"Are Covid-19 vaccines a failure? That's the view in some media quarters amid breakthrough infections and new virus variants. It's also false. Vaccinated people are more prone to mild infections than public-health authorities initially anticipated. But the shots continue to provide strong protection against serious disease, and the mRNA vaccines in particular -- Pfizer/BioNTech's and Moderna's -- are adaptable to new variants.More important, the drama over vaccines has masked a bigger and untold story, which is the vast promise of mRNA technology. Messenger RNA has shown enormous potential for medical applications beyond Covid to other infectious diseases, as well as vaccines and treatments for conditions from cancer to multiple sclerosis. Its development is a tale of scientific perseverance and serendipity that deserves more attention, with a prominent role by an American immigrant from communist Hungary.
The Omicron variant is an example of mRNA's promise and adaptability. Omicron has some 30 mutations on its spike protein that could make it harder for vaccine-induced antibodies to recognize and neutralize the virus. But mRNA vaccines can be reformulated for the new variant.
BioNTech and Pfizer say they could begin shipping vaccines that target Omicron within 100 days if protection from their existing vaccines declines substantially against the new variant. Moderna has already started testing booster shots designed to anticipate mutations. It also says it would rapidly advance an Omicron-specific booster shot, which could be available early next year.
That quick pivot would be impossible with conventional vaccine technologies, which usually take between six and 36 months just to manufacture and deliver. It can take many more years to design vaccines. With mRNA, vaccine makers only need about six weeks to adapt a shot and then take it from the lab to production.
Messenger RNA delivers the genetic code instructing human cells how to create a protein -- in this case, the coronavirus spike, which binds to the ACE2 receptor on human cells. The mRNA is enveloped in lipid nanoparticles, which are fatty blobs that protect the genetic motherload from degradation and facilitate its entry into cells. Once the mRNA is injected into the muscle, human cells become vaccine mini-factories that churn out pseudovirus particles, which in turn prompt the immune system to produce antibodies that respond when confronted with the real thing. The vaccines also induce T cells, which provide a backup defense to antibodies. If a virus mutates, scientists can easily swap new genetic code into the mRNA.
The Moderna and Pfizer/BioNTech Covid vaccines are the first commercially approved mRNA products, but they were made possible by decades of experimentation, innovation and determination. Geneticists established the existence of mRNA in the early 1960s. RNA regulates how genes are expressed and is a single-stranded molecule similar to the double-helix DNA. Messenger RNA carries the instructions from DNA to the protein-making machinery in cells, known as ribosomes.
That's where Katalin Kariko comes in. The 66-year-old Hungarian-born biochemist, now a scientist at BioNTech, first began working with RNA as a graduate student in the late 1970s at the University of Szeged. Researchers were interested in manipulating what is known as small RNA to generate antiviral effects. In 1985 the biological center where she was a researcher ran out of funding, and her postdoctoral position was terminated.
She applied for three research positions in Europe but wasn't eligible for funding. Then she landed a postdoctoral position at Temple University. She and her husband sold their car for GBP900 (about $1,200), sewed the notes into their 2-year-old daughter's teddy bear -- Hungary didn't allow citizens to take cash out of the country -- and moved to Philadelphia.
Years later the University of Pennsylvania hired her as an adjunct professor. At the time, she envisioned using mRNA to create therapeutic proteins that could substitute for medications. But because she failed to obtain grants, she was passed up for promotions. Government, nonprofit institutions and investors were skeptical about mRNA since the genetic material was considered fragile and produced too little protein to be effective. "For two years every month I submitted for a grant and got none," Ms. Kariko says in an interview. Research on mRNA "was a backwater."
Relying on senior faculty to support her research, she was determined to show that mRNA could be used for medical treatments. For a time she collaborated with a cardiologist on designing mRNA coded for proteins that could prevent blood clots after heart-bypass surgery. Later she worked with a neurologist to design mRNA that would instruct cells to create an enzyme that produces nitric oxide, which could dilate the brain's blood vessels to relieve a hemorrhage.
One day she bumped into the immunologist Drew Weissman at a copy machine. "He was interested in doing a vaccine, and he says he was working with Anthony Fauci. I didn't know who Fauci was. He was not in the television at the time," she says. "Drew said he wanted to make a vaccine that can be therapeutic and prophylactic."
She performed many experiments in animals and on cells cultured in Petri dishes. Yet when Dr. Weissmann tested her synthetic mRNA, it triggered an inflammatory response from human immune cells.
Eventually, Ms. Kariko and Dr. Weissman discovered by experimentation that swapping out uridine, one of mRNA's component "letters," for a chemically similar compound called pseudouridine blunted the inflammatory response. "This produced 10 times more protein," she says. Starting in 2005 they published a series of papers describing their discovery.
The studies caught the attention of stem-cell biologist Derrick Rossi, who had the idea of using mRNA to reprogram human adult stem cells. He shared his idea with his Harvard Medical School colleague Timothy Springer, an immunologist. Mr. Springer had even more ambitious ideas to commercialize mRNA and approached Robert Langer, a Massachusetts Institute of Technology biomedical engineering professor with expertise in drug delivery and tissue engineering. With funding from biotech venture capitalists, Moderna was founded in 2010.
