The World Health Organization says there are 25 possible coronavirus vaccines in clinical trials internationally.
The vaccine uses messenger RNA (mRNA), which are cells that are used to build proteins; in this case, the proteins that are needed to build the coronavirus spike protein, which the virus uses to bind and infect human cells. Once the immune system learns to recognize this goal, thanks to the vaccine, it can generate a faster response than if it first encountered the virus due to an infection.
Dr. Barney Graham is the deputy director of the Vaccine Research Center. He spoke to Dr. Sanjay Gupta to explain a little about the technology behind the Modern vaccine. What follows is a part of their conversation, edited for length and clarity, to explain what is going on inside the body.
Dr. Sanjay Gupta: How does the vaccine work? You are giving a small portion of messenger RNA [mRNA] tosomeone. What is mRNA and how does the body respond and create these antibodies?
Dr. Barney Graham: Our human genome is made of DNA; This is a double-stranded molecule. Most people have heard of DNA. The way our bodies make proteins is that, from the DNA template that is made of nucleotides [basic building blocks], it does something called transcription: it uses its DNA template to make an RNA template. So RNA is the template that we normally use in our own body to make proteins that are necessary for cellular function … and that part is called translation …
And so, when RNA is placed directly into the muscle cell, when injected as a vaccine, that RNA goes directly into the cytoplasm [the body, not the nucleus] from the cell, it is translated by ribosomes to form a protein. And in our case, the mRNA we use to make this protein is our vaccine. And when that RNA enters the muscle cell, it creates and produces a protein, and when that protein is found in the muscle cell, it looks like the protein that would be in a virus, except we don’t have to give it’s the entire virus, just we give him the protein. And this is the main point of attack; The immune system recognizes this, it begins to produce antibodies against different surfaces of this protein. And then we count on those antibodies to be present if the virus appears with this exact same protein on its surface. This is how this mRNA vaccine works.
Some of the bases for the development of this vaccine were established during another coronavirus outbreak, MERS in 2012, and work on one of the endemic coronaviruses that circulates each winter. A key discovery came when Graham and his colleagues realized that the spike protein changes shape as part of the process it uses to fuse with the cell it is infecting. And to develop an effective vaccine for any of the coronaviruses, they would have to target the pre-fusion peak protein, the version of the peak protein before it fuses with a human cell receptor and changes shape, not the post fusion. , which is what they did for this new coronavirus.
Graham These types of proteins are important for the virus to enter cells. Those proteins sit on top of the virus, interact with the cell, and then undergo a rearrangement analogous to a Transformer toy, where robots can be turned into automobiles. These proteins are interesting because they start in one way and end in a different way, and depending on the way you use it, you’ll get a good response to a vaccine or a not-so-good response to a vaccine. And for the past 30 to 40 years, people have been using the post-fusion, rearranged, and nonfunctional form in their vaccines, and they haven’t done very well. None of them had really worked … So, in the Transformer analogy, if cars are the important part, it is necessary to make antibodies for the car and not for the robot … And that’s why for 30 or 40 years , the people’s vaccines were not working. Before this, the concept of pre-merger conformation was not really there.
Gupta Obviously, you want to create a protein that represents the pre-fusion form of the spike protein, not the post-fusion form. But other than that, you’re basically making the body recognize the virus as if it had been infected, right? What I’m asking is if people can get sick, really get the infection, from this vaccine.
Graham No. The virus itself, its genome is 30,000 nucleotides. We are only giving around 4,000 nucleotides, or perhaps closer to 3,700 nucleotides, to produce this protein. So we’re only giving a tenth of the genome, and even those nucleotides are modified. There we use what is called codon optimization; We have changed the nucleotide sequence but we do the exact same amino acid sequence. So what we are giving is not really like the virus, but it produces this viral protein.
Gupta In this [New England Journal of Medicine] role that just came out, they talked about people having these side effects. In fact, everyone in the medium dose group (100 µg; two injections separated by one month) and the highest dose (250 µg; two injections separated by one month) had some type of side effect. It was not enough to stop the trial, but there were side effects. They were things like headache, fever, discomfort, and muscle pain. Obviously, it is not getting infected, it is not the virus itself, so why do people develop these side effects?
Graham I am an infectious disease physician who has conducted many clinical trials and, since the mid-1980s, over 100 clinical trials of different experimental vaccines. And these kinds of side effects, which we call reactogenicity, are very common in almost all vaccines, including commonly used and licensed vaccines. What you saw in this setup is that at the 25 µg and 100 µg doses, you saw very little reaction after the first shot, but then some reaction after the second shot. But virtually all of those reactions were mild or moderate. And so soft means that you can notice it; moderate means it bothers you a little.
Now, when it reaches the highest dose of 250 µg, some of those people had more severe reactions. Three of 14 [who received the 250µg dose] She had grade three reactions to fever and muscle aches and the like, similar to what she sometimes experiences after some of our licensed vaccinations. But, you know, the reason for doing these Phase 1 trials is to find out what dose level is acceptable and tolerable. And in this case, it was pretty clear that 250 µg is not something we want to give to people, especially a large number of people, because it was not tolerated. The 100 µg dose was well tolerated. It is still a small number of people, but there have been another 300 people immunized in a Phase 2 that have also shown a similar reactogenicity profile. Therefore, we believe that the 100 µg dose should be acceptable in the future. And that’s what is planned for phase 3 testing.
Gupta Let me ask you about the study that just came out. We obtained the data, showing that there was antibody neutralizing activity. Were you surprised or was that more or less a fact?
Graham We had done many studies with a similar vaccine that we did for the MERS peak and we had done many of those studies in mice and we knew that this protein was immunogenic, meaning that it was very effective in obtaining antibody responses that could neutralize the virus. So we knew this worked in mice before injecting the first person. So it wasn’t a big surprise that we could do that in humans.
I was pleasantly surprised, I think, by the level of neutralizing antibodies: it exceeded my expectations. You almost got what you hoped for. And so we were happy with the level of neutralizing activity this vaccine caused in humans.
The other reason you do Phase 1 trials is not just to find the dose that is tolerable but to find the dose that has optimal immunogenicity. In this case, the 100 µg dose was practically the same as the 250 µg dose in terms of the antibodies produced. And those antibodies reached levels that were in that higher range than do convalescent people who have been infected with the SARS-CoV-2 coronavirus. So, we felt that this was a good result.
Gupta Let me ask you something else. You have about a third of the country that is already showing some vacillation with vaccines; They are already showing some concern about this new vaccine that is not yet available. How is hesitant hesitation handled?
Graham I think if people really understood the biological basis of vaccines and how they work, to see that it is not magical or mysterious, that there really is a very specific logic and understanding down to the angstrom level of the structure of what we are dealing with. make an immune response that can help protect you. I really hope that trying to explain some of this and that people begin to understand the biology of vaccines will make them less hesitant and more likely to join us. trying to establish this community of immunity that we are looking for, what people call collective immunity.
The reason this is important is that I hope this vaccine can be 70 or 80% effective, I think it would be a success. We need 60 or 70% immunity [in the population] to really establish what is called collective immunity. That means that almost 100% of people would have to be vaccinated to establish that level of immunity in the population. So, if a third of people do not take it, we can only achieve around 40 or 50% immunity in the population with that type of vaccine. I think it’s really important that that third of people come in and try to help us understand how these vaccines work so they don’t hesitate as long.
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