Covid and Didier Raoult (supporter of hydroxychloroquine): analyzes on the pandemic

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Re: Resignation of Dr Raoult, supporter of Chloroquine, from the Covid Scientific Council19




View GuyGadebois » 22/07/20, 01:33

Obamot wrote: You for example, you look a lot like a lobbyist ...

(Thanks Magritte)
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View Adrien (ex-nico239) » 22/07/20, 01:52

Study Says Hydroxychloroquine Safe and Effective in Curing Covid-19

Study claims hydroxychloroquine is safe, effective to cure Covid-19

LAHORE: Preliminary results from the country's largest coronavirus drug trial - a randomized, observational trial in Pakistan to evaluate treatment for coronavirus (PROTECT) - not only established the safety of hydroxychloroquine, a drug commonly used for malaria , in terms of mortality, but also showed significant recovery rates in Covid-19 patients when used in combination with two other drugs - azithromycin and oseltamivir.

The demands, along with the results, were made public here at the University of Health Sciences (UHS) on Monday in a ceremony chaired by Governor Chaudhry Muhammad Sarwar and attended by the Minister of Higher Education from Punjab, Raja Yassir Humayun Sarfraz. , vice-chancellors of medical universities, researchers and professors.

Releasing the results of the study, UHS Vice-Chancellor Professor Javed Akram, who is also its principal investigator, clarified that it aims to assess hydroxychloroquine alone and in various drug combinations as a treatment. of the coronavirus.

"This is a multicenter, multi-arm, adaptive and randomized drug trial for newly diagnosed patients," he informed the ceremony attendees.

He said the study found that coronavirus patients, who received the three drugs combined, had an 86% recovery rate.

UHS VC Professor Javed Akram told participants that the trial for the drug was launched on April 30, after approval by the Drug Regulatory Authority of Pakistan (DRAP) and the National Bioethics Committee (NBC).

He added that 12 centers, including 10 universities in eight cities, were included in the study. The study recruited Covid patients over the age of 18, divided into eight groups. The patients included in the research were 60% male and 40% female. The three drugs were administered to seven groups, each consisting of 60 to 65 patients, alone and in different combinations, while a control group received nothing.

Professor Javed Akram revealed that the recovery rate of the combination of the three drugs was the highest at 86%. The second highest recovery rate was 75% from azithromycin. The overall cure rate for patients receiving medication was 73,1%, while the cure rate without medication was 67%. The 27% of patients remained positive for Corona even two weeks after taking the drug. Of the patients who received no medication, 33% remained Corona-positive even after two weeks.

The UHS VC added that the recovery rate in the first week of research was 33,5%, while by the second week it had increased to 72,2%.

Initially, the PCR test was used as a research basis. He said a total of four deaths were reported during the study. Three deaths occurred in the groups receiving a single drug, while one death occurred in the group receiving a combination of hydroxychloroquine and azithromycin.

Akram said the study was still ongoing and would involve around 9 patients when completed. He added that so far 500 million rupees had been spent on research, which the university had raised from its own resources and through donations.

Professor Khalid Masood Gondal of King Edward University of Medicine, said in his speech that if standard operating procedures (SOPs) were implemented on Eidul Azha, the coronavirus would be under control by September.

Paying tribute to frontline health workers, Governor Chaudhry Muhammad Sarwar said the nation will always remember the bravery with which health workers fought the virus.

"A commemorative wall is being erected at the Governor's House in recognition of the services of the health workers who would bear the names of all the soldiers on the front line," he added.

He said while it was an encouraging sign to see coronavirus cases declining, the cattle markets, Eidul Azha and Muharram again posed a big challenge when it came to controlling the spread of the infection.

