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The powerful technology behind Pfizer and Moderna vaccines

So far, two of the three COVID-19 vaccines approved in the United States use synthetic messenger RNA or mRNA to prevent coronavirus. Although these vaccines developed by Pfizer and Moderna, respectively, are the first large-scale use of such vaccines, this historic moment is impossible without decades of research.

There are many ways to make a vaccine, but the ultimate goal of any shooting is to introduce the human body to the bioequivalent of the “most wanted” poster, so that if the real enemy appears, our immune system will know how to shoot. Retreat.

For some vaccines, the poster is a weakened pathogen (such as chickenpox shots) or inactivated (such as most flu shots), so it does not actually cause infection. For other viruses (including HPV and shingles vaccines), it is part of this pathogen, just like the specific protein it was originally used to infect cells.

But the mRNA vaccine takes a different approach. Paul Duprex, an RNA virologist, director of the University of Pittsburgh Vaccine Research Center, said that the platform does not use viruses or parts of them to repair, but uses “the beauty of our biology”

; to provide protection. These vaccines teach the body to remember one of the defining characteristics of the coronavirus-its spike protein-and promote the production of antibodies that can prevent it from infecting cells.

Our DNA resides in the nucleus of our cells. Every day, mRNA molecules continue to carry the genetic information encoded by DNA from the nucleus to the part of the cell (called ribosomes). They can interpret this information and then make proteins that perform basic biological processes. Without it, life would be impossible.

Duprex said: “At this particular moment, almost every cell in my body is producing billions of messenger RNA.”

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Vaccines that use synthetic mRNA add another type of mRNA to the “daily activities” of other molecules in our body, and use it to “make a protein that the immune system sees and makes antibodies against us.” And protect us from disease”, Duprex added.

About 20 years ago, the work of two researchers (Drew Weissman and Katalin Karikó) helped overcome two major obstacles to the use of mRNA technology: inflammation on the human body that makes test animals sick, and the structure of the fragile natural environment molecules themselves. , Both of which hinder its practicality.

Despite these advances, and a lot of research since then, the fact remains that the two mRNA vaccines in use today are the first. Duprex said that this may be partly because it is difficult to generate interest and funding to support the search for “non-mainstream” science after the crisis, which he believes is a “biological short-sighted approach.”

Only now, in a devastating pandemic, has this technology become mainstream. Weissman said: “Considering this choice, I would rather avoid doing this in the past year.” “But we don’t. Now RNA will be our future.”

Here are the visions of how these vaccines succeeded in achieving this feat and some of the key research breakthroughs that made this moment possible.

How the Messenger RNA vaccine works

To develop these vaccines, the researchers took the RNA-based genetic sequence of the coronavirus and converted it into DNA. This critical step allowed them to determine the “instructions” needed to create the spike protein, engineer the corresponding synthetic mRNA, and package it into a vaccine.

As the name suggests, mRNA is a messenger. This special type of RNA is responsible for transmitting information to the microscopic cellular machinery called ribosomes, which is located in the cytoplasm of our cells and is responsible for the synthesis of proteins. The molecular biologist and MIT professor Phillip Sharp explained that those ribosomes would then interpret this information to make proteins and start executing their instructions. He contributed to our understanding of RNA. Won the 1993 Nobel Prize in Physiology or Medicine.

Dendritic cells are the watchdog of the immune system and play a vital role in the response to pathogens. They patrol the body to find foreign invaders, and start to stimulate the immune response when they find a foreign invader. Weisman said that when these cells encounter the mRNA injected through the vaccine, their ribosomes will decode the information and allow the cells to temporarily display the same spike protein as the outer surface of the coronavirus.

He added: “Dendrite cells produce spike proteins, which are then presented to other immune cells and activated to initiate an immune response.”

These proteins can make dendritic cells alert to two other key players in the immune system, namely T cells and B cells. If they see the same spike on any other cell, they should be recognized as foreign invasion And destroy them or produce antibodies. Neutralize them immediately.

Sharp said: “There is a memory component in these cell groups, and it will stay in your body for a long time.” “If a similar virus infects you, these storage units are ready. They can all go out and kill the virus.”

mRNA will naturally degrade rapidly over time, so once it reaches its purpose, it will decompose. The dendritic cells expressing the spike protein eventually die and are replaced by new dendritic cells. These new dendritic cells continue to absorb the mRNA delivered by the vaccine and repeat the process again within about two weeks after immunization.

Some members of the public are concerned about unfounded speculation that these vaccines may have a negative impact on the human body. However, it is impossible for mRNA vaccines to change your DNA, because synthetic mRNA only works in the cytoplasm and cannot enter any other part of the cell, such as the nucleus.

