Most SARS-CoV-2 vaccines elicit an immune response that targets the coronavirus spike protein, which is found 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 allowed scientists to quickly synthesize RNA vaccines and distribute them within cells.
The development and testing of a new vaccine usually takes at least 12 to 18 months. However, just over 10 months after the genetic sequence of SARS-CoV-2 virus was published, two pharmaceutical companies have applied for FDA authorization for emergency use of 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 DNAinstructions for cell protein building machinery. A mRNA-based vaccine has never been approved by the FDA before. However, many years of research have been done on RNA vaccines, which is one of the reasons why scientists were able to start testing these vaccines against Covid-19 so quickly. After the viral sequences were revealed in January, it took just a few days for pharmaceutical companies Moderna and Pfizer, together with their German partner BioNTech, to generate candidate mRNA vaccines.
“What is particularly unique about mRNA is the ability to generate vaccines against new diseases quickly. This is one of the most exciting stories behind this technology, ”says Daniel Anderson, professor of chemical engineering at MIT and member of the Koch Institute for Integrative Cancer Research and the Institute for Medical Engineering and Science at MIT.
Most traditional vaccines consist of dead or weakened forms of a virus or bacteria. They elicit an immune response that allows the body to fight the real pathogen later.
Instead of delivering a virus or viral protein, RNA vaccines provide genetic information that allows the body’s own cells to produce a viral protein. The synthetic mRNA that encodes a viral protein can borrow this mechanism to produce many copies of the protein. These proteins stimulate the immune system to mount a response, without posing any risk of infection.
A key advantage of mRNA is that it is very easy to synthesize, since researchers know the sequence of the viral protein they want to target. Most vaccines for SARS-CoV-2 elicit an immune response that targets the coronavirus spike protein, which is found on the surface of the virus and gives the virus its characteristic pointed 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, a member of the Koch Institute and one of the founders of Moderna. “The beauty of mRNA is that you don’t need this. If you inject nanoencapsulated mRNA into a person, it goes to the cells and then the body is your factory. The body takes care of everything 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 in RNA splicing, who also laid the foundation for today’s mRNA vaccines, began in the 1970s as well.)
“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 discovered more than 200 ways to make it not work. But, finally, I found a way to make it work ”.
This newspaper, which appeared in Nature in 1976, it 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 the nanoparticles, they could last much longer in the body, rather than being destroyed almost immediately.
In subsequent years, Langer, Anderson and others developed fat molecules called lipid nanoparticles, which are also very effective in delivering nucleic acids. These carriers protect RNA from decomposition in the body and help transport it across cell membranes. Both the RNA Moderna and Pfizer vaccines are transported by lipid nanoparticles with PEG.
“Messenger RNA is a large hydrophilic molecule. It does not naturally enter cells by itself, which is why these vaccines are packaged in nanoparticles that facilitate delivery within the cells. This allows RNA to be delivered into cells and then translated into proteins, ”says Anderson.
In 2018, the FDA approved the first carrier of lipid nanoparticles 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 disease-causing mutant genes.
A disadvantage of mRNA vaccines is that they can break at high temperatures, which is why current vaccines are stored at such low temperatures. Pfizer’s SARS-CoV-2 vaccine should be stored at -70 degrees Celsius (-94 degrees Fahrenheit), and the 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 lyophilization, which has been shown to allow some mRNA vaccines to be stored in a refrigerator instead of a freezer.
The impressive efficacy of both Covid-19 vaccines in phase 3 clinical trials (about 95 percent) offers hope that not only will these vaccines help end the current pandemic, but that RNA vaccines in the future will also help. can help fight other diseases like HIV and cancer, says Anderson.
“People in the field, including me, have seen many promises in technology, but you don’t really know until you get human data. So seeing that level of protection, not just with the Pfizer vaccine, but also with Moderna, really validates the technology’s potential – not just for Covid, but also for all these other diseases that people are working on, ”he says. “I think it is an important moment for the field.”