Abstract
As COVID-19 continues to spread rapidly worldwide and variants continue to emerge, the development and deployment of safe and effective vaccines are urgently needed. Here, we developed an mRNA vaccine based on the trimeric receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein fused to ferritin-formed nanoparticles (TF-RBD). Compared to the trimeric form of the RBD mRNA vaccine (T-RBD), TF-RBD delivered intramuscularly elicited robust and durable humoral immunity as well as a Th1-biased cellular response. After further challenge with live SARS-CoV-2, immunization with a two-shot low-dose regimen of TF-RBD provided adequate protection in hACE2-transduced mice. In addition, the mRNA template of TF-RBD was easily and quickly engineered into a variant vaccine to address SARS-CoV-2 mutations. The TF-RBD multivalent vaccine produced broad-spectrum neutralizing antibodies against Alpha (B.1.1.7) and Beta (B.1.351) variants. This mRNA vaccine based on the encoded self-assembled nanoparticle-based trimer RBD provides a reference for the design of mRNA vaccines targeting SARS-CoV-2.
Highlights
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is wreaking havoc worldwide
Characterization of the mRNA vaccine candidates T-receptor-binding domain (RBD) and TFRBD To maintain the natural trimer conformation and enhance the immunogenicity of the SARS-CoV-2 RBD, we designed two trimer conformation antigens, the trimeric form of the SARS-CoV-2 RBD (T-RBD) and a trimeric form of the RBD displayed by Helicobacter pylori ferritin (TF-RBD)
Western blot analysis revealed that the RBD mRNA vaccine (T-RBD) was partially secreted into the cell supernatant, while some remained in the cytoplasm
Summary
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is wreaking havoc worldwide. It causes severe respiratory disease and the failure of numerous organs, thereby posing a substantial threat to human health.[1] As of May 2020, the total number of COVID19 cases had exceeded 160 million worldwide, with more than 3 million confirmed deaths, according to the World Health Organization (https://www.who.int/). SARS-CoV-2 belongs to the coronavirus family and is an RNA virus encoding enveloped and single-stranded RNA. Two COVID-19 mRNA vaccines (BNT162b2, Pfizer-BioNTech; mRNA-1273, Moderna), which were approved by the Food and Drug Administration (FDA) for Emergency Use Authorization (EUA), are based on nucleoside-modified mRNAs encoding the stabilized prefusion S glycoprotein. The current data show high neutralizing antibody titers and effective protection rates (>90%) in human clinical trials.[7,8,9,10] The same selection of the S protein as an antigen has been reported in adenovirus vector vaccines, DNA vaccines, and subunit vaccines.[11,12,13,14,15] Overall, the use of S proteins for vaccines has been verified to produce effective immune protection in animal models and human clinical trials
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