mRNA vaccine – just the beginning?

by Dr. Myriam Mendila, head of development for CureVac

World Immunization Week falls April 24-30, and it is an important week to highlight needed action and to promote the use of vaccines to protect people around the world, of all ages, against infectious diseases.

Dr Myriam Mendila, head of development, CureVac

World Immunization Week aims to promote the use of vaccines to protect people of all ages from disease and provide immunizations. Although vaccination is one of the most effective public health interventions for preventing, controlling and even eradicating disease, and has made one of the greatest contributions to human health and life expectancy, the global need for new and better vaccines continues to be available to everyone. .

Over the past 60-70 years, great strides have been made in the development of vaccines that have provided enormous benefits to human health. With the application of mRNA technology to combat the devastating effects of coronavirus infection as one of the newest, could this technology have a similar impact on other diseases?

Dr. Myriam Mendila, head of development for CureVac, explains how we may have just scratched the surface of how mRNA vaccines have the potential to improve outcomes for many other diseases beyond COVID-19.

The global coronavirus pandemic has resulted in unprecedented cooperation and collaboration to address this significant global threat. Scientists around the world are looking for technologies that can quickly be adapted into vaccines and developed.

Fortunately, mRNA is primed and ready to make what we now know, a huge impact on the severity of the coronavirus infection and allow the world to return to normal.

mRNA is not a new technology

In contrast to general perception as a new technology, the use of mRNA for medical purposes has been under development for about 20 years, with numerous clinical studies being conducted, including its use as a vaccine for infectious diseases and cancer. Since the founder of CureVac, Dr. Ingmar Hoerr, was able to demonstrate that mRNAs could be stabilized and introduced into the body without being destroyed, extensive research has been undertaken to design optimal mRNA backbones that might be adapted for therapeutic use.

mRNA itself is unstable and is quickly broken down by enzymes in the body. To overcome this challenge, lipid nanoparticles (LNP) are commonly used to provide a protective coating, enabling efficient delivery of mRNA into cells.

After sequencing the coronavirus spike protein, which allows the virus to enter human cells, the mRNA strand coding for that spike protein can be adapted to make a vaccine. After administration of the mRNA vaccine, an immune response is triggered against the coronavirus spike protein. Vaccines can be produced within days, which demonstrates the power and versatility of mRNA technology. This is not only critical for preparedness for future pandemics, but also for responding to other infectious diseases that continue to impact global health, including seasonal influenza, respiratory syncytial virus (RSV), malaria and many others. The advantage of mRNA technology is that it is very suitable for combining different antigens into a single vaccine. There are already studies with multivalent vaccines combining influenza and COVID-19, RSV and COVID-19 and the potential to incorporate all three into one vaccine.

In some ways, the clinical development timeline for mRNA technology to gain regulatory approval for use in a specific disease, and then go to market, is very similar to other technologies in the same indication, such as another type of vaccine, monoclonal antibodies. , RNA interference, drug-antibody conjugates, etc. The difference during a pandemic, is the tight clinical development timeline for vaccine product development and the unique situation where multiple stakeholders come together to achieve a common goal. Many people are now wondering, if this was achievable with COVID-19, why haven’t similar efforts worked with other diseases?

It’s still early days for an mRNA vaccine

Despite decades of research, in many ways, we are still in the early stages of understanding mRNA’s potential for medical use. After COVID-19, evaluating the impact of mRNA on other diseases is still in its early stages. Development of a new generation of COVID-19 vaccines is off to a good start, as well as extending the technology to influenza, RSV and other respiratory diseases. But real indicators of the impact of mRNA on human health would work in other key therapeutic areas. Most of the companies developing mRNA technology are also looking into oncology, including at CureVac, which was the company’s initial focus at its founding. The concept of developing a vaccine for cancer is not new, but developing an effective product is elusive.

In oncology – such as prophylactic vaccines for infectious diseases – cancer vaccines teach the immune system to recognize cancer cells and kill them. Because cancer cells are so closely related to normal healthy cells, this has proved extremely difficult and can only be achieved by mimicking specific proteins found on the surface of cancer cells.

