Development of a Vaccine
The Economist published an article by Bill Gates on 23 April 2020 on COVID-19 and in this piece he highlights major medical breakthroughs that can be expected as a result of this pandemic, and the research that is underway to find a workable solution to this global crisis.
The first medical breakthrough referred to is the development of a vaccine. This feat will be
“the fastest humankind has ever gone from recognising a new disease to immunising against it”.
Although research is currently underway to evaluate known compounds (re-purposing drugs), and to screen for new compounds (drug discovery), it is believed that the only way to combat this pandemic will be with a vaccine. One of the vaccine options that is currently being considered and researched, is an mRNA (messenger RNA) vaccine.
The development and successful application of an mRNA vaccine for Covid-19 will, in itself, be an acclaimed medical breakthrough and will likely be the first mRNA vaccine available on the global market.
So how does an mRNA vaccine differ to a conventional vaccine?
Vaccines work by using the body’s natural defences to protect against infection (bacterial, viral), and to develop immunity to it. An infection normally occurs when a virus or bacteria enters the body and multiplies. The immune system is naturally equipped to fight disease. White blood cells (macrophages, T-lymphocytes and B-lymphocytes) are the body’s warriors, and each of these cell types has a specific function when fighting disease or infection. After an initial infection, ‘memory’ cells are created that can quickly trigger an immune response if the body encounters that same infection (bacteria or virus) again. This is the body ‘learning’ from disease.
Conventional vaccines, which are either inactivated viruses or bacteria, or attenuated (weakened) versions, work by causing an initial immune response in the body that trains the body to recognize foreign pathogens (like viruses and bacteria) on subsequent exposure, should it occur. In order for the body to learn this response, something needs to be introduced into the body to trigger that initial reaction. When a conventional vaccine is administered, the body reacts to the foreign substrate and an immune response is triggered. The proteins present in the vaccine act as the antigen that cause the body’s immune system to react. The B-lymphocytes start producing antibodies to fight the antigen and the T-lymphocytes attack infected cells. This reaction is minimal when a vaccine is administered, but the body has then developed the ability to rapidly produce antibodies when the body is re-exposed to the same antigen.
mRNA vaccines do not make use of inactive or attenuated pathogens. Instead they make use of messenger RNA, which encodes for proteins that will then stimulate the immune response. Normally, a cell’s DNA provides the blueprint or genetic code for cells to produce proteins that are required for cellular function. mRNA copies the code from the DNA through a process called transcription and proteins are produced when this code is translated into a protein sequence at the level of the ribosome. With mRNA vaccines, the transcription step is eliminated, and the cells are provided with already formed mRNA that can then be translated into a pathogen-specific protein or antigen: foreign mRNA is incorporated into a cell, the cellular machinery is activated, and specific proteins are produced. Therefore, instead of having to administer an inactive form of the pathogen or part thereof, only mRNA is required. The expressed protein will then be the antigen that illicits the immune response in the body to prepare it for a possible infection in the future.
The development of conventional vaccines is a long and laborious process and requires researchers to be exposed to live pathogens. mRNA development does not require exposure to live pathogens and is a quicker and easier process. The production costs are also significantly less. mRNA vaccines therefore present a very promising alternative to conventional vaccine approaches.
mRNA vaccines have been undergoing development since the 1990’s, but mRNA research has over the years been more focused on cancer and tumour treatment and less on the production of vaccines. The COVID-19 pandemic has put serious pressure on research to develop a vaccine quickly. We have seen a shift in resources and focus with emphasis now being placed on development of an mRNA vaccine. In a review article in the Journal of Vaccines published on 24 April 2019, the authors state quite clearly that “mRNA vaccines have generated significant interest and efforts because of their potential as platform technologies that could be used for a variety of applications ranging from prophylaxis to therapy and from personalized medicine to global health solutions”. It was foreseen that mRNA technology could offer a solution to global health challenges, like we are seeing today with COVID-19.
In January 2020 it was reported that an mRNA vaccine for COVID-19 is already under development and research in a collaborative effort between Shanghai East Hospital of Tongji University and Stermirna Therapeutics Co., Ltd and that manufacture of the sample vaccines will take no longer than 40 days. In the USA, Moderna Therapeutics has provided an mRNA vaccine to the National Institute of Allergy and Infectious Diseases (NIAID), in February 2020 for the first phase of clinical trials, and these trials are currently underway with 45 subjects, in order to assess safety, reactogenicity (ability to elicit expected adverse reactions) and immunogenicity (ability to elicit an immune response) of the mRNA vaccine.
Regulatory considerations for mRNA vaccines
mRNA technology is not only applicable to the development of vaccines. As mentioned above, mRNA technology is also applicable in the treatment of non-infectious diseases and the generation of personalised therapeutics.
Since an mRNA vaccine would be the first of its kind, it is interesting to consider how it will be regulated and whether we can expect any difference in the manner in which it is regulated by the various global regulatory agencies.
Vaccines are regulated by regulatory bodies in countries throughout the world, such as the South African Health Products Regulatory Authority (SAHPRA), the European Medicines Agency (EMA), Therapeutic Goods Administration in Australia and the Food and Drug Administration (FDA) in the United States.
Vaccines are regulated like conventional medicines and biologicals, and are classified as biological medicines. In order for a new vaccine to be approved for commercial use, it is necessary to show that it is efficacious, safe, and of high quality. In order to show this, various studies, including clinical trials and non-clinical studies are required. At present, there are no specific guidelines from the FDA or EMA on how mRNA vaccine products will be regulated. However, there are a number of mRNA vaccine pre-clinical and clinical trials that have been approved by regulatory authorities and registered at Clinical Trials.gov. This suggests that regulators have accepted the approach to safety and efficacy testing used by some researchers
At present the mRNA vaccine trials that are underway (for infectious disease other than COVID-19) have been approved for early-phase clinical trials by applying general principles from overarching regulatory guidelines. The current COVID-19 trials that are underway appear to have been fast tracked by regulatory agencies, showing that the regulatory processes are working to ensure solutions are available as soon as possible. It is likely that as mRNA technology becomes more common, more specific guidelines will be promulgated.
Considering the unique situation that COVID-19 has created and the importance that mRNA technology may have in the solution to this pandemic, it may provide a catalyst for the development of a workable regulatory framework for mRNA technology, as it applies to vaccine therapy. It is probable, and indeed hoped, that regulatory frameworks will be established more rapidly than is normally the case, in order to ensure that there are no unnecessary delays in obtaining approvals.
Alison Levesley
(BSc; MSc; LLB)
Alison is an independent consultant providing legal, regulatory and scientific advisory services to the agricultural, food and human health sectors. She has an MSc in biotechnology and is a qualified patent attorney specialised in Regulatory Affairs and Patent Law in the biological sciences.