"If these challenges are overcome, we will overcome Corona," said the governor of Punjab.
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Re: Resignation of Dr Raoult, supporter of Chloroquine, from the Covid Scientific Council19




View izentrop » 22/07/20, 02:19

He said if it was an encouraging sign to see coronavirus cases dwindle in livestock markets
Interesting indeed. Wait for the end of the study and the opinion of peers : Wink:
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Re: Resignation of Dr Raoult, supporter of Chloroquine, from the Covid Scientific Council19




View ABC2019 » 22/07/20, 06:49

Obamot wrote:
You for example, Image you look a lot like a lobbyist Image(no matter if you touch a small envelope or not)

You will tell me that it is normal, it is you who founded this idea of ​​“hotel"! : Cheesy:

it's decidedly weird that you put so much energy into not answering the simple question of whether you agree that there is a group of people (you, Guy, Adrien, Vetus ... ) who do not share the same conclusions as another group of people (pedro, izentrop, me, perseus, thibr ....) on HCQ-based treatments. I don't see how the word "group" is rude, you can speak of a set or a collection if you prefer. I don't see the connection to being a lobbyist either, just because you agree with each other doesn't mean I think you get paid (and you REALLY think there are people getting paid to post on this. forum, serious : Shock: ???)
So do you agree with the observation that two sets have been formed which do not reach the same conclusions on the HCQ? It seems pretty clear to me, doesn't it?
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View ABC2019 » 22/07/20, 06:52

Adrien (ex-nico239) wrote:It is certain that when we find it normal to compare cohorts over 75 years old and under 50 years old ... we cannot understand anything about Remundo's work.

this is another interesting criterion, these are the same people who think that HCQ is effective and that Remundo's work provides interesting information, or are there any counter examples?
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Re: Resignation of Dr Raoult, supporter of Chloroquine, from the Covid Scientific Council19




View Obamot » 22/07/20, 10:06

ABC2019 wrote:
Obamot wrote:
You for example, Image you look a lot like a lobbyist Image(no matter if you touch a small envelope or not)

You will tell me that it is normal, it is you who founded this idea of ​​“hotel"! : Cheesy:

it's decidedly weird that you put so much energy into not answering the simple question of whether you agree that there is a group of people (you, Guy, Adrien, Vetus ... ) who do not share the same conclusions as another group of people (pedro, izentrop, me, perseus, thibr ....) on HCQ-based treatments. I don't see how the word "group" is rude, you can speak of a set or a collection if you prefer. I don't see the connection to being a lobbyist either, just because you agree with each other doesn't mean I think you get paid (and you REALLY think there are people getting paid to post on this. forum, serious : Shock: ???)
So do you agree with the observation that two sets have been formed which do not reach the same conclusions on the HCQ? It seems pretty clear to me, doesn't it?

It is not so much the fact of these groups rather than the irrational stigma around the person of Professor Raoult which brings many participants out of the focus of the debate. This state of affairs was not born because groups would have formed around the HCQ, it is a consequence. Suddenly, the group (that some qualify as “pro-Raoult”) that you call wanting to “defend” chloroquine-based treatments is not a cause but a consequence of stigma. Nobody among those you see defends the HCQ but the alliance of 2 molecules in a very particular context which is denied not the detractors of the HCQ but overall (which does not make sense, since they defend facts, not a group). The origin of positions taken predates this debate and comes from several factors, among the first of which: this confusion between “causes and effects”, “fallacies”, a (stupid) propensity to defend “the establishment”, the profound lack of skills, the decentring of some of their own evaluation, the need of some to “assert themselves” (ego) which takes precedence over establishing the truth of the facts, then linked to this last point the preferences of people (to name just a few). As for those you see in a homogeneous group defending chloroquine, it is not. For many reasons and in particular among those which precede. Personally, I don't like to see a qualification born out of groups when the one you see (opposing your ideas) is NOT a “body”, at all. I will not go in your direction since this stigmatization is only very far linked to Raoult (or to chloroquine) precisely because of the intellectual dishonesty of some which leads to this stigmatization. And the central point is, as I said before, that stigmatizing on groups is unhealthy and ASCIENTIFIC (with the private “A”). Suddenly, your group theory shatters (laughs) because half of the indecrottables (in the individual sense) do not see the comic situations in which they put themselves because of their deficiencies (Peter's principle) while they are allow us to pass judgment on (really) scientific luminaries. There is a fluctuating spiral effect and you defend that in the extremely reductive form of “group”. The craziest thing is you can't see these things : Cheesy:

And on the contrary, I don't think I'm part of something counterproductive. On the other hand, there is a group which defends often obsolete standards and which is relative to wanting to defend a certain establishment, and not “science” (because those who are part of it do not want to leave their “comfort zone”. ) but it is not because this group exists, that there would exist another one which would face it ...
To think that is a (limited) view of the mind and would be very presumptuous!
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View ABC2019 » 22/07/20, 10:37

