The Path Forward: The Bright Future of mRNA Technology

While the development of SARS-CoV-2 vaccines marked the first widespread use of mRNA technology, research into this method of vaccination first began decades ago [1]. Still, the pace at which the mRNA vaccines were developed over the last two years remains unprecedented. Historically, the approval of new clinical treatments has been a complex and lengthy process. However, the pandemic called for a rapid worldwide response from biotech companies and clinical leaders. “Perhaps one of the most surprising aspects of the industry’s reaction to the SARS-CoV-2 crisis has been how quickly vaccines were developed. The pandemic has shown what’s possible when the right resources, sufficient government support, and genuine collaboration all come together with a singular focus,” said Serena Smith, Director of Market Intelligence & Strategy, mRNA Vaccines & Therapeutics, at Thermo Fisher Scientific.

mRNA technology could very well revolutionize health care beyond vaccines in the near future, as biotech companies explore broad applications of mRNA technology for tackling long-standing challenges plaguing the path to treatment of many diseases. As their exploration and innovation continues, we can expect to see increased momentum in the development and commercialization of novel mRNA-based therapies in 2023 and beyond.
 

mRNA as the technological basis of vaccines and therapeutics may appear to be novel, but scientific research into its development began decades ago. A key turning point in this journey came when, in the 2005, Dr. Katalin Karikó and her colleague Dr. Drew Weissman were successful in minimizing the body’s harmful inflammatory immune response to exposure to a virus’s mRNA while still allowing it to stimulate the immune system [2]—a thorny obstacle in the path for advancement of mRNA therapies.

Traditionally, vaccines are virus-based, using attenuated or inactivated versions of the target virus. Some examples of these virus-based vaccines include the ProQuad^TM vaccine for measles, mumps, rubella, and varicella; the RotaTeq^TM vaccine for rotavirus, Avaxim^TM vaccine for hepatitis A, and many flu vaccines (Fluzone^TM, FluLaval^TM, and Fluad^TM among others). mRNA vaccines, on the other hand, use a synthetic genetic sequence to instruct the cells to recognize a virus and activate the immune system. 

In mRNA vaccine development, researchers begin by creating a strand of mRNA in a lab. This prompts our cells to create protein fragments that are based on the “non-self” characteristics of the virus. When recognized, the protein fragments trigger a response in the patient’s immune system. With COVID-19 vaccines, for example, the mRNA causes the patient’s cells to produce the spike protein of the SARS-CoV-2 virus. When the immune system recognizes the spike as non-self, it produces antibodies that defend the body against SARS-CoV-2.

While there are unique challenges associated with the development and commercialization of both traditional and mRNA vaccines, there are many advantages to the use of mRNA technology. “To put it bluntly, traditional vaccines take a long time to commercialize. The level of difficulty in both developing and testing new vaccines remains a high hurdle for any biotech or pharma company.”, said Natraj Ram, Vice President of Innovation, Bioproduction, at Thermo Fisher Scientific. As mRNA vaccines do not use attenuated or inactivated viruses, there are few, if any, potential safety issues associated with virus particulates. The purification process is also easier, and the mRNA approach avoids the lengthy use of cell cultures and the need for optimization to achieve the right growth conditions. But the greatest appeal of the mRNA technology lies in the fact that it is modular—it can be easily tweaked to encode most proteins without a significant alteration in its chemical nature. This is also what makes the future of this technology so promising.
 

As excitement in the mRNA space continues and new players rapidly join the industry, there is keen interest in the methodologies and practices that enable scaled manufacturing of mRNA products using in vitro transcription (IVT), the gold standard for mRNA synthesis. One of the reasons biotech companies were able to swiftly develop and distribute SARS-CoV-2 mRNA vaccines to the public was their collaboration and innovation in adopting IVT reactions to help make mRNA production rapid, inexpensive, and scalable.

IVT is a robust and efficient process for synthesizing RNA that are long and stable and offers many advantages over conventional plasmid DNA for the expression of target proteins. The use of in vitro synthesized RNA can not only open doors for a new class of gene therapies, but it also has historically been instrumental in the development of CRISPR editing tools.
 

Yet challenges remain when it comes to optimizing the IVT process, and new techniques are still works in progress. For example, researchers are looking at ways to minimize the formation of unwanted byproducts such as double-stranded RNA (dsRNA), which is not removed by the affinity resin and can be tedious and time-consuming to detect using current techniques. If not addressed, larger quantities of dsRNA may require an extra polishing step that could slow down the development process. Potential future solutions for reducing dsRNA include modifying the enzyme used in the reaction or optimizing the template sequence. “It is important to note that the balance is much more likely to be tipped in your favor with high-quality starting materials and raw materials,” said Jeneffer England, R&D Manager, mRNA Vaccines & Therapeutics, at Thermo Fisher Scientific.

