Circular RNA vaccine, effective against delta and omicron

A pneumonia epidemic caused by the new coronavirus SARS-CoV-2 in early 2020 triggered a global pandemic that has lasted to this day. Unfortunately, the situation with the epidemic remains dire to this day. According to the World Health Organization, more than 488 million people have been infected worldwide to date, with a total death toll of more than 6.16 million. According to a Nature article, the number of deaths has been greatly underestimated, and the total number deaths worldwide could be as high as 18 million.

Notably, with the widespread global spread of SARS-CoV-2, new variants continue to emerge, including Alpha, Beta, Gamma, Delta, and more recently, Omicron that spreads rapidly, exhibiting super-contagiousness. More critically, the existing vaccines provide much less protection against Omicron.

This serves as a reminder that, as a result of the continuous mutation of SARS-CoV-2, the efficacy of existing vaccines and therapeutic antibodies is gradually declining. As a result, there is an urgent need to develop safe and effective vaccines against SARS-CoV-2 infection and mutant strains.

On March 31, 2022, Wensheng Wei's team at Peking University published a research paper entitled: Circular RNA Vaccines against SARS-CoV-2 and Emerging Variants in the leading international academic journal Cell.

The paper, which was published ahead of schedule in the preprint bioRxiv in January, builds on a previous paper published in March 2021, in which Wei's team demonstrated in rhesus monkeys that their previously developed circRNA vaccine encoding the trimeric receptor binding domain (RBD) of the SARS-CoV-2 spike protein triggered effective neutralizing antibodies and T-cell responses that produced effective protection against Delta and Omicron strains.

Unlike the linear mRNA vaccines used today, this circular RNA vaccine does not require nucleotide modification and remains effective when stored at room temperature for 2 weeks, due to the high stability of both circular RNAs themselves. This suggests that it has a very promising application against SARS-CoV-2.

Vaccination is the most promising strategy for preventing and ending COVID-19. There have been multiple sorts of vaccines used, including inactivated vaccines, adenovirus vector vaccines, subunit vaccines, and the emerging mRNA vaccines.

mRNA vaccines have the advantages of fast and cheap production and rapid response to virus mutations. However, mRNA vaccines are stored and transported under harsh conditions (-70°C) and have potential immunogenic side effects.

Circular RNA is found in fungi, plants, insects, fish, and mammals, and the genomes of some viruses, such as hepatitis D virus and plant-like viruses, are circular RNAs as well. Circular RNA is more stable than linear mRNA because its covalently closed loop structure protects it from exonuclease-mediated degradation.

The research team used self-splicing type I intron nucleases to generate circRNA-RBD, which encodes the SARS-CoV-2-RBD antigen. To enhance the immunogenicity of the RBD antigen, they fused the phage T4 fibronectin trimer motif to its C-terminus, thereby mimicking the natural conformation of the SARS-CoV-2 S protein trimer.

Cellular experiments showed that circRNA-RBD could express RBD antigen of SARS-CoV-2 in human cells and mouse cells in large amounts, with significantly higher expression than linear mRNA-RBD, and could effectively block SARS-CoV-2 from infecting cells.

In mouse experiments, lipid nanoparticle (LNP)-delivered circRNA-RBD effectively neutralized SARS-CoV-2, and a strong T-cell immune response was generated in the spleen of mice, suggesting that the circRNA-RBD vaccine did induce a durable humoral immune response and a strong T-cell immune response in mice.

The team also designed a circRNA-RBD vaccine that was shown to produce high levels of neutralizing antibodies against Delta and Omicron strains.

This time, the team also tested the circRNA vaccine's effectiveness in non-human primate, and the results showed that it was capable of producing effective protection for rhesus monkey.

Overall, this study confirms the advantages of circRNA vaccine, such as its good thermal stability, high expression of encoded antigens, and broad applicability, as well as the successful design of corresponding circRNA vaccine against infection with SARS-CoV-2 and its mutant strains, implying that circRNA vaccine can be used as a novel vaccine and therapeutic platform in the COVID-19 pandemic.

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