Obamot wrote:It is not so much the fact of these groups rather than the irrational stigma around the person of Professor Raoult which brings many participants out of the focus of the debate. This state of affairs was not born because groups would have formed around the HCQ, it is a consequence. Suddenly, the group (that some qualify as “pro-Raoult”) that you call wanting to “defend” chloroquine-based treatments is not a cause but a consequence of stigma. Nobody among those you see defends the HCQ but the alliance of 2 molecules in a very particular context which is denied not the detractors of the HCQ but overall (which does not make sense, since they defend facts, not a group). The origin of positions taken predates this debate and comes from several factors, among the first of which: this confusion between “causes and effects”, “fallacies”, a (stupid) propensity to defend “the establishment”, the profound lack of skills, the decentring of some of their own evaluation, the need of some to “assert themselves” (ego) which takes precedence over establishing the truth of the facts, then linked to this last point the preferences of people (to name just a few). As for those you see in a homogeneous group defending chloroquine, it is not. For many reasons and in particular among those which precede. Personally, I don't like to see a qualification born out of groups when the one you see (opposing your ideas) is NOT a “body”, at all. I will not go in your direction since this stigmatization is only very far linked to Raoult (or to chloroquine) precisely because of the intellectual dishonesty of some which leads to this stigmatization. And the central point is, as I said before, that stigmatizing on groups is unhealthy and ASCIENTIFIC (with the private “A”). Suddenly, your group theory shatters (laughs) because half of the indecrottables (in the individual sense) do not see the comic situations in which they put themselves because of their deficiencies (Peter's principle) while they are allow us to pass judgment on (really) scientific luminaries. There is a fluctuating spiral effect and you defend that in the extremely reductive form of “group”. The craziest thing is you can't see these things : Cheesy:

And on the contrary, I don't think I'm part of something counterproductive. On the other hand, there is a group which defends often obsolete standards and which is relative to wanting to defend a certain establishment, and not “science” (because those who are part of it do not want to leave their “comfort zone”. ) but it is not because this group exists, that there would exist another one which would face it ...
To think that would be very presumptuous!

but I made no comment on who would be right or who would be wrong, I just asked if you would agree that there were two groups that had formed on this forum, that's all (and indeed it also seems within society, but let's stick to this forum where people can express themselves at least). I do not see what it is "stigmatizing" to talk about groups. When you talk about "indecrottables", whether you like it or not, you also make a group of them!
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View ABC2019 » 22/07/20, 10:39

The origin of positions taken predates this debate and comes from several factors, among the first of which: this confusion between “causes and effects”, “fallacies”, a (stupid) propensity to defend “the establishment”, the profound lack of skills, the decentring of some of their own evaluation, the need of some to “assert themselves” (ego) which takes precedence over establishing the truth of the facts, then linked to this last point the preferences of people (to name just a few). As for those you see in a homogeneous group defending chloroquine, it is not.

I did not speak of a "homogeneous" group, I just said that there was a group defending HCQ, and a group which does not defend it (more exactly which is not convinced that it is efficient), that's all.

Now indeed once this observation has been made we can go a little further, when you say that it is not homogeneous, what do you think of as "non-homogeneity"?
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View ABC2019 » 22/07/20, 10:44

The origin of positions taken predates this debate and comes from several factors, among the first of which: this confusion between “causes and effects”, “fallacies”, a (stupid) propensity to defend “the establishment”, the deep lack of skills, the decentring of some from their own evaluation, the need of some to “assert themselves” (ego) which takes precedence over establishing the truth of the facts


Do you agree that these factors are opposed to the true scientific approach, and therefore those who have these faults are less scientific than those who do not have them?

or perhaps on the contrary do you think that these defects are constitutive of the scientific approach, and that therefore those who have them are "more" scientific than the others, but that it is a defect, because the so-called "scientific" approach does not is not the correct one?
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View Adrien (ex-nico239) » 22/07/20, 11:47

Back to more interesting things like this article


Specific cellular immune response against the SARS-CoV-2 coronavirus: encouraging results, other intriguing

An article accepted for publication in the journal Nature indicates that all the convalescent Covid-19 patients studied (who have therefore been infected with SARS-CoV-2) have immune cells directed against virus proteins. They developed what immunologists call a T lymphocyte response. In these 36 patients included in the study, all have two categories of white blood cells capable of recognizing the virus, namely CD4 T lymphocytes ("conductors" immune response) and CD8 (killer or cytotoxic cells).

These results therefore seem to indicate that the vast majority of patients recovering from Covid-19, if not all, develop an immune response with production of T lymphocytes following infection with SARS-CoV-2. This result is important insofar as it is above all the cellular response that supports the eradication of the virus during viral infections. However, it is this cellular response, in association with the production of specific antibodies, which participates in healing. This explains why ideally a vaccine against SARS-CoV-2 should induce not only the production of specific and neutralizing antibodies but also a robust and lasting cellular immunity.

Conducted by Singaporean researchers, this study was posted on the website of the journal Nature on July 15, 2020. It also reports that patients formerly affected by SARS (severe acute respiratory syndrome) still have, 17 years later, lymphocytes capable of reacting against SARS-CoV-1 [1].

Until now, it was known that the cellular “memory” response (T lymphocytes specific for SARS-CoV-1), that which remains after recovery, could persist for at least eleven years. Indeed, it should be noted that a category of “memory” T lymphocytes persists in the body after recovery. We speak of memory T cells because they are immediately reactivated in the event of a new infection.

Persistence of a cellular T response 17 years after SARS

There is therefore a very long-lasting memory immune response in patients with SARS in patients who have been infected with SARS-CoV-1. These memory T lymphocytes, still present 17 years after viral infection, are also capable of recognizing a similar coronavirus, in this case SARS-CoV-2.

"This result is encouraging insofar as it suggests that patients who have developed Covid-19 have the capacity, like patients formerly suffering from SARS, to develop a memory cellular immunity specific to SARS-CoV-2 from long duration. This is rather reassuring because it suggests that these memory CD4 and CD8 T lymphocytes, capable of persisting for a very long time, could be protective in the event of reinfection by SARS-CoV-2 ”, comments Pr Benjamin Terrier (Cochin hospital, Paris) * who did not participate in the work published in Nature.

According to this specialist, "in such a case, the immune system could indeed quickly remobilize these memory T cells, which could generate killer cells capable of eradicating the virus, even though at that time the neutralizing antibodies would no longer be present. This long-lasting T-cell immunity against SARS-CoV-2 could perhaps protect against severe forms of Covid-19 in the event of reinfection ”.

Surprisingly, this study reveals that T lymphocytes specific for SARS-CoV-2 are also present in more than 50% of healthy people, who have not been infected with either SARS-CoV-1 or SARS-CoV. -2. These results therefore seem to indicate the existence of a certain level of pre-existing immunity against SARS-CoV-2 in the general population.

But how could people who have not been exposed to SARS-CoV-1 or SARS-CoV-2 have developed a memory cellular response to coronaviruses that they have never encountered? American researchers reported last April in the journal Cell that approximately 70% of convalescent Covid-19 patients had SARS-CoV-2 specific T lymphocytes in their blood (70% CD4 lymphocytes and 100% CD8 lymphocytes) .

These scientists claimed to have also detected CD4 lymphocytes reacting against SARS-CoV-2 in about 40% to 60% of individuals who were not yet exposed to this virus. They then suggested the possibility that banal infections by seasonal coronaviruses, by inducing CD4 and CD8 T lymphocyte responses, could be responsible for cross-immunity between these common cold coronaviruses and SARS-CoV2. But this is not the hypothesis adopted by the Singaporean researchers.

Indeed, the new study to appear in Nature advances the hypothesis that this "cross immunity" is due to the fact that our immune system keeps in memory the memory of contact with coronaviruses having nothing to do with the coronaviruses responsible for the common cold. but that they retain the memory of exposure to all other viruses, in this case to animal coronaviruses that we do not know. These are "particularly intriguing results," say Nina Le Bert, Antonio Bertoletti and their colleagues at Duke-NUS Medical School in Singapore in their article.
Schematic representation of a coronavirus and its structural proteins. The N protein binds to genomic RNA and forms a nucleocapsid around it. Coded by viral RNA, non-structural proteins are not incorporated into virions. Juckel D, et al. Med Sci (Paris). 2020; 36 (6-7): 633-641.

Structural and non-structural proteins

But how did these researchers come to such a startling conclusion? A little reminder on coronaviruses is in order. Coronaviruses are composed of so-called structural proteins because they enter into the architectural composition of mature viral particles or virions. Their genome also codes for so-called “non-structural” proteins (NSPs). These are produced only during the infectious cycle because they are essential for viral replication. Although encoded by viral RNA, these non-structural proteins are not, however, incorporated into the structure of the viral particles excreted by infected cells.

T-cell specific immunity in convalescent Covid-19 patients

The Singaporean researchers conducted experiments consisting in testing for the presence of T-cell immunity specific to SARS-CoV-2 first in convalescent Covid-19 patients, then in patients who survived SARS, and finally in people who have not been exposed to either SARS-CoV-1 or SARS-CoV-2 (i.e. individuals who have not suffered from SARS, have not developed Covid-19 and have not who have not been in contact with people infected with SARS-CoV-2).

In these three categories of individuals, immunologists looked for T lymphocytes specifically directed against a structural protein of SARS-CoV-2: the N protein of the nucleocapsid which is very abundant in viral particles and whose structure is very similar among Betacoronaviruses, a group of coronaviruses that mainly infect mammals. They also investigated whether these people had developed specific T-cell immunity to two non-structural proteins (NSPs) of the SARS-CoV-2 coronavirus: NSP7 and NSP13, which are essential to function early in the process. viral replication cycle. The researchers were interested in NSP7 and NSP13 insofar as these two non-structural proteins are 99% identical to those of SARS-CoV-1, SARS-CoV-2 and other animal coronaviruses belonging to the group of Betacoronaviruses [ 2].

Immunologists and virologists cut the N (core), NSP7 and NSP13 proteins into several fragments, thus producing a collection of peptides. They then incubated white blood cells from 36 convalescent Covid-19 patients for several hours with these peptides [3]. In all 36 people tested, the researchers observed specific cellular responses directed against several regions of the N protein. In addition, it was shown (in 7 out of 9 patients) that T lymphocytes which had specifically reacted against the protein N were able to produce interferon-gamma, a marker of the response to infections.

In addition, the researchers observed that people recovering from Covid-19 have specific T cells that recognize the same regions (epitopes) of the N protein as T cells from individuals who have been victims of SARS. The fact that patients who have recovered from Covid-19 and SARS can develop a T-cell immune response against identical viral patterns shows the existence of cross-cell immunity in these two infections. Infection with SARS-CoV-1 therefore induces the production of T lymphocytes capable of also reacting against SARS-CoV-2.

In their experiments with 15 SARS survivors, the researchers showed that these individuals had in their blood, 17 years later, white blood cells still capable of reacting against the N protein of SARS-CoV-1 and of producing l 'interferon-gamma when these immune cells are incubated in the laboratory in contact with viral peptides. This specific T immune response, however, has been observed almost exclusively with peptides of the N protein, not with fragments of the non-structural NSP proteins.

Likewise, the researchers observed that 23 SARS survivors had T lymphocytes in their blood capable of reacting in the laboratory to the presence of peptides derived from the N protein of SARS-CoV-2. They produce interferon-gamma. These cells turn out to be CD4 and CD8 memory T lymphocytes.

According to the researchers, these results therefore allow us to hope that, like SARS-CoV-1, the T cell immunity induced by SARS-CoV-2 could also be long-lasting in patients who have developed the disease. Covid-19.

Finally, the researchers explored the T-cell immunity specific to SARS-CoV-2 in subjects not exposed to SARS-CoV-1 and SARS-CoV-2. Blood samples were taken from 26 subjects before July 2019, so well before the start of the Covid-19 pandemic. Eleven other individuals who had not developed any neutralizing antibody against SARS-CoV-2 or antibodies directed against the N protein of this same virus, participated in this third part of the experiments. In total, the researchers explored the cellular immunity of 37 healthy people who had not been exposed to either SARS-CoV-1 or SARS-CoV-2.