Over the last decade, major technological advances, such as next-generation sequencing, have been made that allow precise data from patient tumor samples to be extracted, including the identification of point mutations that give rise to tumor-specific antigens that are only or mostly found in tumor cells and serve as targets. cancer vaccine candidate. With the ability to sequence the entire exome (only the protein-coding sequences of the genome) of any patient, it is possible to view an inventory of genomic changes in tumors. This information provides the basis for using mRNA technology coding for specific tumor antigens as the basis for cancer vaccine development and hopefully a success that has not been achieved by previous technologies.

This approach is now starting to show potential. Earlier in April at the American Academy for Cancer Research (AACR) annual meeting, Merck and Moderna presented encouraging clinical data using mRNA plus Keytruda cancer vaccines in the treatment of early melanoma, and further data in other cancer settings are eagerly awaited. While the development of mRNA cancer vaccines based on information from whole exome sequencing is heading towards phase III clinical trials, the technology is already advancing to the next stage. Whole genome sequencing, combined with short-term and long-term RNA sequencing, has the potential to provide innovative approaches for broader cancer antigen discovery, enabling the detection of complete inventories of genomic alterations in specific tumors as the basis for cancer vaccines.

reach the patient

The success of vaccine development in general, regardless of the state of the disease, is a great achievement but only the beginning. Then it is necessary to reach the patient. Despite much progress, global distribution of new vaccines remains a challenge. Traditional vaccine production requires multiple steps, from manufacturing the drug substance to filling & finishing, as well as the logistics required to deliver the product to the point of need.

During COVID, there was the added challenge of storing vaccines in cold storage, at much lower temperatures than the typical cold supply chain. However, this issue has now been partially resolved, enabling easier distribution to all parts of the world.

Again, the power and flexibility of mRNA in vaccine development can dramatically disrupt the status quo. Manufacturing infrastructure is now in place to produce new mRNA vaccines quickly on a large industrial scale, potentially resulting in lower prices per vaccine and allowing companies to supply low-income countries more cost-effectively.

Our colleagues at BioNTech have also taken a more hands-on approach in Africa to increase production and supply capacity with the introduction of container solutions. The first container is now in Rwanda.

At CureVac, we pioneered an integrated and automated mobile platform, a “printer” for small-scale and therapeutic manufacturing of mRNA vaccines under Good Manufacturing Practice (GMP) standards. The printer, which covers all the steps for fast and standardized manufacturing, has been designed to potentially facilitate broad access to mRNA technology and is expected to accelerate the transition of innovative product concepts from science to clinic in various therapeutic fields, such as new mRNA-based vaccines in pandemic situations, production of mRNA products for clinical studies as well as personalized mRNA-based therapies in oncology. The printer is RNA agnostic, meaning users can build any RNA sequence, not just from CureVac.

New product development that addresses today’s manufacturing challenges relies on effective mRNA strand design. For example, the 5′ and 3′ UTR elements flanking the coding sequence strongly influence mRNA stability and translation, both of which are critical to vaccine efficacy. This regulatory sequence also influences the half-life and expression of therapeutic mRNAs. Technological innovations have enabled the development of a new generation of mRNA vaccines that not only address current challenges, but also provide a foundation for future research.

The potential of mRNA is enormous, and it has changed industrial policy. Three major companies with expertise in mRNA development and manufacturing are shaping the regulatory environment, and they are setting new standards in the field to enable continuous innovation. But innovation is not limited to a handful of well-known companies that have developed or are developing a COVID-19 vaccine. Partnerships and collaborations have always played a key role in technology development, with start-ups and academia often providing innovation and larger biotech/pharma companies the funding, infrastructure, and expertise for development and commercialization. Collaboration is key to the success of mRNA vaccines in COVID-19 and will be important in the future because the development of mRNA vaccines and therapies is not easy.

In short, we are only beginning to realize the potential of mRNA vaccines. Over the next few years, we can see the technological advances needed to overcome existing limitations – single-shot multivalent vaccines for infectious diseases, incremental success in cancer vaccines and therapeutic applications in other major diseases, such as heart disease, metabolic disorders , and neurological conditions.

Beyond vaccines, mRNA platforms could be the next transformation in medicine that addresses the unmet needs of countless patients around the world.

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