specific and neutralizing antibody responses than RBD dimer, RBD trimer and prefusion-stabilized S protein (S2P). In addition, cross-neutralizing antibodies against Delta and Omicron VOC were also detected in the immune sera. Our results demonstrate that 2RBDpLC is a promising vaccine candidate, and the method of constructing dodecamers may be an effective strategy for designing RBD-based vaccines.
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Project description:Development of safe and efficient vaccines is still necessary to deal with the COVID-19 pandemic. Herein, we reported that yeast-expressed recombinant RBD proteins either from wild-type or Delta SARS-CoV-2 were able to elicit immune responses against SARS-CoV-2 and its variants. The wild-type RBD (wtRBD) protein was overexpressed in Pichia pastoris, and the purified protein was used as the antigen to immunize mice after formulating an aluminium hydroxide (Alum) adjuvant. Three immunization programs with different intervals were compared. It was found that the immunization with an interval of 28 days exhibited the strongest immune response to SARS-CoV-2 than the one with an interval of 14 or 42 days based on binding antibody and the neutralizing antibody (NAb) analyses. The antisera from the mice immunized with wtRBD were able to neutralize the Beta variant with a similar efficiency but the Delta variant with 2~2.5-fold decreased efficiency. However, more NAbs to the Delta variant were produced when the Delta RBD protein was used to immunize mice. Interestingly, the NAbs may cross react with the Omicron variant. To increase the production of NAbs, the adjuvant combination of Alum and CpG oligonucleotides was used. Compared with the Alum adjuvant alone, the NAbs elicited by the combined adjuvants exhibited an approximate 10-fold increase for the Delta and a more than 53-fold increase for the Omicron variant. This study suggested that yeast-derived Delta RBD is a scalable and an effective vaccine candidate for SARS-CoV-2 and its variants.
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Project description:SARS-CoV-2 is the etiological agent of COVID19. There are currently several licensed vaccines approved for human use and most of them target the spike protein in the virion envelope to induce protective immunity. Recently, variants that spread more quickly have emerged. There is evidence that some of these variants are less sensitive to neutralization in vitro, but it is not clear whether they can evade vaccine induced protection. In this study, we tested SARS-CoV-2 spike RBD as a vaccine antigen and explored the effect of formulation with Alum/MPLA or AddaS03 adjuvants. Our results show that RBD induces high titers of neutralizing antibodies and activates strong cellular immune responses. There is also significant cross-neutralization of variants B.1.1.7 and B.1.351 and to a lesser extent, SARS-CoV-1. These results indicate that recombinant RBD can be a viable candidate as a stand-alone vaccine or as a booster shot to diversify our strategy for COVID19 protection.
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Project description:Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is undoubtedly the most challenging pandemic in the current century and remains a global health emergency. As the number of COVID-19 cases in the world is on the rise and variants continue to emerge, there is an urgent need for vaccines. Among all immunization approaches, mRNA vaccines have demonstrated more promising results in response to this challenge. Herein, we designed an mRNA-based vaccine encoding the receptor-binding domain (RBD) of SARS-CoV-2 encapsulated in lipid nanoparticles (LNPs). Intramuscular (i.m.) administration of the mRNA-RBD vaccine elicited broad-spectrum neutralizing antibodies and cellular responses against not only the wild-type SARS-CoV-2 virus but also Delta and Omicron variants. These results indicated that two doses of mRNA-RBD immunization conferred a strong immune response in mice against the wild-type SARS-CoV-2, while the booster dose provided a sufficient immunity against SARS-CoV-2 and its variants. Taken together, the three-dose regimen strategy of the mRNA-RBD vaccine proposed in the present study appears to be a promising reference for the development of mRNA vaccines targeting SARS-CoV-2 variants.
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Project description:With the rapid emergence and spread of SARS-CoV-2 variants, development of vaccines with broad and potent protectivity has become a global priority. Here, we designed a lipid nanoparticle-encapsulated, nucleoside-unmodified mRNA (mRNA-LNP) vaccine encoding the trimerized receptor-binding domain (RBD trimer) and showed its robust capability in inducing broad and protective immune responses against wild-type and major variants of concern (VOCs) in the mouse model of SARS-CoV-2 infection. The protectivity was correlated with RBD-specific B cell responses especially the long-lived plasma B cells in bone marrow, strong ability in triggering BCR clustering, and downstream signaling. Monoclonal antibodies isolated from vaccinated animals demonstrated broad and potent neutralizing activity against VOCs tested. Structure analysis of one representative antibody identified a novel epitope with a high degree of conservation among different variants. Collectively, these results demonstrate that the RBD trimer mRNA vaccine serves as a promising vaccine candidate against SARS-CoV-2 variants and beyond.
