Why mRNA vaccines like those made to treat coronavirus are a big step for biotechnology



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If the Pfizer and Moderna vaccines successfully end the COVID-19 pandemic, as they appear poised to do, we owe our salvation to the development of mRNA vaccines, an unprecedented and novel vaccine technology that can revolutionize the way we that vaccines are manufactured.

In fact, a mass mRNA vaccine has never been produced or licensed to treat an infectious disease. MRNA vaccines to treat the new coronavirus would be the first.

However, understanding the quantum leap that mRNA vaccines represent requires understanding where we are now. Modern biotech giants and Pfizer / BioNTech announced last month that they had seen promising results as they near the end of clinical trials for their candidate vaccines. Both vaccines are likely to be produced on a large scale and mass distributed to the public.

However, what is particularly surprising is that both are mRNA vaccines, with mRNA being short for “synthetic messenger RNA”. Understanding why they are so novel requires some background on the history of vaccination.

Vaccines before mRNA

As Dr. Norbert Pardi, an assistant research professor of Medicine at the University of Pennsylvania and an expert in messenger RNA therapies, explained to Salon, there are three main types of vaccines. You’ve probably heard of the first two and you’ve probably been injected at some point in your life, like almost all Americans.

First, so-called conventional vaccines essentially train the body to recognize and fight antigens, the molecule or molecular structure found in a disease-causing organism (or pathogen) that generally triggers an immune response in the body.

“When using conventional vaccines, the actual protein antigens that will induce immune responses are administered,” Pardi explained.

For example, a conventional vaccine platform is live attenuated vaccines, which use a weakened form of the germ that causes disease. Once in the body, the immune system learns to recognize the antigen and build immunity, but the patient does not get sick because the form of the pathogen has weakened.

“Live attenuated vaccines are often very effective, but they sometimes induce adverse events,” Pardi explained.

Another related subtype of conventional vaccines are called protein subunit vaccines; these are considered very safe, Pardi said, as they introduce “non-living, non-infectious materials” that include one or more antigens for a given pathogen. Once introduced into the body, the immune system learns to recognize the pathogen in the future.

Viral vector-based vaccines and genetic vaccines, such as those using DNA and RNA, are the second and third major vaccine technologies.

“When using genetic or viral vector-based vaccines, a model is delivered that will allow host cells to produce protein antigens that will then induce an immune response,” said Pardi.

This is a bit more sophisticated than the standard conventional vaccine, as you are giving the cells a blueprint rather than a part of the pathogen itself. In other words: conventional vaccines, which are a weakened form of the pathogen or genetic “pieces” of it, teach the immune system to recognize the real pathogen after seeing these similar versions. It would be similar to recognizing a specific make of car after seeing an advertisement, or even just a partial image of its hood. But a vaccine based on viral vectors or a genetic vaccine would be more similar to recognizing what a Ford Focus looks like just by having seen its model.

The third and completely new technology, and the crux of this story, is the mRNA vaccine. For these, scientists create synthetic versions of mRNA, a single-stranded RNA molecule that complements one of the DNA strands of a gene. They then inject a customized version of the mRNA into the body, so that cells can make proteins like those found in a given virus and train the immune system to fight a particular disease before it enters the bloodstream. Think of it as a bit like training a soldier to fight actors who play an enemy so they can be better prepared to fight the real enemy.

In the case of SARS-CoV-2 mRNA vaccines, they train the body’s cells to recognize a protein associated with SARS-CoV-2, the virus that causes COVID-19, known as Spike. Spike is the protein that creates the little dots that stick out around the virus sphere like the spines of a sea urchin. By helping the body’s cells to produce Spike, vaccines in the process train the immune system to recognize it and protect the human body from new coronavirus infections.

The holy grail of vaccine technology?

Dr. Katalin Karikó, a Hungarian biochemist who specializes in RNA-mediated mechanisms and works as Senior Vice President at BioNTech RNA Pharmaceuticals, explained to Salon what makes these new vaccines so different.

“Vaccines that contain killed virus or viral proteins will only induce antibodies,” explained Karikó, referring to the way conventional vaccines work. “Meanwhile, mRNA vaccines, in addition to antibodies, also induce a cellular immune response,” he added, “because the encoded viral proteins are synthesized within the cell of the vaccinated person.” This is an immunological double whammy: the injected mRNA causes the body to synthesize literally the same proteins that the virus will synthesize, as if it were a general test for an actual infection.

