Do mRNA vaccines still have future after the end of COVID-19?

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Do mRNA vaccines still have future after the end of COVID-19?

Do mRNA vaccines still have future after the end of COVID-19?

The mRNA vaccines of Pfizer /BioNTech and Moderna have great achivement in the past few years of the COVID-19 epidemic, making people understand and pay attention to this technology.

Since then, more and more companies and pipelines are developing mRNA drugs at home and abroad .

The field of research and development of mRNA drugs has become the fastest growing biomedical segment in the past two years. Multinational companies such as Pfizer, BioNTech , Moderna , Sanofi, GSK, and AstraZeneca have begun to deploy mRNA technology across the board .

The layout of mRNA vaccine drugs and related industrial chains is carried out through independent / cooperative research and development .

Thirty years ago, mRNA – based nucleic acid vaccines were proposed with the hope of producing safe, versatile, and easy-to-manufacture vaccines.

mRNA vaccines have many advantages over traditional vaccines: unlike some viral vaccines, mRNA does not integrate into the genome, avoiding concerns about insertional mutations; mRNA vaccines can be manufactured in a cell-free manner, making them fast and economical , Efficient production.

Furthermore, a single mRNA vaccine can encode multiple antigens, enhance the immune response against adaptive pathogens, and enable targeting multiple microbial or viral variants in a single formulation.

However, with the end of the COVID-19 epidemic, where will mRNA vaccines go?

The application field of mRNA vaccine is not limited to COVID-19 disease

mRNA vaccines can be applied not only in the COVID-19 field, but also in other fields such as the prevention of cytomegalovirus ( CMV ), Zika virus, respiratory syncytial virus ( RSV ), influenza virus, rabies virus and other pathogens or the development of therapeutic vaccines (mainly cancer vaccines) etc. 1 .

Do mRNA vaccines still have future after the end of COVID-19? Legend: mRNA vaccine development pattern. By geographic area and industry development

Regardless of the field of prevention or disease treatment, mRNA technology can theoretically produce any protein needed by humans . Therefore, the value of mRNA technology is self-evident.

Enterprises are also actively looking for the next export of mRNA vaccines, such as the cooperation between Pfizer and BioNTech to develop a herpes zoster vaccine or the cooperation between Merck and Moderna to develop a personalized cancer vaccine.

On February 23 , 2023 , the FDA has granted the Moderna/ Merk & Co. personalized mRNA cancer vaccine mRNA-4157/V940 and Keytruda combination therapy ” Breakthrough Therapy ” designation for adjuvant therapy after complete resection of high-risk melanoma patients.

The designation means that mRNA therapy could become a new frontier in the treatment of melanoma and other cancers.

In addition, many companies are actively developing new mRNA drugs, such as BioNTech , a company that shines because of the COVID-19 vaccine jointly developed with Pfizer.

In the post-epidemic era, it is actively deploying the application of mRNA technology in other indications 2 .

BioNTech has many layouts in the field of oncology , and treating cancer is the company’s future focus.

Their R&D pipeline includes not only a variety of vaccines and innovative therapies based on mRNA technology, but also cell and gene therapies, targeted antibodies, small molecule immunomodulators, ribologicals ( Ribologicals , such as mRNA- encoded cytokines) and a new generation of Immunomodulatory therapy, these different therapies can also be combined to achieve better efficacy.

Do mRNA vaccines still have future after the end of COVID-19?

In addition to the COVID-19, BioNTech is also developing vaccines against malaria, tuberculosis, and HIV .

Do mRNA vaccines still have future after the end of COVID-19? Legend: BioNTech’s other mRNA vaccine pipelines

Growing pipeline of mRNA drugs entering clinical trials

The product line of mRNA therapy entering clinical trials continues to grow, with more than 200 global R&D pipelines , especially the systemic delivery of protein substitutes for the treatment of rare monogenic diseases , as well as cytokines or antibodies for cancer immunotherapy3 .

AZD8601 is an mRNA encoding vascular endothelial growth factor ( VEGF-A ) , developed by AstraZeneca in collaboration with Moderna. In November 2021 , AstraZeneca announced positive results from the Phase 2a EPICCURE study: in heart failure ( HF ) patients, AZD8601 met the primary endpoints of safety and tolerability.

But in July 2022 , AstraZeneca cut off the AZD8601 R & D pipeline from its Phase 2 clinical pipeline .

The pharmaceutical giant dropped the mRNA therapy months after reporting positive results . But the therapy is still in Moderna ‘s development pipeline.

Legend: Some mRNA drug clinical pipelines

Challenges and Solutions of mRNA Therapy

However, translating mRNA into a new therapeutic modality to benefit patients with rare and common diseases still faces a series of challenges4 :

mRNA therapy needs to produce high levels of protein ;
The protein produced by mRNA therapy has poor tissue bioavailability , short half-life in blood circulation , and low delivery efficiency of the carrier ;
Repeated administration will stimulate the innate immune response, resulting in a decrease in protein expression levels.

