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Development and testing of a new vaccine usually take at least 12 to 18 months. However, just over 10 months after the publication of the genetic sequence of the SARS-CoV-2 virus, two pharmaceutical companies applied for emergency use authorization from the FDA for vaccines that appear to be highly effective against the virus.
Both vaccines are made from messenger RNA, the molecule that cells naturally use to carry instructions from DNA to the protein-building machinery of cells. The FDA has never approved an mRNA-based vaccine before. However, many years of research has gone into RNA vaccines, which is one of the reasons that scientists were able to start testing these Covid-19 vaccines so quickly. Once the viral sequences were revealed in January, the drug companies Moderna and Pfizer, along with their German partner BioNTech, took just days to generate mRNA vaccine candidates.
“What is particularly unique to mRNA is the ability to rapidly generate vaccines against new diseases. I think it’s one of the most exciting stories behind this technology, ”says Daniel Anderson, a professor of chemical engineering at MIT and a member of MIT’s Koch Institute for Integrative Cancer Research and the Institute of Medical Science and Engineering.
Most traditional vaccines consist of killed or weakened forms of a virus or bacteria. These elicit an immune response that allows the body to fight the actual pathogen later on.
Instead of delivering a virus or viral protein, RNA vaccines provide genetic information that allows the body’s own cells to make a viral protein. The synthetic mRNA that codes for a viral protein can borrow this machinery to produce many copies of the protein. These proteins stimulate the immune system to generate a response, without posing any risk of infection.
A key advantage of mRNA is that it is very easy to synthesize once researchers know the sequence of the viral protein they want to target. Most SARS-CoV-2 vaccines elicit an immune response that targets the coronavirus spike protein, which sits on the surface of the virus and gives the virus its characteristic pointed shape. Messenger RNA vaccines encode segments of the spike protein, and those mRNA sequences are much easier to generate in the laboratory than the spike protein itself.
“With traditional vaccines, you have to develop a lot. It takes a large factory to produce the protein or virus, and it takes a long time to grow it, ”says Robert Langer, a professor at the David H. Koch Institute at MIT, a member of the Koch Institute and one of the founders of Moderna. “The beauty of mRNA is that you don’t need it. If you inject nanoencapsulated mRNA into a person, it enters the cells and then the body is its factory. The body takes care of everything else from there. “
Langer has spent decades developing novel ways to deliver drugs, including therapeutic nucleic acids like RNA and DNA. In the 1970s, he published the first study showing that it was possible to encapsulate nucleic acids, as well as other large molecules, into tiny particles and deliver them to the body. (MIT Institute professor Phillip Sharp and others’ work on RNA splicing, which also laid the foundation for today’s mRNA vaccines, also began in the 1970s.)
“It was very controversial at the time,” recalls Langer. “Everyone told us it was impossible and my first nine grants were rejected. I spent about two years working on it and found over 200 ways to make it not work. But then finally I found a way to make it work. “
That paper, which appeared in Nature In 1976, he showed that small particles made from synthetic polymers could slowly transport and release large molecules such as proteins and nucleic acids. Later, Langer and others showed that when polyethylene glycol (PEG) was added to the surface of nanoparticles, they could last in the body much longer, rather than being destroyed almost immediately.
In the following years, Langer, Anderson, and others have developed fat molecules called lipid nanoparticles that are also very effective at delivering nucleic acids. These transporters protect RNA from breakdown in the body and help transport it across cell membranes. Moderna and Pfizer RNA vaccines are carried by lipid nanoparticles with PEG.
“Messenger RNA is a large hydrophilic molecule. Naturally, it does not enter cells on its own, so these vaccines are wrapped in nanoparticles that make it easy to deliver them inside cells. This allows the RNA to be delivered into cells and then translated into proteins, ”says Anderson.
In 2018, the FDA approved the first lipid nanoparticle carrier for RNA, which was developed by Alnylam Pharmaceuticals to deliver a type of RNA called siRNA. Unlike mRNA, siRNA silences its target genes, which can benefit patients by turning off mutated genes that cause disease.
One drawback of mRNA vaccines is that they can break down at high temperatures, which is why current vaccines are stored at such cold temperatures. Pfizer’s SARS-CoV-2 vaccine should be stored at -70 degrees Celsius (-94 degrees Fahrenheit) and Modern vaccine at -20 C (-4 F). One way to make RNA vaccines more stable, Anderson notes, is to add stabilizers and remove the water from the vaccine using a process called freeze-drying, which has been shown to allow some mRNA vaccines to be stored in a refrigerator rather than a freezer.
The surprising effectiveness of these two Covid-19 vaccines in phase 3 clinical trials (approximately 95 percent) offers hope that not only will those vaccines help end the current pandemic, but also that in the future, the RNA vaccines can help in the fight. against other diseases like HIV and cancer, says Anderson.
“People in the field, including me, saw a lot of promise in the technology, but you don’t really know until you get human data. So seeing that level of protection, not only with the Pfizer vaccine but also with Moderna, really validates the potential of the technology, not just for Covid, but also for all these other diseases that people are working on, ”he says. “I think this is an important moment for the field.”
