Modernity Vaccine – first results
The New England Journal of Medicine published a short article on the results of the first-stage vaccine trial from the Modern company: Jackson et al., An mRNA Vaccine against SARS-CoV—2 - Preliminary Report.
First, briefly about the vaccine itself
The vaccine is aimed at the repeatedly discussed envelope protein S (see previous entries). During the formation of a viral particle, this protein is embedded in the lipid envelope and cut into two parts, which, however, remain connected together. A cut protein is like a cocked spring, it contains the energy needed to merge the viral membrane with the cell membrane that the virus infects. After this protein binds to the receptor on the cell surface, one part of it falls off, and the second changes its shape so as to merge the two membranes. Therefore, this protein is inherently unstable, but researchers have learned to make mutations that stabilize this protein and prevent it from falling apart. It is this protein that is used in the Modern vaccine in order for the antibodies produced against it to recognize the S protein in the form in which it is located on the surface of the viral particle.
In our cells, all proteins are encoded in DNA, which is located in the nucleus, a copy of RNA is removed from DNA, which goes to the cytoplasm of the cell and is used there for protein synthesis. The Modern vaccine is an RNA encoding the S protein described above. After its introduction into the muscle, the RNA enters the cytoplasm of the surrounding cells, and these cells produce the S protein for a while. This protein appears on the surface of the cells, but does not leave them, because there are no other proteins in the cells needed to create a viral particle. An immune response is produced to this protein. RNA does not live in cells for a long time, it is gradually destroyed. In addition, the immune response perceives cells with such RNA as infected with a virus, and kills them. Therefore, after a while, the vaccine in the body is destroyed, and the immune response to the protein remains.
Test design
The test was not blind, i.e. everyone knew who was receiving what dose of the vaccine. It also did not use a placebo, all volunteers received the vaccine. Given that the RNA-based vaccine technology is very new, the trial was conducted with a very gradual increase in dose. The volunteers were divided into three groups, one received a dose of 25 micrograms, another 100, and the third 250. There were 15 people in each group. They started the test with the lowest dose and even it was not given to everyone at once – first to a small group, if everything is fine, then to another small group, if everything is fine, then to the rest, if everything is fine, then to a small group with a higher dose, etc.
Each volunteer was given two doses – one on the first day, the second after 4 weeks (on day 29).
The volunteers were aged 18-55. Moderna has already recruited older volunteers (their immune response is usually worse), but there are no results for them yet.
Safety results
Of 45 people, 42 received both doses. One volunteer had a rash on his legs 5 days after the first dose. It is unclear whether it was related to vaccination, but they decided not to give the second dose. Two volunteers simply could not come to the second visit on time due to quarantine, due to the fact that they had a suspicion of COVID-19, and the results (negative) were not yet known.
No serious side effects were observed, there were standard for vaccines, mainly pain or irritation at the injection site. After the second dose, there were significantly more side effects, but again – nothing serious. This is generally consistent with the experience of testing RNA and DNA vaccines on animals and humans – they are usually quite harmless and do not cause serious reactions.
Results on the immune response – antibodies
All the main results are shown here in this picture:
Let's analyze panel A in more detail to understand what you should pay attention to. Here are the titers of antibodies binding to the protein used in the vaccine. Each point is a volunteer, the higher it is, the more antibodies the volunteer binds to the S protein. The doses received by the volunteers are written at the bottom, as well as the days on which the credits were measured.
Consider a group that received 25 micrograms of the vaccine. On the first day when they are given the first dose, they do not yet have antibodies to protein S, as should be expected. 2 weeks after the injection (day 15) we see titers 10 3-10 4. This is not very much and again is consistent with the experience of RNA and DNA vaccines – they do not cause a very strong immune response. On day 29, they are given a second dose of the vaccine, the antibody titers on that day are comparable to what they were two weeks before. Two weeks after the second dose (day 36), the titers rose about 10 times, to about 10 5. This is very good, but not stunning – some vaccines give titers at 10 6 and 10 7. 4 weeks after the second dose, the titers remained at about the same level, maybe they went down a little, which is normal – antibody titers always drop a little after the initial peak.
Groups with 100 mcg and 250 mcg can be considered by yourself. The main conclusion there for me is that the titers are significantly higher after the first dose, but about the same after the second, i.e. a higher dose may give faster protection, but in the long term, most likely, there will not be much difference. It is important, of course, to look at how long these titers will last, and Moderna is going to measure them 3, 6 and 12 months after the second dose. It is possible that higher doses will give a more durable response. There is no such data yet.
Note that the very last column on the right in panel A is the antibody titers of coronavirus patients. Unfortunately, it is not specified how these people were selected, how their illness proceeded, and how long after recovery these samples were taken. But in general, we see that the vaccine has produced comparable or even higher titers than a natural infection. On the one hand, this is very good, on the other hand, the studies of antibodies that have already appeared in those who have been ill indicate that their antibody titers are not very high, so this is a fairly low bar.
Panel B shows the titers of antibodies for binding not to the whole protein S, but to its most important part, recognizing the receptor on the surface of the target cell. In general, they are close to the titles on panel A, so I can't add anything particularly interesting here.
Panel C has slightly different data. This is not the binding of antibodies to a protein, but the ability of these antibodies to neutralize the virus. In this case, it is not the coronavirus itself, but a lentivirus (maybe even HIV, I did not delve into the details), carrying the coronavirus protein S on its surface. As I wrote somewhere earlier, such viruses are much safer than live viruses, so they are often used for such experiments. Similar to the results with binding antibodies, the neutralization results again look good with their titers in the region of 128-512, but not stunning. Again, they are slightly higher than those who have been ill, which is encouraging, but the difference is small.
On panel D is the neutralization of the coronavirus itself. The same comments as for panel C.
Results: Cellular immunity
Recently, several articles have been published indicating that the cellular immune response may play an important role in the control of coronavirus in natural infection. What does this vaccine have with the cellular response? Practically nothing. They see a response with CD4 T cells, which are important for the production of antibodies, which is quite consistent with the results above (without CD4 T cells, they would hardly have received such antibody titers), but they do not see a CD8 T cell response (CD8 lymphocytes recognize and kill infected cells). This is not surprising – previous experience with RNA and DNA vaccines predicted such a result, they always give a rather weak CD8 response.
Conclusions
In general, this article confirmed my expectations of the modern vaccine. Quite normal security. Not bad, but not stunning titers of antibodies, both binding and neutralizing the virus. Almost no cellular response. Whether this will be enough to protect or at least to mitigate the disease is unknown, and I do not undertake to predict, but there is every reason to conduct an efficiency test. It is quite possible that this will be enough.
A separate important question is how long these antibodies will last. Now there is a lot of noise about falling titles with a natural infection. This is somewhat strange to me, because immunologists are very well aware that after recovery, antibody titers always fall 10 times (sometimes 100 times), this is the case with almost all infections (and vaccines). After this initial fall, they usually remain at the received level for quite a long time. It is important that this stable level is high enough to provide protection, and we do not yet know what this level is necessary for protection. So it's a little early to panic, we need data.
Portal "Eternal youth" http://vechnayamolodost.ru