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Most SARS-CoV-2 vaccines elicit an immune response that targets the coronavirus spike protein, which is on the surface of the virus. Messenger RNA vaccines encode segments of the spike protein, and these mRNA sequences are much easier to generate in the laboratory than the spike protein itself. Credit: Image: Christine Daniloff, MIT; and stock images
Many years of research have enabled scientists to quickly synthesize RNA vaccines and administer them inside cells.
Development and testing of a new vaccine usually takes at least 12 to 18 months. However, a little more than 10 months after the genetic sequence of SARS-CoV-2 virus has been released, two drug companies have applied for emergency use clearance 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 transport DNAthe instructions of the cell protein construction machinery. An mRNA-based vaccine has never been approved by the FDA before. However, many years of research have gone into RNA vaccines, which is why scientists were able to start testing these vaccines against Covid-19 so quickly. Once the viral sequences were revealed in January, it only took a few days for pharmaceutical companies Moderna and Pfizer, as well as its German partner BioNTech, to generate mRNA vaccine candidates.
“What is particularly unique about mRNA is the ability to rapidly generate vaccines against new diseases. I think this is one of the most exciting stories behind this technology, ”says Daniel Anderson, professor of chemical engineering at WITH and Fellow of MIT’s Koch Institute for Integrative Cancer Research and Institute of Medical Engineering and Science.
Most traditional vaccines consist of killed or weakened forms of a virus or bacteria. These elicit an immune response which allows the body to fight off the actual pathogen later.
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. Synthetic mRNA that encodes a viral protein can borrow this machinery to produce many copies of the protein. These proteins stimulate the immune system to mount a response, without presenting a 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 is on the surface of the virus and gives the virus its characteristic spiky shape. Messenger RNA vaccines encode segments of the spike protein, and these mRNA sequences are much easier to generate in the laboratory than the spike protein itself.
“With traditional vaccines, you have to do a lot of development. You need a big factory to make the protein, or the virus, and it takes a long time to grow them, ”says Robert Langer, professor at the David H. Koch Institute at MIT, 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 a person with nanoencapsulated mRNA, it goes into the cells and then the body is your factory. The body takes care of everything else from there.
Langer has spent decades developing new ways to deliver drugs, including therapeutic nucleic acids such as 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. (The work of Professor Phillip Sharp of the MIT Institute and others on RNA splicing, which also laid the groundwork for current mRNA vaccines, also began in the 1970s.)
“It was very controversial at the time,” Langer recalls. “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 keep it from working. But I finally found a way to make it work.
This paper, published in Nature in 1976, showed that tiny particles made of synthetic polymers could safely transport and slowly 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 much longer in the body, instead of being destroyed almost immediately.
Over the next few years, Langer, Anderson, and others developed fatty molecules called lipid nanoparticles that are also very efficient at delivering nucleic acids. These transporters prevent RNA from being broken down in the body and help transport it across cell membranes. Moderna and Pfizer RNA vaccines are both transported by lipid nanoparticles with PEG.
“Messenger RNA is a large hydrophilic molecule. It does not naturally enter cells by itself, and therefore these vaccines are enveloped in nanoparticles which facilitate their delivery inside cells. This allows RNA to be delivered inside 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 provide 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 disadvantage of mRNA vaccines is that they can decompose 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 Moderna vaccine at -20 C (-4 F). One way to make RNA vaccines more stable, Anderson points out, is to add stabilizers and remove water from the vaccine through a process called freeze-drying, which allows some mRNA vaccines to be stored in a refrigerator instead. a freezer.
The striking efficacy of these two Covid-19 vaccines in phase 3 clinical trials (around 95%) gives hope that not only will these vaccines help end the current pandemic, but also that vaccines in the future. to ARN will be able to help in the fight. against other diseases such as HIV and cancer, Anderson says.
“People in the field, myself included, saw a lot of promise in the technology, but you don’t really know it until you get some 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 pitch.”
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