A research team from China has developed an mRNA-based T-cell-inducing antigen vaccine that strengthens the COVID-19 vaccine against SARS-CoV-2 variants.

Herd immunity through mass vaccination is an effective way to prevent infectious diseases. However, the common SARS-CoV-2 mutant strains have largely escaped the humoral immunity induced by the COVID-19 vaccine, which was developed on the basis of the S protein.

On May 23, 2023, a research team from Shenzhen Bay Laboratory, Tsinghua University, Institute of Medical Biology, Chinese Academy of Medical Sciences, and Fudan University published a paper in Nature Communications titled "An mRNA-based T-cell-inducing antigen strengthens COVID-19 vaccine against SARS-CoV-2".

The study developed a LNP-delivered mRNA-based T-cell induced antigen vaccine that induces both high titers of cross-neutralizing antibodies and efficient induction of activated cellular immune responses for synergistic function and efficient protection against infection and pathogenesis by beta and Omicron variants. It demonstrates the feasibility of enhancing vaccine efficacy by synergistically activating cellular and humoral immune responses and provides new insights for optimizing the COVID-19 vaccine, enhancing immune protection and addressing immune escape caused by viral mutations.

There are two major issues that need to be further addressed in the design of the current COVID-19 vaccine:
* How can the next-generation COVID-19 vaccine provide more potent protection, since antibodies may not be able to provide long-lasting protection due to the rapid rate of antibody depletion after immunization?
* How can the next-generation vaccine effectively avoid immune escape due to mutation of SARS-CoV-2, which may lead to the reduction or loss of protection of the existing vaccine?

To address these two questions, the research team first systematically analyzed the genome of SARS-CoV-2 and found that NSP-3, NSP-4, and NSP-6 contain cellular immune epitopes that are highly conserved among different prevalent mutant strains, and experimentally verified that these epitope-enriched regions can effectively activate the human cellular immune response. The research team also used mRNA vaccine technology to generate a novel HLA-EP antigen containing three cellular immune-enrichment regions that can target and activate T-cell immunity. Immunological characterization using an HLA-humanized mouse model of immune attack demonstrated that the cellular immune antigen could induce an efficient immune protective response.

The results suggest that a novel COVID-19 vaccine development strategy using synergistic activation of cellular and humoral immunity may enhance the immune protection of existing vaccines. The research team also proposed a "bivalent" mRNA vaccine design. On the one hand, the HLA-RBD target antigen was designed to induce neutralizing antibodies based on the receptor binding region (RBD) of SARS-CoV-2, and on the other hand, the HLA-EPs were screened and identified as the target antigen to induce efficient T-cell immunity, relying on the ability to induce T-cell immunity for long-lasting immune protection.

Subsequently, the research team used HLA-humanized mouse model and non-human primate model to evaluate the immune protection effect, and proved that the designed novel mRNA vaccine, HLA-RBD+HLA-EPs, can induce both high titer cross-neutralizing antibodies and efficient activation of cellular immune response, which can synergistically provide functional and efficient protection against infection and pathogenicity of beta and Omicron variants.

In this study, the research team focused on enhancing the activation of cellular immunity in the vaccines, providing ideas for the development of next-generation COVID-19 vaccines. The vaccine design strategy of synergistic activation of cellular and humoral immune responses will effectively enhance the immune protection of new vaccines against infectious diseases.

RESOURCE: https://mrna.creative-biolabs.com/mrna-vaccines-development.htm

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