Since the COVID-19 pandemic began, mRNA vaccines have moved from a niche platform to a widely deployed vaccine technology, and in doing so they reset expectations for how fast a new vaccine can be designed. Driven by the overall increase in medical insurance and R&D expenditure, the development of mRNA-based vaccines has surged.
The Clinical Rollout Since 2020
The first mRNA vaccine to receive emergency use authorization (EUA) was Comirnaty developed by Pfizer/BioNTech (December 2020) and Spikevax developed by Moderna (December 2020). Subsequently, mRNA vaccines that obtained local emergency use rights emerged one after another. GEMCOVAC-19 from Gennova Biopharmaceuticals in India was approved for emergency use in India (June 2022), AWcorna from Watson Biotechnology in China was approved for emergency use in Indonesia (October 2022) and a COVID-19 mRNA vaccine from Sway Biotechnology was approved for emergency use in Laos (December 2022). The platform was not confined to coronavirus: work on HIV began in parallel (NIH News March 14, 2022), and the phase III clinical trial of preventing respiratory syncytial virus (RSV) caused respiratory disease also showed that the vaccine developed by mRNA technology has good safety and clinical efficacy (Moderna News January 17, 2023).
That sequence matters for anyone planning a program today. The approval pathway that opened in 2020 established both a regulatory precedent and a manufacturing base, and later entrants inherited both.
A Pipeline Of More Than 195 Candidates
With the growing interest of various stakeholders and the promotion of clinical trials, the market for RNA-based therapies and vaccines is expected to continue to grow before 2035 under the advancement of molecular biology of RNA and the prospect of breakthrough candidate drugs. At present, more than 35 companies are involved in more than 195 mRNA-based therapies or vaccines that are in different stages of clinical development for different diseases, and some RNA-based therapies are expected to keep emerging clinically and be commercialized in the next decade.
As investors see the success of RNA therapy, they show more and more investment interest in biotechnology companies engaged in mRNA technology; meanwhile, biotechnology companies invest funds in improving mRNA technology platforms, streamlining operations and providing a wider range of services. The active participation of multinational pharmaceutical companies in the development of mRNA technology and drugs is also important. The global biotechnology companies in this field include (region, establishment time, employees. Sorted by company size): BioNTec (Germany, 2008, 1,200), Moderna (USA, 2005 ,760), CureVac (Germany ,2007 ,700), Sway Biotech (China ,2016 ,500), ImmoRNA (USA ,2019 ,200), Omega Medical (USA ,2017 ,200), eTheRNA (Belgium ,2013 ,50), Blue Magpie Biotech (China ,2019 ,50), Chimeron Bio (USA ,2015 ,10+).
What mRNA Offers Over DNA And Protein Approaches
Based on mRNA technology, emerging therapies have some advantages, such as engineering candidates to deliver mRNA molecules that encode functional proteins, which can replace defective proteins. The main advantages are as follows:
- mRNA therapies have the potential to restore gene expression or alter the genome without entering the cell nucleus;
- mRNA therapies do not require intracellular transcription, which makes them less prone to errors, thus achieving faster gene translation;
- the expression of mRNA is transient and controllable, due to the fact that mRNA cannot replicate in principle, thereby reducing the risk of overexpression or any related side effects;
- mRNA therapies have better transfection ability than other nucleic acid-based therapies (such as DNA), thus providing better expression opportunities and higher success rates;
- mRNA therapies have the possibility to cure diseases that are currently incurable, mainly because mRNA therapies use the cell's own mechanisms to produce natural and fully functional proteins;
- mRNA therapies have drug-like characteristics, which can simplify dose changes and repeated adjustments;
- mRNA therapies are faster from target gene selection to candidate products, so their development is relatively faster.