Like almost all vaccines, vaccines that use mRNA may cause temporary symptoms at the injection site, such as fever, fatigue, and soreness. These symptoms will disappear within a few days. However, clinical trials conducted before the vaccine was approved and subsequent trials have shown that these vaccines are safe and effective in preventing serious illness and death.

Duprex said: “The risk of this disease is always much higher than the risk of vaccination.”

How did we get here?

In 1990, mRNA was injected into the muscles of mice for the first time in order to deliver therapeutic proteins. However, Weisman believes that this effort “did not go too far”, largely due to the strong inflammatory response it caused, which caused severe discomfort to the relevant animals.

This is because in animals and humans, cells have many different receptors that can recognize mRNA as a foreign body that must be destroyed. These receptors help these cells distinguish their companion cells from invaders such as viruses, bacteria and even tumor cells.

Both RNA and DNA consist of four nucleotides. More than ten years after the first injection of mice, Weissman and Karikó (now senior vice president of BioNTech, which cooperates with Pfizer to produce a combined vaccine) found a way to insert modified nucleotides that can make the synthesis The mRNA disguised as normal cells and evaded those receptors, no longer causing extreme inflammation. This also makes mRNA stimulated protein production more efficient.

“Our major discovery is that we can modify RNA so that it does not become inflammatory. This has several important features, but first, it greatly increases the protein quality of RNA extraction,” Weissman said.

After solving the inflammation problem, Weissman and Karikó then began to adjust the delivery method of mRNA so that once it is injected into the body, it can really do its job. mRNA is an inherently “unstable” or unstable substance that can be rapidly degraded to the point of failure.

After testing about 40 different types of delivery systems, the researchers discovered their golden light: lipid nanoparticles. These “fat droplets” wrap the mRNA and make it successfully enter our cells, which are also wrapped in oily substances.

Traditional vaccines are usually formulated with adjuvants designed to stimulate the immune response of their recipients. In Weisman’s lucky development, lipid nanoparticles act as adjuvants, stimulating specific types of “helper cells”, thereby promoting antibody responses.

“We use lipid nanoparticles to overcome a lot of vulnerabilities [problems] Because that protects [mRNA] When you inject it into the body, it promotes the absorption of these cells [mRNA] And start the vaccination process,” Weissman said.

The status of mRNA today

Since Weissman and Karikó made these breakthroughs, mRNA research has continued. Weissman and his current colleagues have studied a variety of mRNA vaccines, including a “universal” influenza vaccine that can cover most influenza viruses. So far, they have been proven effective in animal experiments.

Compared with traditional vaccine platforms that require a series of complex steps (for example, mass propagation of mammalian cells and virus purification processes that look different depending on the pathogen used), mRNA is now easy to produce on a large scale.

Weissman said: “There is no need to reinvent the wheel every time a new vaccine is made,” [mRNA,] This is the same reaction, the only thing to do is to insert new sequences for any virus, so that new vaccines can be easily produced. “

After two doses in the clinical trial, Moderna and Pfizer’s vaccines both produced more than 90% protection, and the trial worked before the new virus variant slightly reduced its efficacy. Even so, both still give the recipient a significantly high level of protection, especially protection against serious illness and death.

The Centers for Disease Control and Prevention (CDC) recently released a new study that found that these vaccines reduce the chance of infection with the coronavirus in fully vaccinated people by 90% in “real” environments, such as the workplace.

Given that no vaccine has ever been approved to protect people against any type of coronavirus, and the FDA’s initial hope is to ensure that it can obtain at least 50% of the efficacy to contain the pandemic, these results represent another important milestone in the history of RNA technology. .

These vaccines will undergo more research in the future. In the past few months, these two vaccines have been launched in the United States and some other countries. In addition to continuing to track safety and efficacy data, researchers also need to understand how these vaccines effectively prevent recipients from spreading COVID-19, and how long the protection they provide can last. Experts say that until we know the answers to these questions, recipients should continue to follow popular precautions, such as wearing masks, even after taking two doses.

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Johnson & Johnson’s vaccine is a single-dose vaccine that uses a platform that is different from mRNA but is similarly innovative to provide immunity. The vaccine has also been approved for use in the United States. Its powerful efficacy and the ability to store in a less stringent temperature range make experts hope that the introduction of this vaccine will help narrow some of the gaps in vaccine availability between the country and abroad.

Duprex said that in response to COVID-19, Pfizer and Moderna’s vaccines “paved the way,” which illustrates the practicality of synthetic mRNA. However, although he expects that researchers will “make better adjustments” to better deliver and stabilize the technology, he pointed out that we are still in the early stages of exploiting its practicality-nor can we assume that mRNA is the solution to us The “next big panacea” for all problems.

But Duprex said: “The beauty related to this is that it provides us with another novel treatment option. [and] Some new ideas in the next generation of scientists will be able to [use to] painting. ”

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