In 1978, almost two decades after the discovery of messenger RNA (mRNA), the concept of a vaccine made from mRNA was realized. As the name suggests, mRNA is a messenger that helps decode genetic information from DNA to synthesize proteins, a major cellular function.
Previous attempts to develop vaccines using mRNA failed because mRNA is negatively charged, so it can’t just squeeze into the cell membrane. To avoid this, scientists use liposomes – fatty vesicles – which package and protect the mRNA as it enters, a tool that is now at the forefront of drug delivery systems.
Since then, delivery of mRNA into cells has been studied extensively for the development of infectious disease vaccines, but it was only in 2020, when the COVID-19 pandemic hit, that mRNA vaccines were commercialized globally.
One of the major players, Moderna, whose Spikevax vaccine is gaining traction in 2021 after being approved by the United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA), is spearheading the push for a COVID mRNA vaccine on the market.
mRNA vaccine for COVID 19: a game changer
The idea behind Spikevax is relatively straightforward. The vaccine contains elasomeran, an mRNA with instructions for making a spike protein. This protein is located on the surface of the coronavirus cell, which mediates its entry into human cells. When mRNA is injected into the bloodstream, it activates the immune system after it is recognized as a foreign substance. The body then produces antibodies and triggers T cells to attack the protein, and soon after, the vaccine mRNA molecule is broken down and excreted from the body.
Extensive clinical trials proved Spikevax’s efficacy, based on a two-dose regimen for the vaccine. Out of 30,000 people, there was a more than 94% reduction in the number of symptomatic COVID-19 cases among those who received the Spikevax vaccine compared to those who were given the dummy injection.
As of March 2023, more than 250 million people in the US have been given the dose. The efficacy of the vaccine for the COVID Omicron variant has also been measured, leading to regulatory approval from the UK government in 2022.
Meanwhile, Pfizer biopharma’s global collaboration with German biotech BioNTech has dominated the COVID vaccine space. Its mRNA vaccine has been administered more than 400 million times in the US alone. Like Spikevax, the BNT162b2 partnership – sold under the name Comirnaty – is a two-dose vaccine that employs a similar mechanism in which host cells are instructed to make copies of the spike protein to induce an immune response for antibody production.
The first COVID 19 vaccine to receive an Emergency Use Authorization (EUA) from the US Food and Drug Administration (FDA) in 2020, Comirnaty surpassed initial projections when phase 3 clinical trials demonstrated 95% efficacy against COVID 19.
As protection from viruses diminishes over time, boosters have been designed to return the immune system to a strong level. However, the Pfizer-BioNtech and Moderna vaccines have shown promising results within six months, before booster shots, after monitoring antibody levels – a significant marker of vaccine effectiveness. And, because mRNA vaccines show a gradual decrease in antibody protection, their protective effect lasts longer.
Therapeutic potential to treat infectious diseases
In addition, mRNA vaccines can be produced much more quickly than traditional vaccines. According to Ethan Settembre, vice president of research at CSL’s Vaccine Innovation Unit, mRNA vaccines do not contain antigens in protein form, which is often the case with other vaccines.
“Unlike other vaccines where protective antigens are made in factories and proteins are administered to the vaccine, with RNA, the body acts as an ‘antigen factory’ to make protective antigens as encoded by RNA. Conventional RNA vaccines, such as those used in current COVID 19 vaccines, have RNA that goes into cells, and the RNA makes proteins of interest,” said Settembre.
CSL, a global biotech headquartered in Melbourne, Australia, advances mRNA-based technology. The company has signed a partnership agreement with American biopharma Arcturus Therapeutics for the development and licensing of its next-generation sa-mRNA platform – a low-dose technology – for COVID 19, influenza and other respiratory viruses.
Settembre said: “Next generation mRNA technologies have the potential to use lower doses, and therefore, be better tolerated than conventional mRNA technologies. Also, it may be easier to have multiple vaccine strains in a single vaccine because each will require a lower dose, whereas using conventional mRNA technology, there may be tolerability challenges that limit the number of strains that can be included in a single vaccine. ”
Settembre explains that because mRNA uses body cells to make specific protective antigens, which closely resemble pathogen antigens, the immune system will be protected from viruses in the future.
As well as tackling respiratory viruses, mRNA vaccines are also pioneers in the fight against Zika virus, an emerging global health threat. Zika is a virus carried by mosquitoes that can affect the nervous system and cause birth defects. So far, 89 countries and territories have reported Zika virus infections. Moderna’s MRNA-1893 received the FDA fast-track designation of Zika in 2019.
According to clinical trials, MRNA-1893 elicited a strong virus-specific response, which persisted for more than a year.
mRNA technology for immunotherapy
While mRNA vaccines for infectious diseases have been created to prevent disease, the scope of mRNA cancer vaccines is very broad. With the first cancer vaccine approved in 1990 by the FDA for treatment against bladder cancer, mRNA vaccines have shown promise as immunotherapy.
Other examples are BioNtech’s FixVac and its individual mRNA cancer vaccine platform (iNeST), which target solid tumors.
The first, which consists of a combination of non-mutated tumor antigens encoded in lipid-enveloped mRNAs, aims to activate immune cells. With optimized use of uridine mRNA (uRNA) to enhance its immunostimulating effect, this platform targets tumors, for the treatment of melanoma – skin cancer. The iNEST platform, however, contains mRNA encoding patient-specific proteins, to induce a robust immune response.
Various clinical trials for mRNA cancer vaccines are ongoing, with the German CureVac biotech vaccine candidate CV8102 currently in preclinical and clinical studies for different indications, as the company has also developed a broad line of prophylactic vaccines for infectious diseases.
However, mRNA technology is not without its challenges. Currently, mRNA vaccines are not as stable for unfrozen storage conditions as more traditional protein-based vaccines, according to Settembre, who stated that was the case with the CSL COVID vaccine.
“This means that for COVID-19 mRNA vaccines, additional cold chains need to be set up to ensure the vaccine can have the right potency after storage. Groups around the world are focused on producing mRNA technologies that can be stable at refrigerated temperatures over long periods of time to enable wider use in all countries,” he said.
Nevertheless, because the transformative therapeutic potential outweighs concerns about storage, these new applications could be critical to addressing future pandemics.
“When fully worked out, mRNA vaccine platforms need to be very versatile to have the same platform produce multiple vaccines. On a manufacturing scale, this should enable a high-speed response either to new pathogens (as in a pandemic) or to produce vaccines in large quantities to multiple targets,” said Settembre.
“MRNA technology has a bright future… Although vaccines as a whole are a good target for mRNA technology, other areas such as protein replacement therapy, cancer therapy, etc. also manageable.”
New technologies regarding mRNA vaccines: