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  • I see news about repeated infection with coronavirus - at first it becomes scary, then I think that this is a fake.So is it possible or not?And will the vaccine save?

I see news about repeated infection with coronavirus - at first it becomes scary, then I think that this is a fake.So is it possible or not?And will the vaccine save?

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We will answer the main questions right away

Можно ли заразиться второй раз?

Yes, now it has been proven.So far, four cases have been reliably described, several more cases are discussed.

Во второй раз болезнь проходит легче или тяжелее?

Unfortunately, the repeated infection is not always easier than primary: there are examples when the second time the disease was severe, one person was hospitalized.Why this happens is unknown.

Часто ли происходит повторное заражение?

What is the share of repeated infections is also unknown.There are very few described examples of repeated infection, and statistical conclusions are impossible to draw on their basis.

Значит, иммунитет не вырабатывается? А от вакцин?

How long the immunity to coronavirus lasts in most people with a natural disease and how long will the immunity will last when vaccinating are two most important issues, on which, first of all, the development of pandemia will depend.There is no answer to them yet.

То есть мы ничего не знаем про иммунитет?

We know something.There are results of animal experiments, analysis of other viral infections, mass testing on antibodies in thousands of people and analysis of the structure of viral proteins.Together, data say that, most likely, most people have protective immunity - and it will persist for at least many months.

The picture may change if strongly changed varieties of the virus, “leaving” from the developed immunity are discovered.Until now, there was no evidence that this was happening, although the existence of one such variety has already been discussed.

Now more details: how to relate to news about repeated infections?

About whether the ill-fledged Covid-19 could be infected by them re-argued from the very beginning of the pandemic.News about re -infection come across quite often:

Whether to believe these news is an illegal question: if there are a lot of repeated infections, then in a significant number of people the immunity is not formed at all or is unstable.And this, in turn, makes it unlikely to achieve population immunity naturally and reduces the chances of obtaining working vaccines.

Medusa also wrote about this: when in Russia a version was widely discussed that many were ill back in December 2019;When it became clear that the repeated infection in Korea, which was reported in the news, turned out to be a mistake;When the first case of re -infection in Hong Kong was reliably confirmed.

How our testimony changed

In changing news, it is easy to get confused, and there is no guarantee that after the release of this material, new data will not appear, indicating, for example, of the mass of repeated infection in the case of asymptomatic first infection.Therefore, before discussing the current situation, it makes sense to speak important basic facts about the diagnosis of viruses that will not change in the near future: knowing them, it is easier to navigate in the news.

Факт № 1. Мазок на коронавирус — ненадежный метод тестирования

The presence of infection in the vast majority of cases is determined using PCR analysis of the material obtained from the smear of the nasopharynx (in some cases-from the model of saliva).The problem with the smear is that it cannot fundamentally be a quantitative method: firstly, from time to time, the amount of material in the smear can change, and secondly, the virus with the course of the disease can “descend” below the respiratory tract.This is how false negative results appear: there is actually an infection, but the virus is not determined in the smear.

Если сделать несколько мазков немного по-разному или в разные фазы течения болезни, может возникнуть ситуация, когда за отрицательным тестом следует положительный — из этого можно сделать ошибочный вывод, что произошло повторное заражение, тогда как на самом деле речь идет об обычной ошибке метода. С тестированием было бы проще работать, если бы для анализа использовалась кровь, но, в отличие от многих других вирусов, SARS-CoV-2 в крови не циркулирует.

Кроме того, нужно понимать, что хотя ПЦР-анализ дает качественный результат «да/нет», это до некоторой степени условность: «да» может быть разным. Полимеразная цепная реакция — очень чувствительный метод, он основан на экспоненциальном размножении нужного фрагмента ДНК в ходе циклов репликации. Циклов этих может быть несколько десятков, и чем больше вируса в образце, тем на меньшем цикле появится сигнал. Если число циклов неадекватно увеличить, можно будет получить положительный сигнал просто «из шума» (по некоторым данным, при пороговом цикле >35 только 8% образцов содержат жизнеспособный вирус).

Two conclusions follow from this: to compare the results of the analysis obtained in different laboratories, and especially in different countries, you need to be careful - the difference can be explained simply by different standards.Secondly, when discussing positive results, you should pay attention to the threshold cycles of detection, if such information is: maybe a positive result is not as reliable as it seems.

Факт № 2. Генетический материал — это не жизнеспособный вирус

Not so long ago, The New York Times has released a material that discusses the problem of false positive tests for coronavirus. The article said that “up to 90% of people who received a positive test result, practically had no virus” and such people should not be quarantined. Judging by the reviews, some readers understood this phrase as the assertion that 90% of positive results are actually false (and, therefore, there is no epidemic). This is not true. The point is that a significant part of the positive tests is cases when the genetic material of the virus is detected in the reaction of the PCR, while the most viable virus in the body is no longer. In some people, tests can give positive results after 60 days, sometimes longer. In this case, sometimes negative tests come across between positive. This is a well-known problem, but this is not “fake” infections, but the restriction of the method: PCR analysis cannot distinguish the virus from its genetic information. The level of “real” false positive errors of PCR tests on coronavirus is now estimated at about 0.8–4%.

The point is that quite often positive tests mean the detection of traces of a past infection in a person who is no longer contrast.In order to determine the level of non -RNA, but viable viruses in saliva or sputum, a completely different type of test (a seven test on cell cultures) must be carried out.But, firstly, in the vast majority of cases it simply does not need it, and secondly, it is necessary for it to have appropriate equipment and a license to work in the BSL-3 biobeal safety class.There are not many such laboratories.

В контексте проблемы повторных заражений вывод здесь такой: положительный ПЦР-тест при адекватном пороговом цикле — это довольно надежная гарантия произошедшего контакта с вирусом, но он ничего не говорит о заразности и о том, какой именно вирус присутствует в организме: первый, второй или какой-либо еще.

Факт № 3. Антитела у разных людей бывают разные

During a viral infection, an immune response usually begins, during which B-lymphocytes and T-lymphocytes that can independently destroy cells infected with virus or help in this matter are activated.The development of a significant number of antibodies specific to the virus usually takes 2-4 weeks, then their number goes to the peak and gradually falls after a few months - more on this a little later.

It is important to understand that different people develop different antibodies - they differ not only in quantity, but also with two other important parameters: “power”, with which they are associated with the virus (vitality), and that place (epitope) on the surface of the viral particle with whichThis antibody interacts.

Вижу новости о повторных заражениях коронавирусом — сначала становится страшно, потом думаю, что это фейк. Так возможно это или нет? И спасет ли вакцина?

Different antibodies are produced by different B cells, the repertoire of which is formed at birth. During the infection, those cells that are able to contact a new infectious agent are activated and propagated. At the same time, the quality of the binding of antibodies usually improves: B cells in the population evolve, and those that interact with fragments of antigens are better than others, get an advantage-this is called clonal selection. In the laboratory from individual B cells, completely standardized monoclonal antibodies can be obtained (which, by the way, are considered as one of the options for therapy), but each person has a whole cocktail of different antibodies created by different B cells and associated with the virus in different places And with different power. In some infected people, most antibodies can be associated with an important S-Belak virus to neutralize, while others have some kind of internal proteins, so there will be no much use from such antibodies. If you want to learn more about how and where antibodies are associated with coronavirus proteins, start with this article.

Вывод из этого такой: судить о наличии или отсутствии защиты по общему уровню антител нельзя, даже если используются одни и те же тест-системы (а они бывают очень разные). Нужно знать хотя бы уровень именно нейтрализующих антител, то есть таких, которые в пробирке могут связываться с вирусной частицей и подавлять инфекцию (90% таких антител связываются с частью S-белка вируса, которая называется RBD). Такие сравнения можно делать в хорошо оборудованных лабораториях (это тот же плашечный тест, о котором шла речь выше, его проводят при изучении новых вакцин), но на основании обычных ИФА-тестов что-то однозначное сказать об иммунитете нельзя.

Факт № 4. Уровень антител со временем всегда падает, это нормально

Антитела вырабатываются B-клетками. В ходе инфекции они размножаются и часть из них превращается в короткоживущие плазматические клетки, которые специализируются только на производстве антител. Другая часть превращается в клетки памяти — их количество никакие «обычные» лабораторные тесты не определяют, но они важны для реакции на повторную инфекцию (они начинают быстро производить антитела при повторной инфекции). Сами антитела IgG имеют период полужизни около трех недель, поэтому неудивительно, что со временем их титр падает. Это падение может служить лишь косвенным признаком снижения защиты, но не является доказательством того, что ее нет.

Факт № 5. Никто не знает, какой уровень иммунитета защищает от повторной инфекции COVID-19 (вот это со временем должно измениться)

Unfortunately, even knowing both the level of neutralizing antibodies and the number of T cells specifically recognizing the virus in humans, it is impossible to say exactly how protected it is.If this could be done, clinical studies of phase III vaccines would not be needed, it would be enough to study the immune system of volunteers very well.It is not known now how many viral particles are enough for infection - and this also affects the necessary level of protection.