Despite the difficulties, researchers are working on developing a series of innovative technologies to solve problems in mRNA optimization, delivery, production and pharmaceuticals :

1. Using chemically modified nucleosides to replace natural nucleosides (especially uridine) to optimize the mRNA sequence, significantly reducing the possibility of mRNA being recognized by the innate immune system and improving protein expression levels ;

2. Based on the self-amplification mechanism of RNA viruses, the replication of self-amplifying mRNA (samRNAs) sequences can be induced in the cytoplasm, thereby reducing the frequency of administration ;

3. Use circular RNA (circRNA) instead of linear RNA ;

Circular RNAs ( circRNAs ) are stable and ubiquitous RNAs in eukaryotic cells that are generated by back-splicing. Synthetic circRNAs and some endogenous circRNAs can encode proteins, raising the prospect of circRNAs as gene expression platforms.

First part 1-6 corresponds to upstream intron and 5 ′ UTR , IRES , N- terminal ( N′ ) tag, coding sequence ( CDS ), C- terminal ( C′ ) tag and 3′ UTR and downstream intron by Golden Gate reactions were individually cloned into partial plasmids5 .

Partial plasmids and circRNA backbones were then combined in a second Golden Gate reaction to generate circRNA plasmids.

The circRNA backbone contains a CAG promoter that enables circRNA transcription after transient transfection in cellulose , an IVT – enabled T7 promoter, homologous sequences to assist RNA recycling, a low-structure region that promotes RNaseR synthesis capacity, and bacterially expressed GFP Shedding sequences to negatively select for incorrect assemblies.

If using a CDS without N’ or C’ tags , parts 3-5 are replaced with individual parts. The PCR product of the circRNA plasmid was subsequently used as a template for IVT to synthesize RNA .

Finally, RNaseR purification was performed to digest linear RNA and isolate circRNA .

4. Improve the purity of mRNA ;

5. Optimize the carrier delivery system, such as using lipid nanoparticle ( LNP ) delivery system, extracellular vesicle delivery system, biomimetic carrier system ;

The success of mRNA therapeutics depends largely on the availability of delivery systems that can safely, efficiently and stably translate genetic material into functional proteins. The delivery system refers to the technology of how to wrap the single strand of mRNA so as not to be degraded, and successfully fuse with the cell membrane into the cell. In the delivery system, the mainstream method is to use LNP technology .

Other carrier delivery systems are also currently being developed. You et al. reported on nature biomedical engineering that extracellular vesicles ( EVs ) produced by cell nanoporation of human dermal fibroblasts encapsulated the extracellular matrix α1I type collagen ( COL1A1 ) mRNA induces the formation of collagen – protein grafts and reduces wrinkle formation in the collagen-depleted dermis of photoaged mice6 .

6. Increase tissue targeting by changing the administration method, such as inhalation administration instead of intravenous infusion can directly deliver the drug to the lungs, intranasal administration instead of direct intracerebral injection becomes a non-invasive method targeting the central nervous system. Invasive mode of administration ;

7. By adding different types of lipids to the LNP formulation, the tissue specificity of LNP delivery can be altered .

The end of the epidemic does not mean the end of mRNA drugs. mRNA drugs can be applied not only to COVID-19 diseases, but also to other infectious diseases and cancers. At present, many companies at home and abroad are deploying mRNA drugs , and perhaps in the future Let’s look forward to discovering the m RNA that prevents cancer !

References

1. Arun Kumar, Jeremy Blum, Tung Thanh Le, Nicolas Havelange, Diletta Magini and In-Kyu Yoon, The mRNA vaccine development landscape for infectious diseases, Nature Reviews Drug Discovery 21, 333-334 (2022)

2. BioNTech | Technologies for customized treatment approaches

3. Ken Garber, mRNA pioneers refocus on therapeutics, Nature Reviews Drug Discovery 21, 699-701 (2022)

4. Eduarde Rohner, Ran Yang, Kylie S. Foo, Alexander Goedel & Kenneth R. Chien, Unlocking the promise of mRNA therapeutics, Nature Biotechnology volume 40, pages 1586–1600 (2022)

5. Robert Chen, Sean K. Wang, Julia A. Engineering circular RNA for enhanced protein production, Nature Biotechnology volume 41, pages262–272 (2023)

6. Yi You, Yu Tian, Zhaogang Yang, Junfeng Shi. Intradermally delivered mRNA-encapsulating extracellular vesicles for collagen-replacement therapy, Nat. Biomed. Eng (2023).

Do mRNA vaccines still have future after the end of COVID-19?

(source:internet, reference only)

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