The term "mRNA" has only entered the average household in recent months as Moderna and Pfizer-BioNTech released their COVID-19 vaccines. But a handful of scientists have spent decades studying this new approach to immunization. At the outbreak of the pandemic, technology was already so advanced that Chinese researchers were then published the genetic sequence for the coronavirus Moderna succeeded in mid-January make a vaccine within 48 hoursClinical trials began a few weeks later. In nine months, the world was well on the way to viral protection.
It was a stunning debut for mRNA – short for messenger ribonucleic acid, the sidekick of DNA – which has long been considered a promising but unproven treatment. After this encouraging success, proponents predict an equally impressive future. They have always believed in mRNA's ability to protect not only against coronavirus, but also against a host of deadly diseases that are resistant to traditional vaccines, from malaria to HIV and cancer. In 2018, well before last year's confidence showed, a group of researchers announced "a new era in vaccinology
It remains to be seen whether mRNA will live up to the hype. With concrete results demonstrating its potential, interest from investors and researchers is growing. It helps that regulators and the public are now also familiar with it, says Yale immunologist Rick Bucala. "That really changed the landscape."
Andrew Geall, co-founder of one RNA vaccine testing company and chief scientific director of another, notes that mRNA is only in its infancy after a long pregnancy. That is the nature of scientific progress. “We've been bubbling the technology for 20 years, and the most significant breakthrough is this clinical evidence from two vaccines,” he says. "Now we are ready for 10 years of excitement."
Next steps for mRNA
The purpose of any vaccine is to train the immune system to recognize and defend a virus. Traditional vaccines do this by exposing the body to the virus itself, weakened or dead, or to a part of the virus called an antigen. The new shots, as their name suggests, only introduce mRNA – the genetic material that, as you may recall from high school biology, contains instructions for making proteins.
Once the mRNA enters the cells, particles called ribosomes read the instructions and use them to build the encoded proteins. In the case of the COVID vaccines, those proteins are the crown-shaped "spike" antigens from which the coronavirus gets its name ("corona" means crown in Latin). They are harmless on their own, but the immune system attacks them like foreign invaders, learning how to ward off the real virus. If it ever rears its spiky head after that, the body will remember it and destroy it quickly.
But in addition to ridding the world of the worst pandemic in generations, mRNA could help overcome many intractable diseases. If all the proponents' dreams come true, then the COVID vaccines could only be a proof of concept in retrospect. For example, in February, Bucala and his colleagues filed for a patent for one malaria vaccine, which has likely killed more people than any other single cause and has largely passed immunization.
Justin Richner, an immunologist at the University of Illinois, Chicago, is developing an mRNA vaccine against dengue, another highly resistant virus. Since mRNA is simply a genetic sequence, scientists can easily modify it as needed to find the most effective combination. “One of the advantages of the mRNA platform is that it can be so easily adapted and manipulated to test new hypotheses,” says Richner.
Geall says the obvious candidates for mRNA vaccines are what he calls the "Big 6," all of which remain devious enemies: malaria, cancer, tuberculosis HIV, cytomegalovirus and respiratory syncytial virus. His own company, Replicate Bioscience, works on the cancer front, as do several others, including BioNTech. Through genetic analysis of individual tumors, patients could one day receive personalized vaccines designed to target the specific mutations that affect them.
It is currently difficult to say whether an mRNA vaccine will work against a particular pathogen. Many have shown promise in animal studies, only to hesitate in our species. As Geall said, "mice are not humans." Some seem to be better bets than others – notably cytomegalovirus and RSV respiratory syncytial virus – but for now, it's too early to say where mRNA will pay off next time. “Despite everything we know about immunology, a lot of it is really empirical,” says Bucala. "You just have to try things and see if they work."
The pandemic tamer
Based on its recent achievements, the next act of mRNA could well be the next pandemic. Perhaps its greatest strength is that it can be manufactured at speeds unheard of in the realm of traditional vaccines, making it well suited to handle sudden spikes of viruses. “One of the great things about the mRNA field is how quickly you can go from concept to a therapy that is ready for clinical trials,” says Richner. "We can make several different vaccines and test them in a very fast process."
Since 2018, Pfizer and BioNTech have been working on an mRNA vaccine against seasonal flu. Under the status quo, experts must predict which variant of the virus will pose the greatest threat each year and produce vaccines that meet it. But because mRNA is so easy to edit, it can be more efficiently adapted to keep up with the ever-mutating strains. "I think the field of flu vaccines will be transformed in the not too distant future," said Richner.
A similar kind of gene-based vaccine, made with self-amplifying RNA (saRNA), is even more nimble. While basic mRNA vaccines – such as Modernas and Pfizer-BioNTechs – inject all the genetic material at once, the self-amplifying version replicates itself in the cell. Just a small dose of this powerful product can trigger the same immune response as a syringe full of current shots. Bucala's malaria vaccine and Geall's cancer vaccines both use this technology. "The big problem is that vaccines don't prevent infections," says Bucala. "Vaccinations Prevent Infections." With saRNA, manufacturers can assure much more of it.
After mRNA's brilliant battle against Covid, it's tempting to consider it a panacea. But, says Bucala, “is there anything intrinsically revolutionary about mRNA? We do not know yet. "
It does entail a number of logistical challenges. For example, MRNA breaks down easily, so it must be cooled during the distribution process. But hurdles aside, the possibilities are enormous, and investments can increase to deliver on the industry's ambitions. Vaccine development is usually not a lucrative business, but COVID-19 has produced more than a few billionaires, "and others are watching," Bucala said. "I think it must become economically viable in our Western model to start vaccination again."
Geall agrees. Even if some mRNA attempts fail, at least a few will make the world proud. “There is a lot of money out there that will be invested in these new approaches,” he says. "We will see failures, but we will certainly see successes."