This is a difficult problem, but there are two kinds of indirect data that allow you to draw preliminary conclusions:

But you started with the fact that there are repeated infections ...

Yes, just not so often.

There are other reports of repeated infections (for example, from Brazil and Qatar), but not all of them are reliably confirmed by sequencing and included in the ECDC report dedicated to the issue of repeated infections and an operational review-commentary published in The Lancet. The author of the latter is the famous American immunologist Akiko Ivasaki. In August, after the first message about reliably proven reinfection, she wrote a detailed twitter-trend that the case in Hong Kong is not a reason for panic, but a “textbook example of how immunity should work”. After the description of reinfection in Nevada, when the re -infection turned out to be much harder than the first, the tone of Ivasaki changed.

What does it mean?

Ivasaki notes that so far we know very little about how repeated infections are undergoing, and there are much more questions here than answers. For example, it is not known what role antibodies played: the tests before the second infection were made only by two of the four patients, but one of them was a test for antibodies to N-Belka, and not important for infections of the S-protein, so draw some conclusion about The importance of antibodies is not even from these data (about the clinical role of antibodies not to S-Belka, very little is very clear, perhaps they are also important). How often there are repeated infections and in what other cases the symptoms become heavier for the second time, we also do not know: several cases described above are not statistics, and to answer the question you need to launch targeted screening programs in which the same people are long -term Time is tested and observed. To the question of whether people with a repeated infection can be contagious, Ivasaki responds carefully, but positively: the level of viral load in the described cases corresponds to a normal disease.

Finally, the most important question concerns what the possibility of repeated infections means for the development of vaccines. In other words, are repeated infection related to the fact that the overheating came into contact with another strain of the virus - not to which antibodies were originally developed? If this is the case, as well as if the same situation is repeated in the case of vaccination (and not natural immunity), then for population control the Covid-19 may require different vaccines and revaccination-that is, the epidemiological situation with the new coronavirus will be the same as now with The flu.

Ivasaki in his comments notes that there are no arguments in favor of this: the strains from repeated infections did not particularly differ from the initial ones.In addition, the immunologist notes that on the basis of a recent evolutionary analysis of tens of thousands of strains, we can say that all the now -known coronavirus options are very similar from the point of view of immunity, which means that there are no obstacles to creating a single vaccine.

However, after the publication of Ivasaki, work came out, based on which another scenario, when several different vaccines for different strains of the virus may be needed in the future, looks quite realistic (the article has not yet passed the review and published as a preprint). A large international group of researchers discovered a mutation in a fragment of the S-protein, directly associated with the ACE2 receptor on the surface of human cells. This mutation (N439K) arose twice regardless of different lines of the virus, which now circulate in different countries. Researchers found that in approximately 7.4% of the emirable virus with such a mutation is twice as worse with antibodies than the “ordinary” SARS-COV-2. At the same time, everyone who was ill with a virus with the mutation N439K, antibodies with it are connected normally (there were only six people in the study). In other words, the immunological differences between the variants of the virus with the mutation and without it still have, although they do not appear in all people. As far as you can judge by literature, this is the first such case - if the results are confirmed, the creators of the vaccines will have to apparently update their developments.

Do you have good news?

Yes.Although we do not know the true share of repeated infections, while they still remain an exotic exception.For example, in addition to the above -mentioned six episodes, there is a small study of cases of potential reinfection in Qatar.It did not secure strains, but, according to a simple analysis of test statistics, the authors concluded that even if all that they discovered is real repeated infection, their frequency is extremely low: 54 suspects at 133,266 tested.

Meanwhile, for the development of pandemia, primarily cases, not exceptions are important. It is now well known that in most cases, the SARS-COV-2 infection leads to the formation of an immune response, but it is difficult to compare the results from different laboratories due to differences in the test systems used. Recently, a very major study of the American Mount Sinai hospital was published, where under standardized conditions an immune response was analyzed by more than 30 thousand residents of New York, and a long five-month observation was carried out from these people.

The results of the study are reduced to the fact that in the vast majority of cases, antibodies are produced after a confirmed infection (both mild and severe).Typically, antibodies appear in high quantities, and the total titer antibodies correlates with the presence of neutralizing antibodies.The level of these antibodies in the vast majority of cases exceeds one that is considered protective for many other infections.

These data suggest that repeated infections will remain an exception, not a rule.There are several more arguments:

All this still does not prove that in a person the infection in the vast majority of cases protects against re -infection, but these are rather strong indirect arguments in favor of this state of affairs.

Caught an important thing: to support the "jellyfish" -

Бегу!

Alexander Ershov