Meantime, Ugur Sahin and Ozlem Tureci, a husband-and-wife immunologist team from Germany, were also working on mRNA. The couple envisioned using mRNA for immunotherapies, which mobilize the immune system to fight cancer. In 2008 they launched BioNTech.
BioNTech and Moderna both licensed the Kariko-Weissman innovation and have spent more than a decade building on it. Beyond a genetic sequence that encodes a protein, mRNA also includes elements that provide an instruction manual to the human cell machinery.
Every cell has the ability to make proteins, Dr. Sahin, CEO of BioNTech, says. "But the regulation of the 'translation' is a complex process." By translation, he means the process by which mRNA is converted into a protein. "You have to imagine that the ribosome where the mRNA is translated is a privileged place in the cell. Not every mRNA can go there," he says; mRNA needs "a passport to reach the ribosome. And when it is in the cell, there are many other mRNAs produced by the cell. So there's a competition for how long the mRNA can stay at the ribosome and be translated. And it makes a difference whether the mRNA stays long enough to make five copies of a protein or 20 or 100 copies of a protein."
Scientists don't only have to design the genetic sequence for the proteins they want cells to create. They also have to create the "passport" to tell the cell's machinery to create more or less of a protein.
BioNTech is working on "self-amplifying" mRNA that can produce large amounts of protein from a small amount of mRNA. This could enormously improve manufacturing efficiency -- effectively moving more mRNA production from the lab into human cells -- and the efficacy of future vaccines and treatments.
In 2018 BioNTech paired with Pfizer to develop a flu vaccine. With conventional flu shots, viruses are injected and fertilized in chicken eggs. Scientists harvest the fluid containing the virus and inactivate it, a cumbersome process that takes at least six months. Scientists have to guess the strains likely to be predominant at least eight months before flu season. That's one reason flu vaccines are only 50% effective at preventing illness on average.
An mRNA flu vaccine could improve that efficacy by better matching the strains in circulation. And mRNA generates a stronger immune response than the inactivated viruses. Pfizer and BioNTech started a flu-vaccine trial in September, and Moderna launched one in July.
Moderna is also advancing vaccines for other infectious diseases, including Zika, HIV, Epstein-Barr, CMV, human metapneumovirus, parainfluenza virus and respiratory synclinal virus. The last three are respiratory viruses that can cause severe illness in children and people over 65. Moderna aims to combine vaccines for seasonal flu, RSV and Covid-19 into a single shot.
Before the pandemic, Moderna and BioNTech were each working on using mRNA for therapeutic purposes. Moderna paired with AstraZeneca on an mRNA therapy to regenerate heart tissue patients with heart failure. Their mRNA encodes a protein called vascular endothelial growth factor A, which promotes new blood-vessel growth. A phase 1 trial completed in early 2019 showed the mRNA, after being injected into the skin of men, caused a localized production of the protein without severe side effects. Last month they reported positive early results from a Phase 2 trial.
As Mr. Rossi recognized a decade ago, mRNA also offers the potential to reprogram cells. "We have shown that mRNA can be used to take a blood cell and generate a stem cell," Dr. Sahin says. "This opens up the potential to address various diseases including aging and tissue repair." Future mRNA uses could include stimulating the production of cartilage to ease arthritis and collagen to reduce wrinkles.
Autoimmune diseases, in which the immune system attacks parts of the body, are another promising area of research. BioNTech this year published a study that showed an mRNA vaccine has potential to treat multiple sclerosis without suppressing the immune system like existing therapies do.
BioNTech's main focus is cancer. It has 21 mRNA products in its clinical pipeline that use 11 different approaches to killing cancer cells. One of Ms. Kariko's first projects at BioNTech involved injecting mRNA coding for cytokines -- proteins that control the immune response -- into the surface of a tumor. That makes "the cold tumor hot, so that immune cells migrate there so they can see the metastatic tumor there and kill it."
Another approach is cancer immunotherapy personalized for the patient. Dr. Sahin explains how it works: After taking a biopsy, "we identify the mutations" and use machine learning "to select those mutations that are the best suited to detect the patient's tumor. And then we prepare mRNA for the patient. This is something we can do in less than six weeks."
The patient is then injected with mRNA that codes for "neoantigens" on the tumor, which turbocharges the immune system to attack it. BioNTech has already begun Phase 2 trials for personalized melanoma and colon-cancer therapies, with initial results expected next year. It is also working on using mRNA to prevent relapses by inducing T cells to patrol throughout the body and kill hidden cancer cells that metastasize.
While Moderna and BioNTech were pioneers in mRNA, large drug makers including Pfizer, Sanofi and Merck are now investing heavily in the technology, which means more advances may come even sooner. Venture capitalists are pouring money into mRNA startups such as Strand Therapeutics and Kernal Biologics.
Not all experimental mRNA products will succeed. "There are many times I thought something was a good idea and then I realized it was not feasible," Ms. Kariko concedes. But as her career shows, "there are windows of opportunities from closed doors."” [1]
1. The Vast Promise of mRNA Technology
Finley, Allysia. Wall Street Journal, Eastern edition; New York, N.Y. [New York, N.Y]. 04 Dec 2021: A.11.
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