Karikó added that the cellular immune response is important because although antibodies will eliminate and recognize viruses in the blood, there is a second type of white blood cells called T cells that recognize infected cells and destroy them. In other words, the antibodies patrol the bloodstream; T cells look for houses that have already been infiltrated. “That’s what the BioNTech mRNA vaccine showed,” Karikó said. “Induced coronavirus-specific antibodies and T cells.”

Regarding mRNA vaccines such as those developed by Moderna and Pfizer / BioNTech, which are technically known as “nucleoside-modified mRNA vaccines,” Pardi explained that “they have two more critical advantages: the flexibility of the design of the antigen derived from their the nature and ease of production “. He stressed that “once you have the coding sequence (s) for your antigen (s) that you want to target, you can quickly make these shots.” He noted that Moderna manufactured its vaccine in just 42 days after discovering the genetic sequence of SARS-CoV-2.

These mRNA vaccines are also faster and easier to modify if necessary, Pardi noted. “You can use the same manufacturing procedure to produce different mRNAs … this makes production much faster, simpler, and potentially cheaper.”

The long road to mRNA vaccines

MRNA vaccines are a very new technology and they had a long way to go. In fact, thirty years have passed since the first article that proposed the use of mRNA for vaccines came out.

“There was very slow progress in developing mRNA-based therapeutic approaches because there were two major hurdles that needed to be overcome,” Pardi told Salon. The first hurdle was “the instability of the mRNA and the lack of a safe and efficient carrier molecule that can protect the mRNA from rapid degradation.” Because mRNA is fragile, you can’t just put it in water and inject it; you need to sit inside something.

The second problem was more macroscopic: inflammation. Or, as Pardi described it: “the lack of methods that could decrease the inflammation induced by the administration of mRNA.”

The problem of inflammation was solved in 2005 by Karikó and a colleague from the University of Pennsylvania, Dr. Drew Weissman. The two found that, by “replacing some of the building blocks of mRNA,” they could almost eliminate inflammation.

“This key discovery allowed them to produce safe, therapeutic-grade mRNA, the so-called nucleoside-modified mRNA,” Pardi said.

As for the carrier molecule problem, Pardi added that subsequent technological advances helped develop better mRNA delivery materials, in particular a material called lipid nanoparticles, or LNPs. “Both the Moderna and Pfizer / BioNTech SARS-CoV-2 vaccines use the nucleoside-modified mRNA-LNP platform,” said Pardi. This method has been found to be safe and effective in phase III clinical trials of both companies.

Karikó made considerable professional sacrifices in the name of mRNA vaccine development. Her belief that they could work demoted her at the University of Pennsylvania in 1995, according to STAT News, which pointed to the fact that there was no money to sponsor her work on mRNA. However, Karikó has been widely vindicated ever since; her and Weissman’s 2005 articles were noted by scientists who later helped found Moderna and BioNTech, the future partner of Pfizer.

Dr. Derrick Rossi, who helped found Moderna, bluntly told STAT News that Karikó and Weissman deserve the Nobel Prize in Chemistry. “If someone asked me who to vote for one day, I would put them front and center,” Rossi said. “That fundamental discovery will apply to medicines that help the world.”

Indeed, one wonders how the world would be different if Karikó and Weissman had not succeeded in realizing their vision for mRNA technology.

“It’s hard to say,” Pardi said. “One thing’s pretty sure, we couldn’t have developed nucleoside-modified mRNA vaccines,” or the kind of vaccines that Pfizer / BioNTech and Moderna use.

Karikó herself told Salon that other biotechnologies had made tremendous progress in the last ten years, including the ability to sequence viral RNA rapidly, and that this helped speed up the vaccine. “Those who were making vaccines against this coronavirus this year were relying on the sequence information published by Chinese scientists in early January 2020,” he humbly noted.

It also seems safe to speculate that if Karikó and Weissman had not prevailed through hard work and ingenuity, we may not have the technology available at this time to develop COVID-19 vaccines. The vaccines would probably have arrived, albeit later, and it’s all because they were ahead of the curve on the potential of mRNA vaccines.

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