As mRNA production continues to change and grow, the gradual scale-up of IVT mRNA can provide the foundation for a broad range of applications. IVT mRNA can be manufactured at relatively low cost and within a few hours, enabling the generation of mRNA ranging from a few hundred to more than 10,000 nucleotides in length. This can facilitate drug discovery and optimization, which is integral for this field at this time of growth.

From emerging biotech companies to global biopharma companies, we continue to see industry investments in the mRNA landscape. While the technology itself and manufacturing processes are still evolving, mRNA vaccines and therapeutics show incredible promise in fulfilling currently unmet medical needs. In fact, there are clinical research projects already underway to develop mRNA therapies that could treat or prevent a myriad of diseases and conditions beyond COVID-19. These include therapeutics for influenza, HIV, Lyme disease, Ebola virus, Zika virus, and even colorectal cancer.

In a phase 1 safety and immunogenicity trial in humans, the International AIDS Vaccine Initiative tested an mRNA vaccine for HIV. The researchers reported that it produced strong anti-HIV antibody responses in study subjects [3], stimulating the development of B cells capable of producing the neutralizing anti-HIV antibody VRC01. Meanwhile, Moderna, one of the key leaders in the mRNA vaccine arena, has been pursuing the development of an HIV vaccine for years. Approximately 38 million people are currently living with HIV worldwide [4], with 1.2 million in the US [5]. The company’s research in the development of an HIV vaccine paved the path for the creation of the Moderna COVID-19 vaccine.

A group of international researchers is also testing whether mRNA technology can potentially prevent colorectal cancer from recurring. Many colorectal cancer patients rely on surgery for the removal of cancerous tumors, but even after surgery, cancer cells can remain in the body. These cells shed DNA into the bloodstream, which can help researchers identify if the patient is at high risk for recurring colorectal cancer [6]. Now a clinical trial is following high-risk patients with stage II and stage III colorectal cancer who test positive for circulating tumor DNA after surgery [7]. Lastly, clinical leaders are also exploring the potential of mRNA for producing proteins missing in many diseases, such as cystic fibrosis, diabetes, and sickle cell anemia [8].

As mRNA-based therapeutics continue to garner increased interest, it is also important to remember key lessons the pandemic has taught us: collaboration and partnership are critical to problem solving. The biotech industry is ushering the world into a new era where the ways in which clinicians care for their patients may more closely align with what’s very important: high-quality, accessible, and equitable treatments. 
 

1. Dolgin E. The tangled history of mRNA vaccines. Nature 597.7876 (2001): 318–324. 
2. Karikó K, Buckstein M et. al. Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity 23.2 (2005):165–175. 
3. Henderson, Emily. “Phase 1 Clinical Trial of Novel HIV Vaccine Approach Shows Promising Results.” News Medical, February 3, 2021. 
4. World Health Organization. “HIV.” World Health Organization, July 2022. 
5. Centers for Disease Control and Prevention. “The State of the HIV Epidemic in the U.S.” Centers for Disease Control and Prevention, June 23, 2022. 
6. Cheng F, Su L, Qian C. Circulating tumor DNA: a promising biomarker in the liquid biopsy of cancer. Oncotarget 7.30 (2016):48,832–48,841. 
7. BioNTech SE. “A Phase II Clinical Trial Comparing the Efficacy of RO7198457 Versus Watchful Waiting in Patients With ctDNA-positive, Resected Stage II (High Risk) and Stage III Colorectal Cancer.” ClinicalTrials.gov, February 14, 2023. 
8. Qin, S, Tang, X et al. (2022) mRNA-based therapeutics: powerful and versatile tools to combat diseases. Sig Transduct Target Ther  7(1):166–200.

ProQuad and RotaTeq are trademarks of Merck & Co., Inc. Avaxim and Fluzone are trademarks of Sanofi Pasteur Limited. FluLava is a trademark of GSK plc. Fluad is a trademark of Seqirus UK Limited.

This article was published originally in the “Making the promise of mRNA a reality: overcoming scale-up challenges” eBook in collaboration with Genetic Engineering & Biotechnology News (GEN).Click here to read additional articles in the eBook