Covid-19: the three steps of the revolutionary method for creating RNA vaccines – 11/30/2020

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The technique has been in constant development since the 1990s, but it has only recently been possible to make it efficient in humans and test it quickly.

The covid-19 pandemic accelerated the development and testing of a method for vaccines that until today had not worked in humans: the use of messenger RNA (mRNA).

Both Pfizer (USA) and BioNtech (Germany) and Moderna (USA) used the technique in their immunizers, which reached the third and final phase of testing in humans in a record eight months.

According to the companies, preliminary results showed an efficiency of over 95%.

But how is it possible that this happened so fast? And, if this process is so efficient, why hasn’t anyone managed to make a messenger RNA vaccine until now?

The answer lies in the evolution of technology and scientific research, according to Norbert Pardi, an immunologist and professor at the University of Pennsylvania, USA.

But, also, in the need caused by the pandemic.

“The normal development of a vaccine can take up to 10 years under normal conditions. First because often neither companies nor regulatory agencies prioritize these vaccines. Second, there is not always enough funding. Testing vaccines is very expensive, especially in phase 3, “he told BBC News Brasil. In phase 3, the researchers try to assess the vaccine’s effectiveness and confirm its safety in tests that usually involve thousands of people.

“Now, because of the pandemic, everyone wants to do everything faster and there is abundant funding available. And that was the main obstacle. The chemical process of producing a vaccine does not normally take long. 95% of the time is spent on testing . “

The method that uses mRNA in vaccines also did not come up suddenly. In fact, it started to be developed in the 1990s, and took a leap in the last 15 years, with discoveries that made it, little by little, safer and more efficient.

The role of the RNA messenger

Is messenger RNA a molecule that appears in the transcription process, copying a stretch of DNA? where our genetic information is.

It transports this information to the part of the cells where the proteins that make up the body will be manufactured.

RNA viruses? like common flu, dengue, Zika, Sars-cov-2 and others? use the same mechanism to infect a human cell and produce copies of its own genetic code.

This is how they replicate in our body.

Most vaccines are made with an attenuated virus or a fragment of it, which causes our immune system to produce antibodies.

Gene vaccines, like those developed by Pfizer / BioNTech and Moderna, seek to make our own bodies produce a protein from the virus – but without putting it inside us.

Image: BBC

Why is the method so innovative?

Scientists in the laboratory create a synthetic messenger RNA, which contains a copy of part of the viral genetic code.

This mRNA will make our cells manufacture a protein characteristic of the virus, and this is what will alert our immune system.

“This technique has some important advantages. First, safety. Since it does not use the virus, there is no danger that it will cause infections in people with very low immunity, as can happen in vaccines like yellow fever or polio , for example. Everyone can get the mRNA vaccine “, says Norbert Pardi.

“It is also a simpler technique than the others, because the RNA used is completely synthetic. Therefore, we do not need to maintain complex cell cultures and purification systems in the laboratories”, he explains.

According to Pfizer, the use of RNA made in the laboratory makes the vaccine production faster compared to conventional vaccines, which use attenuated viruses, for example.

“Producing the right strain of a virus can be difficult, and producing enough virus for thousands of doses can take months,” says a company statement.

“Since the production of an mRNA vaccine uses synthetic methods, it can offer a more flexible approach to pathogens that are evolving rapidly, as well as a faster response to large outbreaks or pandemics,” he says.

The creation of the vaccine

But developing a vaccine from a synthetic messenger RNA is not as easy as it may seem.

For starters, according to Pardi, RNA is a molecule capable of generating a strong reaction of the human immune system, which can cause severe inflammation and lead to death.

three steps of creating the RNA vaccine - BBC - BBC
Image: BBC

“This is because there are many viruses whose genetic material is composed of RNA. To protect themselves, organisms have developed RNA sensors. Today, they are all over our bodies”, says the researcher.

This was the problem that was initially encountered with RNA vaccines that were tested on animals.

“But, about 15 years ago, researchers from the team I joined at the University of Pennsylvania found that by exchanging one of the molecules that make up the mRNA, uridine, for pseudouridine, it would be possible to solve this.”

This substitution meant that the sensors were unable to identify the vaccine’s synthetic mRNA as a threat. That way, he had free passage to the cell, his ultimate goal.

According to Pardi, this discovery was the key to making Pfizer / BioNTech and Moderna vaccines possible.

Another crucial innovation was the development of a better lipid layer, that is, fat, that could envelop and protect messenger RNA, preventing it from degrading on the way to cells.

“When I joined the team in 2011, they were already able to produce the modified messenger RNA, but the vaccine still did not work, because the RNA is unstable. So we started testing lipid layers made by different companies”, recalls the researcher.

Moderna and Pfizer say they have their own patented variations of lipid nanoparticles, as the technology is called,. The companies did not respond to requests to explain the structure of these particles.

How does the vaccine work in the body?

Once absorbed by our cells, the messenger RNA acts as an instruction manual for the production of the virus protein, called S or Spike.

Then it disintegrates completely in the body, since it is made of organic compounds.

What the vaccine does to the body - BBC - BBC
Image: BBC

The cell makes thousands of copies of this protein and releases them into the bloodstream. This alerts the sentinels of the immune system, the dentritic cells, which locate these copies and capture them.

When the body identifies the Spike protein as invasive, the production of antibodies and T lymphocytes begins, which are ready to defend it from a possible infection by Sars-cov-2.

This is how the vaccine gives us immunity against the virus.

However, it is not yet known how long the immunity generated by messenger RNA vaccines lasts.

Both Moderna and Pfizer tests began on July 27, so patients have been followed for just four months.

“Immunity is unlikely to be permanent, but we still don’t know if it will last six months, a year or more. What we know from studies for vaccines against Sars-cov-1 and MERS, for example, is that immunity decreases with time, “says Pardi.

According to the immunologist, what the new studies need to show is whether from the mRNA vaccine the body will remember how to produce antibodies against the virus in the future.

“That, yes, would be important. With immunological memory, it may only be necessary to vaccinate people once more, for example, to ensure more permanent protection”, he concludes.





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