In 1978, nearly two decades after the discovery of messenger RNA (mRNA), the concept of a vaccine made from mRNA was materialized. Like its name suggests, mRNAs are messengers that aid in decoding genetic information from DNA to synthesize proteins, a key cellular function.
Previous attempts at developing a vaccine using mRNA failed because mRNA is negatively charged, so can’t just pass into the cell membrane. To circumvent this, scientists used liposomes – fatty vesicles – that package and protect the mRNA upon entry, a tool that is now at the forefront in drug delivery systems.
Since then, the delivery of mRNA into cells has been extensively studied for the development of vaccines for infectious diseases, but it was not until 2020, when the COVID-19 pandemic hit, that mRNA vaccines were globally commercialized.
One of the major players, Moderna, with its Spikevax vaccine gaining traction in 2021 after being approved by the U.K’s Medicines and Healthcare products Regulatory Agency (MHRA), spearheaded the push for mRNA COVID vaccines in the market.
mRNA vaccines for COVID 19: a game changer
The idea behind Spikevax is relatively straightforward. The vaccine contains elasomeran, an mRNA with instructions for making spike proteins. These proteins are located on the surface of coronavirus cells, which mediate the entry into human cells. When the mRNA is injected into the bloodstream, it activates the immune system upon being recognized as a foreign substance. The body then produces antibodies and triggers T cells to attack the protein, and soon after, the vaccine’s mRNA molecules are broken down and removed from the body.
An extensive clinical trial 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 given a dummy injection.
As of March 2023, more than 250 million people in the U.S. have been dosed. The vaccine’s efficacy for the Omicron COVID variant has also been measured, leading to regulatory approval from the U.K. government in 2022.
Meanwhile, global biopharma Pfizer’s collaboration with German biotech BioNTech has dominated the COVID vaccine space. Its vaccine has been administered more than 400 million times in the U.S. alone. Like Spikevax, the partnership’s BNT162b2 – sold under the name Comirnaty – is a two-dose vaccine that applies a similar mechanism whereby host cells are instructed to make copies of spike proteins to induce an immune response for antibody production.
The first COVID 19 vaccine to receive Emergency Use Authorization (EUA) from the U.S. Food and Drug Administration (FDA) back in 2020, Comirnaty surpassed initial projections when its phase 3 clinical trial demonstrated 95% efficacy against COVID 19.
As protection from the virus dwindles over time, boosters have been designed to bring the immune system back to robust levels. Yet, both the Pfizer-BioNtech and the Moderna vaccines have yielded promising results at the six-month mark, before the booster jab, following the monitoring of antibody levels – a significant marker for vaccine effectiveness. And, because mRNA vaccines show a gradual decline in antibody protection, its shielding effect lasts longer.
Therapeutic potential to tackle infectious diseases
In addition, mRNA vaccines can be manufactured much more quickly than traditional vaccines. According to Ethan Settembre, vice president of research at CSL Vaccine Innovation Unit, mRNA vaccines do not contain antigens in a protein form, which is often the case with other vaccines.
“Unlike other vaccines where the protective antigen is made in a factory and the protein is given to the vaccine, with RNA, the body acts as the ‘antigen factory’ to make the protective antigen as encoded by the RNA. Conventional RNA vaccines, like those used in current COVID 19 vaccines, have RNA that gets into a cell, and the RNA makes the protein of interest,” said Settembre.
CSL, a global biotech headquartered in Melbourne, Australia, is advancing mRNA-based technology. The company has entered into a partnership deal with American biopharma Arcturus Therapeutics for the development and licensing of its next-generation sa-mRNA platform – a lower dose technology – for COVID 19, influenza and other respiratory viruses.
Settembre said: “Next-generation mRNA technology has the potential to use lower doses, and hence, to be better tolerated than conventional mRNA technologies. In addition, it may be easier to have multiple vaccine strains in a single vaccine because each would require a lower dose, whereas using conventional mRNA technologies, there may be tolerability challenges that limit the number of strains that can be included in a single vaccine.”
Settembre explained that since mRNA uses the body’s cells to make specific, protective antigens, which are quite similar to pathogenic ones, the immune system would be protected against the virus 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 mosquito-borne virus 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 FDA fast-track designation for Zika in 2019.
According to the clinical trials, MRNA-1893 elicited a vigorous virus-specific response, which persisted for more than a year.
mRNA technology for immunotherapies
While mRNA vaccines for infectious diseases have been established to prevent illnesses, the scope for mRNA cancer vaccines is vast. With the first cancer vaccine approved in 1990 by the FDA for treatment against bladder cancer, mRNA vaccines have shown promise as an immunotherapy.
Other examples are BioNtech’s FixVac and individualized mRNA cancer vaccines (iNeST) platforms, which target solid tumors.
The former, which consists of a combination of lipid-wrapped mRNA-encoded non-mutated tumor antigens, aims to activate immune cells. With its use of optimized uridine mRNA (uRNA) to enhance its immunostimulatory effect, the platform targets tumors, for the treatment of melanoma – skin cancer. The iNEST platform, however, contains mRNA that codes for patient-specific proteins, in order to induce a potent immune response.
Various clinical trials are planned for mRNA cancer vaccines, with German biotech CureVac looking into its potential for different indications, as the company has evolved a broad pipeline for prophylactic vaccines for infectious diseases as well.
However, mRNA technology is not without its challenges. Currently, mRNA vaccines are not as stable to non-frozen storage conditions as more traditional protein-based vaccines, according to Settembre, who expressed that such was the case with CSL’s COVID vaccine.
“This means, as for COVID-19 mRNA vaccines, an additional cold chain needed to be set up to assure the vaccines could be appropriately potent after storage. Groups around the world are focused on generating mRNA technology that can be stable at refrigerated temperatures for long periods of time to enable broader use in all countries,” he said.
Nevertheless, as the transformative therapeutic potential outweighs concerns over storage, the novel application could be crucial for tackling future pandemics.
“When fully worked through, mRNA vaccine platforms should be highly versatile to have the same platform generate multiple vaccines. At manufacturing scale, this should enable high speed responses to either new pathogens (as in a pandemic) or to generating large volumes of vaccines to multiple targets,” said Settembre.
“mRNA technologies have a bright future… While vaccines are an overall good target for mRNA technologies, other areas like protein replacement therapies, cancer therapies, etc. may also be addressable.”
New technologies related to mRNA vaccines (Powered by IN-PART)
- mRNA Therapeutic Against the SARS-CoV-2 Spike Protein – Oregon State University
- Bacterial RNAs as Vaccine Adjuvants – Cornell University
- Artificial Intelligence for Designing mRNAs with High Translation Power – Australian National University
- Pseudouridine for RNA Vaccines – Southern Illinois University