Coronavirus Vaccine: First Phase 3 Vaccine Trial in US Scheduled to Start Next Week

One of those vaccines is being developed by Vaccine Research Center At the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, we partner with biotechnology company Moderna. The vaccine is expected to enter Phase 3 trials next week. At this stage of the trial, 30,000 volunteers are expected to be involved, testing whether the vaccine protects people from coronaviruses.

The vaccine uses messenger RNA (mRNA), which is the cell that is used to build the protein-in this case, the spike protein of coronavirus that the virus uses to attach to and infect human cells It is a protein needed for Thanks to the vaccine, learning to recognize this target by the immune system can initiate a reaction faster than if the virus was first encountered for infection.

The initial results of the Phase 1 trial are Published in New England Medical Journal Mid-July. This study showed that vaccines given in three different doses elicited an immune response in those who received it (higher dose, higher immune response). Over half of the participants experienced side effects such as fatigue, chills, headaches, muscle aches and injection site pain. Phase 3 trials include a medium dose–100 micrograms (µg).

Dr. Bernie Graham is the Deputy Director of the Vaccine Research Center. He talked to Dr. Sanjay Gupta and explained a little about the technology behind the Moderna vaccine. The following is part of a conversation, edited for length and clarity to explain what is happening in the body.

Dr. Sanjay Gupta: How does the vaccine work? Give a piece of messenger RNA [mRNA] To someone. What is mRNA? How does the body react to make these antibodies?

Dr. Bernie Graham: Our human genome is made of DNA. This is a double-stranded molecule. Most people have heard about DNA. The way our bodies make proteins is from a DNA template made of nucleotides [basic building blocks], It does something called transcription: it uses that DNA template to make an RNA template. RNA, therefore, is the template that we normally use in our own bodies to make proteins needed for cell function…that part is called translation…

When RNA is put directly into muscle cells and injected as a vaccine, the RNA goes directly into the cytoplasm. [the body, not the nucleus] It is translated by the ribosome of the cell and makes a protein. In our case, the mRNA we use to make this protein is the vaccine. And when that RNA enters muscle cells, it makes and produces proteins, and when that protein sits in muscle cells, it sits on a virus, except that we don’t have to give it It looks like a protein that’s in it, it’s the whole virus, it just provides the protein. And this is the main attack point. The immune system recognizes this and begins to make antibodies to different surfaces of this protein. And if the virus appears on its surface with this same exact protein, we expect those antibodies to be present. This is how this mRNA vaccine works.

Part of the basis for this vaccine development came from research on another endemic coronavirus in 2012, during MERS, and one of the endemic coronaviruses that prevail every winter. An important finding was when Graham and his colleagues recognized that the shape of spike proteins changed as part of the process used to fuse to infected cells. And in order to develop an effective vaccine against any of the coronaviruses, it is necessary to target the pre-fusion spike protein-not the post-fusion one but the shape change upon fusion with the human cell receptor. The previous spike protein version, this is what they did for this new coronavirus.

Graham: These types of proteins are important for the virus’ entry into the cell. These proteins are placed on top of the virus, interact with cells, and undergo a rearrangement that resembles a robot toy’s Transformers toy. These proteins are interesting because they start in one form, end in another, and depending on the form used, a good response to the vaccine or a poor response to the vaccine. Also, for the past 30 or 40 years, people have been using rearranged, non-functional foams after fusion with vaccines, which has been less successful. None of them actually worked… Transformer’s analogy is that if the car is an important part, you need to make antibodies against the car, not the robot… and that is Vaccines for people for 30 to 40 years. It wasn’t working. Prior to this, there was really no concept of pre-fusion structure.

Gupta: Clearly, we need to make a protein that represents the pre-fusion spike protein, rather than the post-fusion form. But other than that, you basically let the body recognize the virus as if you were infected with it, right? What I’m asking for is this vaccine can cause people to get sick and actually get infected?

