On the Cell: Wei Wensheng's team develops a circular RNA vaccine that is effective against Delta and Omicron

Written | Edited by nagashi | Typesetting by Wang Cong | Shui Chengwen At the beginning of 2020, the pneumonia epidemic caused by the new coronavirus (SARS-CoV-2) began to become a global pandemic and has continued to this day
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Unfortunately, to this day, the situation of the new crown epidemic is still very serious
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According to the World Health Organization (WHO), as of now, more than 488 million people have been infected worldwide, and the cumulative death toll has exceeded 6.
16 million
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An article in Nature pointed out that the number of deaths from the new crown has been greatly underestimated, and the number of new crown-related deaths worldwide may be as high as 18 million
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It is worth noting that with the wide spread of the new coronavirus around the world, new variants of viruses are emerging, including Alpha, Beta, Gamma, Delta, and Omicron, which has recently begun to spread rapidly, showing super contagiousness
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More critically, the protection against Omicron by the existing COVID-19 vaccines has been greatly reduced
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This reminds us that in the context of the constant mutation of the new coronavirus, the effectiveness of existing vaccines and therapeutic antibodies has begun to gradually decline
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Therefore, there is an urgent need to develop safe and effective vaccines to prevent the infection of 2019-nCoV and its mutants
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On March 31, 2022, the team of Wei Wensheng of Peking University published an article entitled: Circular RNA Vaccines against SARS-CoV-2 and Emerging Variants in the estimated top academic journal Cell.
) research paper [2]
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The paper was launched on the preprint bioRxiv in January this year.
Based on the bioRxiv paper published in March last year, Wei Wensheng's team verified the binding of the trimeric receptor encoding the new coronavirus spike protein they had previously developed on rhesus monkeys.
Domain (RBD) circular RNA vaccine (circRNA-RBD) was able to elicit potent neutralizing antibodies and T cell responses, resulting in effective protection against Delta and Omicron mutants
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Different from the linear mRNA vaccines currently used, this circular RNA vaccine, because the circular RNA itself has high stability, does not require nucleotide modification, and can be stored at room temperature for 2 weeks without affecting the effect
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This shows that the circular RNA vaccine has very good application prospects in the fight against the new coronavirus variant virus
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It is worth mentioning that Professor Wei Wensheng founded the circular RNA-based vaccine and treatment company Yuanyin Bio, and completed the PreA round of financing of over 100 million yuan at the end of 2021
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Vaccination is the most promising way to end and prevent the Covid-19 pandemic
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There are many types of new crown vaccines that have been applied, including inactivated vaccines, adenovirus vector vaccines, subunit vaccines and emerging mRNA vaccines
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mRNA vaccines have the advantages of fast production speed, low cost, and rapid response to virus mutation
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But at the same time, the storage and transportation conditions of mRNA vaccines are harsh (minus 70°C) and have potential immunogenic side effects
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In nature, circular RNAs (circRNAs) are ubiquitous in fungi, plants, insects, fish, and mammals, and even the genomes of some viruses themselves are circular RNAs, such as hepatitis D virus and plant viroids
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Unlike linear mRNA, circular RNA is highly stable because its covalently closed loop structure protects it from exonuclease-mediated degradation
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So far, only a few endogenous circular RNAs have been shown to serve as templates for protein translation
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Although circular RNA lacks elements necessary for translation into protein, it can achieve protein translation through m6A modification at the internal ribosome entry site (IRES) or its 5'UTR region
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Wei Wensheng's team designed a circular RNA vaccine for the new coronavirus and its variants.
Wei Wensheng's laboratory is also the first laboratory in the world to apply circular RNA to vaccine development
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The research team used self-splicing type I intron ribozymes to generate circular RNAs - circRNA-RBDs - encoding SARS-CoV-2-RBD antigens
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To enhance the immunogenicity of the RBD antigen, they fused the phage T4 plasmin trimer motif to its C-terminus, thus mimicking the natural conformation of the SARS-CoV-2 S protein trimer
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Design pattern diagram of circRNA-RBD Cell experiments show that circRNA-RBD can massively express the RBD antigen of 2019-nCoV in human cells and mouse cells, and the expression level is significantly higher than that of linear mRNA-RBD, and can effectively block 2019-nCoV pseudovirus infected cells
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In mouse experiments, circRNA-RBD delivered by lipid nanoparticles (LNP) could effectively neutralize the new coronavirus pseudovirus, and a strong T cell immune response was generated in the spleen of mice
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This indicated that the circRNA-RBD vaccine indeed induced a durable humoral immune response and a strong T cell immune response in mice
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The circRNA-RBD vaccine induces durable humoral immune responses and strong T-cell immune responses in mice.
The research team also designed a circRNA-RBD vaccine against the Delta mutant strain.
The experimental results show that the vaccine can produce Delta and Omicron mutants.
high levels of neutralizing antibodies
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This time, the research team also tested the effect of the circular RNA vaccine in monkeys, and the experimental results showed that the circular RNA vaccine can effectively protect rhesus monkeys
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Lipid nanoparticle (LNP)-delivered circular RNA vaccines elicit potent neutralizing antibody and T-cell responses, producing stronger and longer-lasting effects than modified linear mRNA vaccines
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Importantly, the study found that a circular RNA vaccine against Omicron could only induce high levels of neutralizing antibodies against Omicron, while a circular RNA vaccine against Delta could induce both high levels of neutralizing antibodies against Delta and high levels of neutralizing antibodies against Delta.
High-level neutralizing antibodies against Omicron
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This suggests that the circular RNA vaccine against Delta is a powerful vaccine option that could provide broad protection against the current major strains of COVID-19
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Overall, this study confirms that circular RNA vaccines have the advantages of good thermal stability, high expression of encoded antigens, and wide applicability, and the corresponding circular RNA vaccines have been successfully designed to fight 2019-nCoV and its mutants infection, suggesting that circular RNA vaccines could serve as a novel vaccine and therapeutic platform in the COVID-19 pandemic
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Paper link: 1.
https:// https:// "Biology" World" launched the "circular RNA" column, which interprets and introduces the latest research progress and review of circular RNA every week, as well as related startup company reports and interviews
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We have also established a professional circular RNA exchange group, long press the QR code below, add the editor-in-chief WeChat, and note the unit-research direction/position-name
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Open reprint welcome to forward to Moments and WeChat groups