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Project description:mRNA vaccines have been instrumental in controlling the SARS-CoV-2 pandemic, but the short-lived protection mediated by Receptor Binding Domain (RBD)-specific antibodies necessitates frequent revaccinations to enhance vaccine-induced immunity. The development of RBD-specific B cell memory is critical for improving the qualitative and quantitative characteristics of the immune response. However, the effect of additional doses of mRNA vaccines on the composition of the RBD-specific B cell memory pool remains unclear. In this study, we found that dual BNT162b2 vaccination significantly increased both total RBD-specific and memory RBD-specific B cells and neutralizing antibodies. Following the second BNT162b2 dose, we showed a trend for the enrichment of CD27+IgM- memory RBD-specific B cells, which are known to correlate with a strong humoral response upon re-challenge. Repeated Measures Correlation (rmcorr) analysis revealed a significant correlation between antibody titers and both total and memory RBD-specific B cells, demonstrating that B cell and antibody responses are generated in a coordinated manner following BNT162b2 mRNA immunization. Our findings indicate that additional doses of the BNT162b2 mRNA vaccine enhance the qualitative and quantitative enrichment of the memory B cell pool against the vaccine antigens and collectively demonstrate the induction of a coordinated immune response to mRNA vaccination.
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Project description:Variants of SARS-CoV-2 continue to emerge and evade immunity, resulting in breakthrough infections in vaccinated populations. Continued vaccination with vaccines based on the antigens of newly emerged variants does not necessarily result in long-lasting protection. Thus, there is an urgent need for the development of vaccines with a broad spectrum of protective effects. In this study, we selected hotspot mutations in the receptor binding domain (RBD) based on immune escape properties and integrated them into the original RBD protein to obtain a complexed RBD protein (cRBD). We designed a total of three cRBD (cRBD1-3) and thoroughly evaluated their immunological properties. Compared with the BA.1 RBD protein, the cRBDs induced higher levels and broader spectrum of neutralizing antibodies, with cRBD3 being the best performer. In vivo protective capacity of cRBDs was further validated in Balb/c mice attacked by live virus. In order to investigate the reason for the broad protective efficacy of cRBD, whole blood from mice that had completed the immunization process was subjected to RNA sequencing. Transcriptome analysis revealed that the vaccine was able to stimulate an immune response.
2024-03-15 | GSE261311 | GEO
Project description:The emergence of SARS-CoV-2 variants with mutations in key antibody epitopes has raised concerns that antigenic evolution will erode immunity. The susceptibility of immunity to viral evolution is shaped in part by the breadth of epitopes targeted. Here we compare the specificity of antibodies elicited by the mRNA-1273 vaccine versus natural infection. The neutralizing activity of vaccine-elicited antibodies is even more focused on the spike receptor-binding domain (RBD) than for infection-elicited antibodies. However, within the RBD, binding of vaccine-elicited antibodies is more broadly distributed across epitopes than for infection-elicited antibodies. This greater binding breadth means single RBD mutations have less impact on neutralization by vaccine sera than convalescent sera. Therefore, antibody immunity acquired by different means may have differing susceptibility to erosion by viral evolution.One sentence summaryDeep mutational scanning shows the mRNA-1273 RBD-binding antibody response is less affected by single viral mutations than the infection response.
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Project description:The development of clinically actionable pharmaceuticals against coronavirus disease (COVID-19); an infectious disease caused by the SARS-CoV-2 virus is very important for ending the pandemic. Coronavirus spike glycoprotein (GP)-Receptor Binding Domain (RBD) and its interaction with host receptor angiotensin converting enzyme 2 (ACE2) is one of the most structurally understood but therapeutically untapped aspect of COVID-19 pathogenesis. Binding interface based on previous x-ray structure of RBD/ACE2 were virtually screened to identify fragments with high-binding score from 12,000 chemical building blocks. The hit compound was subjected to fingerprint-based similarity search to identify compounds within the FDA-approved drug library containing the same core scaffold. Identified compounds were then re-docked into of RBD/ACE2. The best ranked compound was validated for RBD/ACE2 inhibition using commercial kit. Molecular dynamics simulation was conducted to provide further insight into the mechanism of inhibition. From the original 12000 chemical building blocks, benzimidazole (BAZ) scaffold was identified. Fingerprint-based similarity search of the FDA-approved drug library for BAZ-containing compounds identified 12 drugs with the benzimidazole-like substructure. When these compounds were re-docked into GP/ACE2 interface, the consensus docking identified bazedoxifene as the hit. In vitro RBD/ACE2 inhibition kinetics showed micromolar IC50 value (1.237 μM) in the presence of bazedoxifene. Molecular dynamics simulation of RBD/ACE2 in the presence BAZ resulted in loss of contact and specific hydrogen-bond interaction required for RBD/ACE2 stability. Taken together, these findings identified benzimidazole scaffold as a building block for developing novel RBD/ACE2 complex inhibitor and provided mechanistic basis for the use of bazedoxifene as a repurposable drug for the treatment of COVID-19 acting at RBD/ACE2 interface.
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