Graham: No. The virus itself has a genome of 30,000 nucleotides. We provide about 4,000 nucleotides, or perhaps close to 3,700 nucleotides, to make this protein. Therefore, it provides only one-tenth of the genome, and their nucleotides have also been modified. There we use so-called codon optimization. I changed the nucleotide sequence, but the amino acid sequence is exactly the same. Therefore, what we offer is actually a different virus, but it produces this viral protein.

Gupta: with this [New England Journal of Medicine] Just came out the paper, they talked about people who have these side effects. In fact, everyone in the medium dose group (100 µg; 2 shots per month) and the highest dose (250 µg; 2 shots per month) all had some side effects. Discontinuing the trial was not enough, but there were side effects. They were like headaches and fever, fatigue and muscle aches. You are not infected with a virus. I’m not infected, but why do people cause these side effects?

Graham: I am a doctor of infectious diseases who has done many clinical trials and has conducted over 100 clinical trials of various vaccines since the mid-1980s. And these types of side effects, which we call reactogenicity, are very common in almost all vaccines, even those commonly used and licensed. What we saw with this setting was that at the 25 and 100 µg doses, there was little reaction after the first shot and some reaction after the second shot. However, virtually all of these reactions were mild or moderate. And it’s calm so you can notice it. Medium means a little worrisome.

Now, when they reached the higher dose of 250 µg, some of those people showed a more severe reaction. 3 out of 14 [who received the 250µg dose] There were grade 3 reactions such as fever and muscle aches. This is similar to what we experienced with some of the licensed vaccines. But, as you know, the reason for doing these Phase I trials is to find an acceptable dose level. And in this case it was clear that we didn’t want 250g to be given, so we didn’t want to give it to people, especially a lot of people. The 100 µg dose was well tolerated. Yet a small number, another 300 who were vaccinated in Phase 2 show a similar reactogenicity profile. Therefore, we believe that a dose of 100 µg will remain acceptable. And that is the Phase 3 trial plan.

Gupta: I would like to ask you about the research that has just emerged. When we obtained the data, we found that there was neutralizing antibody activity. Am I surprised or was it quite a matter of course?

Graham: We did a lot of research with a similar vaccine we created for the MERS spike and we did a lot of those studies in mice and knew that this protein was immunogenic-that is, medium A virus that was very effective in eliciting a compatible antibody response. Therefore, it was known that this would work in mice before the first person was injected. So it wasn’t a big surprise that humans could do it.

I was pleasantly surprised at the level of neutralizing antibodies-exceeded expectations. It has achieved almost what I wanted. And we were satisfied with the level of neutralization elicited in humans by this vaccine.

Another reason to do Phase 1 trials is not only to find an acceptable dose, but also one that has optimal immunogenicity. In this case, the 100 µg dose was virtually the same as the 250 µg dose for the antibodies produced. And those antibodies reached levels that were in the upper range of those produced by convalescent people infected with the SARS-CoV-2 coronavirus. So I felt this was a good result.

Gupta: Let me ask you another question. About one-third of the country is already hesitant about the vaccine-they are still showing some anxiety about this new, yet unreleased vaccine. How do you deal with the hesitation of the vaccine?

Graham: If people really understood the biological basis of vaccines and how they work-the Angstrom-level structure of what we are trying to make sure it is neither magical nor mysterious. I think in fact there is a rationale and a very specific understanding of what to do to make an immune response that helps protect you-by trying to explain some of this, And we really hope that by starting to understand the biology of vaccines, they will not hesitate to join us and be more likely to be this immune community we are looking for, people Is trying to establish what is called herd immunity.

The reason this is important is because we expect this vaccine to be 70% or 80% effective-I think it will succeed. Requires 60 or 70% of immunity [in the population] To really establish what is called herd immunity. That means almost 100% of people must be vaccinated to establish that level of immunity in the population. Therefore, if one-third of a person is not vaccinated, and if they are vaccinated with that type of vaccine, they can only reach immunity in about 40 or 50% of the population. I think it’s very important that a third of people come together to help us, understand how these vaccines work, and don’t hesitate.