Cell opens up new directions!

iNature As emerging SARS-CoV-2 variants continue to drive the global pandemic, the need for vaccines that provide more effective and broad-spectrum protection continues
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On March 31, 2022, Peking University Wei Wensheng's team published a research paper titled "Circular RNA Vaccines against SARS-CoV-2 and Emerging Variants" in Cell Online, which reported a circular RNA (circRNA) vaccine that The vaccine elicits potent neutralizing antibody and T-cell responses by expressing a trimeric RBD of the spike protein, providing robust protection against SARS-CoV-2 in mice and rhesus monkeys
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Notably, the circRNA vaccine was able to generate higher and longer-lasting antigens and elicit a higher proportion of neutralizing antibodies and a pronounced Th1-skewed immune response compared to the 1mΨ-modified mRNA vaccine
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Importantly, this study found that the circRNARBD-Omicron vaccine induced potent neutralizing antibodies against the Omicron but not the Delta variant
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In contrast, the circRNARBD-Delta vaccine was protective against both Delta and Omicron, or acted as a booster after two doses of native or Delta-specific vaccination, making it a promising candidate against the SARS-CoV-2 variant of current concern.
Favorable choice for VOCs
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Coronavirus disease 2019 (COVID-19) is a serious global public health emergency caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2)
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To date, COVID-19 has resulted in more than 470 million confirmed cases and more than 6 million confirmed deaths (World Health Organization)
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As the outbreak progressed, variants with immune evasion capabilities emerged, the most severe of which was Omicron
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By January 2022, Omicron accounted for approximately 85% of COVID-19 cases (GISAID)
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Omicron carries more than 30 mutations on the spike protein, 15 of which are located in the receptor binding domain (RBD), resulting in a significant reduction in the effectiveness of previously neutralizing antibodies
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Although it has been recently reported that additional boosting with the original SARS-CoV-2 vaccine after two pre-vaccination doses partially improves neutralizing capacity, the neutralizing capacity of the Omicron pseudovirus is 4–13-fold lower than that of the wild type
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This presents a serious challenge to the efficacy of current vaccines, highlighting the urgent need to develop effective vaccines against this rapidly spreading variant
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SARS-CoV-2 belongs to the Betacoronavirus genus of the family Coronaviridae
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SARS-CoV-2 is a single-stranded, positive-sense, enveloped virus with an inner shell formed by a 30 kb RNA genome encapsulated by a nucleocapsid (N) protein, an inner shell consisting of membrane (M), envelope (E) and Spike (S) protein encapsulation
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The S protein of SARS-CoV-2 consists of S1 and S2 subunits and is the major surface protein of the virion
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The S protein mediates viral entry into host cells by binding to its receptor angiotensin-converting enzyme 2 (ACE2) via the receptor-binding domain (RBD) at the C-terminus of the S1 subunit
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This binding subsequently induces fusion between the SARS-CoV-2 envelope and the host cell membrane mediated by the S2 subunit, resulting in the release of the viral genome into the cytoplasm
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The S protein, S1 subunit or RBD antigen of SARS-CoV-2 can induce B cell and T cell responses to produce highly potent neutralizing antibodies against SARS-CoV-2
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Vaccination is the most promising way to end the COVID-19 pandemic
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Traditional vaccine platforms such as inactivated, virus-like particles, and viral vector-based vaccines have been used to develop SARS-CoV-2 vaccines
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Importantly, mRNA vaccines against SARS-CoV-2 have been developed at breakneck speed and quickly approved for use, although the strategy is still in clinical trials and has never been commercialized before
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 Schematic diagram of the article (pictured from Cell) mRNA vaccines contain linear single-stranded RNA consisting of a 5' cap, an untranslated region (UTR), an antigen coding region, and a 3' polyadenylation tail, and are produced by lipid nanoparticles ( LNP) encapsulated delivery into the body
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Clinical-scale mRNA vaccines can be rapidly manufactured following release of viral antigen sequences
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However, due to their susceptibility to exonuclease digestion, current mRNA vaccines still suffer from certain limitations, including inherent instability following in vivo administration after LNP encapsulation
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Therefore, the production of mRNA vaccines requires an extremely sterile and strictly RNase-free environment throughout the production process, and their storage and distribution often require a low-temperature cold chain, limiting their availability in resource-poor countries or regions
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Furthermore, since in vitro transcription (IVT)-produced mRNAs have a rather short half-life in cells, additional nucleotide modifications such as 1-methylpseudouridine are required to increase their stability while reducing unwanted immunogens sexual risk
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Unlike the linear conformation of mRNA, circular RNAs (circRNAs) are covalently closed circular RNA molecules, a large class of which are produced in eukaryotic cells by a non-canonical RNA splicing event called backsplicing noncoding RNA
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Compared with linear mRNAs, circRNAs are highly stable due to their covalently closed loop structure, which protects them from exonuclease-mediated degradation
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CircRNAs are reported to be more stable than their linear mRNA counterparts, and the median half-life of circRNAs in mammalian cells is at least 2.
5-fold longer than that of their linear mRNA isoforms
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To date, only a few endogenous circRNAs have been shown to serve as templates for protein translation, which can be engineered to achieve protein translation through internal ribosome entry sites (IRES) or incorporation of m6A modifications upstream of the open reading frame (ORF)
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Therefore, the researchers envisioned that circRNAs could be used as platforms for generating immunogens
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This study reports a circular RNA (circRNA) vaccine that elicits potent neutralizing antibody and T cell responses by expressing a trimeric RBD of the spike protein, providing mice and rhesus monkeys with anti-SARS- Strong protection against CoV-2
.

Notably, the circRNA vaccine was able to generate higher and longer-lasting antigens and elicit a higher proportion of neutralizing antibodies and a pronounced Th1-skewed immune response compared to the 1mΨ-modified mRNA vaccine
.

Importantly, this study found that the circRNARBD-Omicron vaccine induced potent neutralizing antibodies against the Omicron but not the Delta variant
.

In contrast, the circRNARBD-Delta vaccine was protective against both Delta and Omicron, or acted as a booster after two doses of native or Delta-specific vaccination, making it a promising candidate against the SARS-CoV-2 variant of current concern.
Favorable choice for VOCs
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