(CN) — The United States marked a new age in vaccine science when the first candidates it deployed against the coronavirus also marked the first time a vaccine has relied on messenger RNA, or mRNA.
Like all vaccines, the goal of mRNA vaccines is to prime the immune system to respond to a specific foreign agent. In preventing the spread of Covid-19, the target is the pandemic-unleashing coronavirus known as SARS-CoV-2.
Vaccines like the Oxford-AstraZeneca version — which is available in Europe but not yet approved in the United States — achieve that goal using virus DNA: Genes from the spike proteins that stud the coronavirus are put into a cold virus that has been weakened, and then injected into patients.
Unlike vaccines that use virus DNA, however, the two U.S.-approved Covid-19 vaccines from Pfizer and Moderna use mRNA, genetic material that gives cells the necessary blueprints to make proteins.
Comparing mRNA to software development, Dr. John Cooke, chair of the Department of Cardiovascular Sciences at Houston Methodist hospital, says mRNA “is like biological code.”
Instead of weakening a virus to create a vaccine, mRNA starts with a blank template, Dr. Cooke explained in a phone interview. That allows researchers to “rapidly generate new RNA molecules,” synthesize them in a relatively simple process, and “quickly get a drug into testing.”
Studying mRNA drug therapies could unleash new scientific possibilities that go well beyond controlling Covid-19. Taking a step back to understand mRNA vaccine development explains how we got here, and what challenges remain in mRNA vaccine distribution.
Sequencing spike proteins
In January 2020, months before the U.S. closed schools and sent office workers home, Chinese scientists published the sequence of SARS-CoV-2, which researchers used in turn to identify the sequence of its spike protein.
It is their coating of spike proteins that allow viruses to attach to the cell of a human or another animal. So having the virus information from China told researchers what information to plug into the blank slate that is mRNA.
The mRNA in a vaccine, encoded for that spike protein, tells the body to create the protein — and then attack it, by creating antibodies. That beneficial self-destruction readies the immune system for next time. Antibodies remain present in the body, and, if an infection occurs, they will go after the virus, having memorized, so to speak, the spike protein sequence.
After the sequence was known to researchers, mRNA vaccine development was off to the races.
“It only took a couple of days for scientists to construct an RNA vaccine at the National Institute of Allergy and Infectious Diseases,” Dr. Cooke explained.
Within a month of scientists sharing the coronavirus sequence, mRNA vaccine tests in animals began. By April, mRNA vaccine doses were being tested in people.
“It’s incredible,” Dr. Cooke said, noting that the three-month process can ordinarily take five years or even longer.
“With this pandemic, global crisis, it provided an opportunity to think differently about how to respond with a vaccine program,” he said. “Everything became more accelerated.”
By mid-December, the FDA allowed the first two mRNA vaccines to be administered in the United States.
Working with mRNA
While allowing its use in medicine is new, scientists have known about mRNA since the 1960s. Testing of mRNA therapies in animals began in the 1990s. What have stood in the way of faster development are the properties of the genetic material.
Compared to DNA, mRNA is fragile.
In human bodies, after mRNA makes a protein, it is quickly broken down by enzymes called RNases. The enzymes are found in all cells of plants and animals: “They’re everywhere, they’re ubiquitous — they’re on your fingertips,” Dr. Cooke explained.
As a result, it would take just a small amount of contamination in a lab to destroy mRNA as it’s being studied.
“When we make RNA, we have to work in a very clean environment that is RNase-free,” Dr. Cooke says.
In answering the challenge of finding a way to work with mRNA without letting it fall apart, researchers began to bubble-wrap the genetic material, delivering it to cells in lipid nanoparticles, described by Dr. Cooke as “small globules of fat.”
The protective layer solved a big problem for mRNA. But the lipid nanoparticles are also the reason behind the dry-ice temperatures needed to keep the Pfizer and Moderna vaccines steady, a big factor in distributing Covid-19 vaccines.
Limits and possibilities of mRNA
The limits of the “cold chain” required to transport deeply frozen vaccines have already posed barriers to vaccine rollout.
Dry ice is dangerous to handle, and distributors have already reported some issues with getting their (gloved) hands on enough of it. Some vaccine distributors have even reached out to the company that makes Dippin’ Dots, the ultra-frozen beaded ice cream, to discuss renting its freezer equipment.
The danger is most concerning in rural and poor areas where the cold chain simply does not reach. Experts have concerns about scaling up mRNA technology to the point where it can reach all parts of the world, fighting the coronavirus and its variants.
Dr. Peter Jay Hotez, professor and dean of the National School of Tropical Medicine at Baylor College of Medicine, outlined those issues during a Wednesday talk at the New York Academy of Sciences.
“We’re particularly worried about the world’s low and middle-income countries, and that they’re simply not going to benefit from some of the newer technology vaccines,” Hotez said. “I’m worried about the mRNA vaccines in terms of how robust they are for scale-up, for production and delivery in resource-poor settings.”
Hotez is working the India-based company Biological E on a vaccine candidate that would be kept at refrigeration levels, like the Oxford-AstraZeneca version.
In the longer term, however, the possibilities of mRNA remain expansive. Because of the blank slate offered by mRNA, Cooke says, mRNA has “limitless promise.”
Even before tests began for a Covid-19 vaccine, researchers had looked at mRNA vaccines to treat Zika virus, rabies and influenza. The therapies have also been explored in cancer and HIV research.
“What we’re witnessing is the emergence of an entirely new field of therapeutics,” Cooke said.
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