The mRNA breakthrough

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The two approved COVID-19 vaccines are not just game changers in the fight to contain the novel coronavirus but could be an exponential leap forward in development of many future vaccines.

The key difference between the Pfizer/BioNTech and Moderna vaccines and any previously developed ones lies in the mechanism they use to spur the body to produce antibodies to fight viruses, a molecule called messenger ribonucleic acid, or mRNA for short.

“These are very, very different vaccines,” says Ann Falsey M.D., a University of Rochester Medical Center infectious disease researcher and co-leader of the local Pfizer clinical trial. Volunteers here were the first to receive late-stage trial injections. “Initially, when Pfizer announced their results, it was so extraordinary that you almost think it’s too good to be true. But then Moderna, which also an mRNA vaccine, had almost the identical results.”

Ann Falsey

Falsey’s view is shared by many others. Some have called the development of mRNA vaccines an advance comparable to or of even greater significance than Louis Pasteur’s 19th century discovery of microbes as the cause of diseases. 

Brought from the lab to Food and Drug Administration approval and frontline use in record time, both vaccines are reported to be more 90 percent effective and have very low instances of adverse effects, Falsey says. In the relatively few cases where inoculated individuals caught COVID-19, symptoms were mild and less serious than they might otherwise have been. By comparison, the effectiveness of flu vaccines is generally in the 40 percent range, and 70 percent at best. 

The broad sweep and similar results of the two vaccine trials, in which some 75,000 individuals—including several hundred locally—took part, “validate each other,” Falsey says. 

She asks: “Why is this so different than a flu vaccine? You think about the kind of infections we’re trying to prevent. They’re respiratory infections. Respiratory infections begin in your nose and throat. 

“It seems quite clear to me that (when) you get a vaccine that produces an antibody in your blood, you might not be able to prevent every mild infection of your upper respiratory tract because that’s not where the antibody is. These are fundamentally different vaccines. We have a lot to learn.” 

Decades of work

Though it might seem that mRNA vaccines just arrived on the scene, researchers have been studying them for decades. Early-stage clinical trials using these vaccines have been carried out against the flu, Zika, rabies and other viral diseases. However, the instability of free RNA in the body, along with inflammatory outcomes and modest immune responses, stood in the way of bringing these vaccines to market.

Anthony Komaroff M.D., editor in chief of Harvard Medical School’s Harvard Health Letter, in a recent blog post writes how research into mRNA’s use in vaccines was stymied by several obstacles. Scientists had to figure out, for example, how to modify artificially produced mRNA to keep it from causing a violent immune-system response. In addition, they had to devise ways of convincing bodies’ immune systems to use mRNA introduced into the bloodstream by vaccination.  

In a lab at the University of Pennsylvania, Drew Weissman M.D. and Katalin Karikó found a way to use mRNA without causing a significant inflammatory response by modifying RNA nucleosides. Weissman is a professor at the Perelman School of Medicine at Penn and Karikó is an adjunct at Penn and senior vice president at BioNTech. Moderna and BioNTech licensed this technology for the COVID-19 vaccine mechanism.

Roughly two decades after their collaboration began, Weismann and Karikó on Dec. 18 received their first dose of the Pfizer/BioNTech vaccine.

“We understand there are concerns the vaccine was developed quickly, but Kati (Karikó) and I developed our enabling technology 15 years ago, and we and other scientists have been working on how to use it to develop mRNA ever since,” Weissman said at the event. “This isn’t brand new—scientists have been studying vaccines using this mRNA platform for at least six or seven years. 

Katalin Karikó and Drew Weissman received the vaccine in December.
(Photo: University of Pennsylvania)

“Based on all of the data available to date,” he added, “these mRNA vaccines have shown a good safety profile. Clinicians always consider risk/benefit scenarios whenever we recommend a new treatment or a new vaccine to patients and to the public, and with this vaccine there’s no comparison—the benefit is huge and there’s really little to no risk.”

Mechanism of action

Traditional vaccines like those developed to fight flu, polio or measles work by introducing a weakened form of disease agents or a critical part of a disease-causing microbe into the body. This spurs production by the body’s own immune system of antibodies to fight the disease.  

mRNA vaccines work differently. Whether artificially produced for vaccines or as a naturally produced agent by a living organism, mRNA copies information encoded in DNA and uses that blueprint to tell the body to produce certain types of cells. 

Viruses are microscopic specks that cause illness by entering cells and appropriating genetic material to make copies of themselves. Because they do not have their own genetic material, some question whether viruses can be called living organisms at all. The mRNA COVID-19 vaccines tell the body to produce an antibody that disarms the virus by cutting off its ability to worm its way into a cell.

With the appearance of COVID-19, mRNA vaccine research already under way by Pfizer/BioNTech and Modern teams was fast tracked.

The greater effectiveness of the vaccines developed in that effort is not a fluke but a bonus of the way mRNA vaccines work, Komaroff explains. 

Traditional vaccines only stimulate antibody production, but mRNA vaccines stimulate two types of immune-system defense: antibodies to disable invading disease agents and so-called immune system killer cells that destroy disease-causing invaders.

Signal for the future

The success of the Pfizer and Moderna vaccines has raised hopes for many in the biotech and pharmaceutical industries. They present an alternative to existing vaccine approaches not only because of their high potency but also because of their capacity for rapid development and low-cost manufacturing. Contract manufacturers see great opportunity.

Of paramount advantage, a facility dedicated to mRNA production should be able to rapidly manufacture vaccines against multiple targets, with minimal adaptation to processes and formulation, a February 2020 article in Nature states. 

Scientists believe mRNA vaccines can be used to fight cancer, in addition to other diseases.

“Cancer cells make proteins that also can be targeted by mRNA vaccines: indeed, recent progress was reported with melanoma. And theoretically, mRNA technology could produce proteins missing in certain diseases, like cystic fibrosis,” Komaroff writes. 

mRNA technology research has received a big boost with COVID-19. Researchers working on the next generation of delivery systems are likely to continue their pursuit with renewed fervor. 

Over the decade since BioNTech was founded in Mainz, Germany, and Moderna launched in Cambridge, Mass., experts hailed mRNA biologics as the next big thing—poised to revolutionize the biotech and pharmaceutical industries. 

Now, that time has come.

Will Astor is Rochester Beacon senior writer. Managing editor Smriti Jacob contributed to this article.

One thought on “The mRNA breakthrough

  1. Great piece! With all of the anxiety about the vaccine, we need the media to help educate people about how a vaccine was possible so quickly without presenting risk. Thank you!

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