A New Paradigm in Infectious Diseases Treatment & Prophylaxis Shaped by the Current Pandemic
“There is nothing more powerful than an idea whose time has come”- Victor Hugo
By: Jovana Andonovska Burilovska, MD, Medical Director, Infectious Diseases at Medpace
The Past: A brief look back at key discoveries
Hand hygiene and prophylactic vaccines are one of the major achievements of medicine. As is well known, the first concept (hand hygiene) was proposed by the Hungarian physician Ignaz Semmelweis in the mid -19th century. Despite the evident strength of the concept, Semmelweis was outcast by his contemporaries. In 1990, another Hungarian born scientist, Katalin Karikó, recognized the concept of using mRNA to synthetize any desired protein within the host whether antibodies to protect against infection, enzymes to reverse a rare disease, or growth agents to repair damaged tissue. Her research went on unnoticed, until another scientist in the early 2000’s managed to create pluripotent stem cells out of fully differentiated adult cells, using mRNA templates to produce or silence proteins within a cell.
In the meantime, academia concentrated on harnessing the natural power of viruses to provoke immune responses or even to integrate within the genome of the host, exhibiting their effects on the long run as the cell divides. The power of this machinery was first harnessed in the 1970’s by an American scientist, and later a Nobel Laureate, Paul Berg. The concept was that by using replication defective viruses, one can try and force the body to produce the desired proteins that can be used primarily as options for treatment of untreatable chronic diseases. Among the many viral vector vaccines that had been used in preclinical and early phase clinical research, the adenoviral vector vaccine combined with the Modified Vaccinia Ankara (MVA) viral vector vaccine had shown the most promise.
The Platforms: From conventional to promising alternatives
Initially, viral vectors were developed as an alternative to transfection of naked DNA to be used in experiments of molecular genetics. Research had shown that some of the viral vectors integrate in the cellular genome granting stable expression of the desired proteins (viral vectors with these properties are generally used in gene therapy, while non-integrating viruses are used in vaccine development). The characteristics include:
- Safety: Modified via deletion of a part of the genome critical for replication, the end result is a virus that can efficiently infect cells, but cannot produce new virions on its own (it needs a helper virus to do so);
- Low toxicity: Chosen and tailored in such a way to have a minimal effect on the physiology of the infected cell;
- Stability: overcoming the inherent instability and potential to rapidly rearrange the genomes, and;
- Cell type specificity: designed to infect as a wide array of cells as possible, however can be modified to target a specific cell type;
The mRNA vaccine platform, on the other hand, represented a promising alternative to conventional vaccine approaches because of the high potency, the capacity for rapid development and potential for low-cost manufacture and safe administration. What was once an obstacle in mRNA delivery into cells, now has been overcome by coating of the mRNA with LNP (lipid nano particles). As a result, multiple mRNA vaccine platforms for infectious diseases and several types of cancer emerged. Two major types of RNA are currently studied as vaccines: non-replicating mRNA and virally derived, self-amplifying RNA.
Ultimately, the use of mRNA has several beneficial features over subunit, killed and live attenuated virus vaccines, as well as DNA-based vaccines including:
- Safety: A non-infectious, non-integrating platform, there is no potential risk of infection or insertional mutagenesis, with regulatable in vivo half-life;
- Efficacy: Stability and the capacity for translation can be regulated via various modifications, while efficient in vivo delivery is achieved by the use of carrier molecules, allowing for rapid uptake and expression in the cytoplasm. As a minimal genetic vector, anti-vector immunity is avoided, and mRNA vaccines can be administered repeatedly, and;
- Production: mRNA vaccines have the potential for rapid, inexpensive and scalable manufacturing, mainly owing to the high yields of in vitro transcription reactions.
The Pandemic: Vaccine development on the fast track
As COVID-19 struck, all focus, fear and billions of dollars flew into the companies who held the licensed technologies, inspiring them to defocus from the primary oncologic sphere and enter the dynamic realm of infectious disease.
The crushing and volatile impact of the Pandemic allowed for some experimental drugs (among them the mRNA vaccines) to gain Emergency Use Authorization (EUA) by the FDA and conditional marketing approval in the European Union. It took approximately eight months for the novel mRNA vaccines from start of the clinical trial program in March/April 2020 until the EUA was granted in November 2020. This was an unprecedented timeline which overlapped among the different contesting companies offering both the mRNA and adenoviral vector vaccine platforms.
Since the first roll-out to the general public in mid-December 2020, both vaccine types have been given to millions of people, with more waiting in line (literally) to receive one or the other. Meanwhile, the medical community gains exponential insight into the safety, reactogenicity and immunogenicity of the platforms themselves.
The Promise: A lasting impact for the future of clinical development
The Covid-19 pandemic will end, or as any pandemic in the past will lose its momentum. Yet, the precedents and the new paradigms formed in clinical research as a result of it will last.
In the aftermath of the Pandemic, we will face a world and a Pharma industry shaped by it including:
- The use of the new vaccine platforms used on a large population scale with demonstrated safety and efficacy, for different indications.
- The necessity to deliver a promise will drive the speed of gaining IND approvals and the Emergency authorization programs being used to add to the greater good.
- mRNA technology positioned as a promising prophylactic and therapeutic modality with a broad potential including infectious disease vaccines, cancer immunotherapies, mRNA passive immunotherapies, therapeutic protein replacement therapies, treatments of genetic diseases.
- Public health issues trumping most other aspects of society.
CROs can bring depth of knowledge and experience to clinical development in vaccine research
The bond formed among the science of the small biotech and resources and logistics of large pharma will only grow stronger, tied and delivered under the vigilante eye of the competent CROs. The impact and value of a global CRO for vaccine development include regulatory expertise with resources to keep pace with the newly shaped and emerging guidance for the Industry. CROs that understand the necessity of delivering prophylactic vaccines, which are safe and intensely and easily reproducible, as a primary focus. CROs like Medpace with front-line COVID-19 trial experience, which have demonstrated success working with sites and patients in overlapping, yet different, indications and can work with greater speed and agility in any indication in which the new vaccine platforms can be utilized.
In the wake of the pandemic, there is a tremendous opportunity to new ways of tackling old issues. There are opportunities to find a functional cure for chronic Hepatitis B infections; to combat HPV induced diseases in its tracks; to meet the rising need for prophylactic and treatment vaccines for CMV infections; to fight the ever-increasing resistance to antimicrobials by creating treatment vaccines to combat resistant microorganisms; to prevent a new devastating pandemic of a hemorrhagic fever by prophylactic large scale manufacturing of combined filovirus vaccines; to find a promise of crushing the bastion that HIV holds for decades, or even, the promise of a world where in the race for survival, prophylaxis outruns the contagious diseases.