Biotechnology advances and molecular advantages drive this work. Compared with other therapeutic methods, RNA-based therapies combine multifunctional delivery platforms with high efficacy, high immunogenicity and low toxicity. They carry a low risk of adverse infections related to interferon responses or insertional mutations, since the RNA does not integrate into the host genome. The in vivo half-life of mRNA can be regulated by bioengineering, and modifying or improving delivery methods makes the drug more stable, which is a question for Pharmacokinetics (PK) rather than for formulation alone. Transcripts are also degraded through typical cellular activities, which limits how long they persist in the body, and the high yield of in vitro transcription reactions gives mRNA candidates good cost-effectiveness, speed and scalability.
Delivery, Stability And Manufacturing Constraints
Despite the many benefits of mRNA therapies, current research still faces many challenges. In addition to the stability of candidates and technical difficulties related to targeted delivery, other major issues include limited expertise and talent, lack of specialized infrastructure requirements, high capital investment requirements and constraints, and unclear and inconsistent production standards (GMP).
Targeted delivery is the constraint that shapes the rest of the field. An mRNA molecule on its own is large, charged and easily degraded in circulation, so the formulation carries as much of the burden as the sequence does; lipid nanoparticles are the usual answer, and how they distribute outside the injection site determines both effect and tolerability. Measuring that distribution is a separate discipline, covered under Biodistribution Imaging Service, and the formulation chemistry itself is reviewed in Application Prospects of Gene Drugs Based on Lipid Nanoparticles.
In addition, the current market-driven design of mRNA-based therapies is mainly through intramuscular injection, which seems unlikely to change significantly, at least not in the near future. Moreover, the marketed mRNA products are concentrated in infectious diseases and do not hold a clear advantage in cancer or rare diseases. In any case, more and more RNA-based therapies are being developed in different disease fields, which indicates that this technology has a very wide range of applications and is a highly active research field.
mRNA Vaccines Against Rapidly Mutating Pathogens
Vaccination is one of the main successes of modern medicine. For example, the prevalence of infectious diseases such as measles has decreased with vaccination programs, and smallpox has been basically eliminated after vaccination. Although traditional vaccines have achieved great success, these methods are still not very effective for rapidly mutating pathogens, such as influenza virus, Ebola virus or Zika virus, which remain a considerable risk for global public health. Once these viruses become epidemic, they bring large costs to the world.
The disadvantages of traditional vaccines can be addressed by mRNA vaccines based on mRNA technology. They can be manufactured in a shorter time with lower production costs and better anti-infective effects. mRNA vaccines have various advantages, including:
- They can simulate many aspects of natural viral infection; when an mRNA sequence enters a cell, it can synthesize viral antigen proteins that can even mimic the subtle details of viral infection. This can greatly enhance the body's immune response, including B and T cell responses;
- They can develop and produce multivalent mRNA for vaccines against complex viruses: using mRNA technology to produce multiple mRNA fragments targeting different viral proteins is feasible. This can produce vaccines that target complex multimeric antigen viral infections at the same time;
- They can quickly advance from pathogen discovery to clinical trial development: due to recent advances in bioinformatics, it is now possible to record sequences of several viral antigen proteins. It also becomes easier to identify target genes. Therefore, it is generally believed that mRNA vaccines provide new alternative treatments for life-threatening diseases or infection prevention.
Neoantigen Vaccines In Oncology
Antigens or factors related to tumor cell growth are sometimes called neoantigens. Neoantigens can be used as targets for human mRNA vaccines. Cancer vaccines are aimed at expressing these specific antigens in cancer cells and further achieving therapeutic effects. Most available cancer vaccines are therapeutic because they help stimulate immune cell responses that eliminate or reduce tumor cells.
Dolgin pointed out in a retrospective article that the concept of using RNA-based vaccines to treat tumors was first proposed 20 years ago and its feasibility was published. Since then, many preclinical and clinical studies have used mRNA vaccines to treat tumors.
For a platform whose pharmacology depends on host translation machinery, cross-species comparability is not a formality: the same construct can behave differently depending on how efficiently the transcript is taken up and translated in a given species. That is the question NHP Pharmacology work is set up to answer. The first article in this series, MRNA-based Therapies: Past, covers how the platform reached this point, and the next installment takes on what remains unsolved.