Truly confusing results

Surprisingly, the researchers indicated that they had detected specific SARS-CoV-2 interferon-gamma responses in 19 of these 37 subjects not exposed to SARS-CoV-1 or to SARS-CoV-2. And to specify: while the patients victims of Covid-19 and SARS reacted preferentially to peptides derived from the N protein (66% of Covid-19 patients and 91% of SARS patients with T lymphocytes recognized only the protein N), this group of unexposed individuals exhibited an immune response directed against both the N protein and the non-structural proteins NSP7 and NSP13. In addition, the researchers observed a cellular immune response against the NSP non-structural proteins in a single patient among 59 individuals with Covid-19 or SARS, such a response was observed in 9 unexposed subjects out of the 19 tested.

Detailed characterization of regions of viral proteins recognized by T cells

More precisely, it turns out that those people who have never encountered SARS-CoV-2 (like SARS-CoV-1) have T lymphocytes which recognize a particular region (epitope) inside the structural protein. N, also recognized by the T lymphocytes of patients who have been victims of Covid-19 or SARS. In these people who had never encountered SARS-CoV-1 and SARS-COV-2, the researchers also succeeded in identifying CD4 T lymphocytes specific for a sub-region (epitope) of the non-structural protein NSP7 and CD8 T lymphocytes specific for a subregion of the non-structural protein NSP13 [3].
Human and animal coronaviruses. Vabret A, et al. Pathol Biol (Paris). 2009; 57 (2): 149-160.

Cross-immunity with animal coronaviruses?

It is truly intriguing that people who have never encountered SARS-CoV-2 (like SARS-CoV-1) can develop specific T cell immunity against these particular regions within the NSP7 and NSP13 non-structural proteins. Indeed, the structure of these sub-regions (epitopes) of SARS-CoV-1 and SARS-CoV-2 differs greatly from those of winter coronaviruses (OC43, HKU1, NL63, 222E) [4] responsible for the common cold each winter. . This is even more true for the epitope recognized by CD8 T lymphocytes whose structure differs even more from that present in these four seasonal coronaviruses.

If the coronaviruses that circulate every winter are not involved, how can these results be explained? According to the authors, the explanation could lie in the fact that “other coronaviruses still unknown, perhaps of animal origin, could be at the origin of this cross-immunity with SARS-CoV-2 observed in the population general ”.

“That betacoronaviruses from animals, and not as one might have believed from human alphacoronaviruses which plague every winter, can be the source of cross-immunity with SARS-CoV-2, is a really intriguing hypothesis. These results suggest that half of us would have been in contact with animal coronaviruses that we do not yet know and that therefore remain to be discovered ”, confides in me Professor Benjamin Terrier.

Exposed but not infected

The researchers hypothesize that a small part of the population exposed to animal coronaviruses not yet known could have developed T lymphocytes specific for certain proteins involved in the start of the viral replicative cycle. However, infection with these coronaviruses would have been abortive. In other words, the replication cycle would have been initiated but would have been interrupted. The infection would therefore have ended. Therefore, it would not have made it possible to produce mature viral particles (virions). However, it would have been enough for the immune system to react against non-structural proteins which assemble to form the machinery essential to start the replication of viral RNA [5]. Conversely, in patients with Covid-19 or SARS, the N protein is produced in very large quantities by infected cells. It binds to viral RNA and forms a "nucleocapsid" around it. Located within the viral particle, it is released in large quantities upon the death of infected cells when they release mature virions.

In support of their thesis, the Singapore researchers point out that the genomic sequences [6] which code for these non-structural proteins involved in the early stages of the viral replicative cycle are extremely close in many coronaviruses. The abundant presence of these viruses in many animal species could therefore result in repeated exposure in humans. These viral infections would not go through to term but could all the same induce a cellular immune reaction specifically directed against non-structural proteins (NSP).

This immune reaction directed against certain regions of NSP that are very similar between different coronaviruses could be the cause of cross-immunity with SARS-CoV-2. Healthy individuals, not exposed to SARS-CoV-1 or SARS-CoV-2, but having been in contact with other animal coronaviruses, could have developed T-memory cells specific for SARS-CoV-2.

Could this specific T cell immunity against SARS-CoV-2, possibly acquired during infections with animal coronaviruses "currently unknown", explain the differences observed in terms of infection rates between different populations or the differences in susceptibility to SARS-CoV-2 infection between individuals? Could such pre-existing T cell immunity in the general population influence the course of SARS-CoV-2 infection? Would this pre-existing specific T cell immunity thus be capable of interrupting the viral infection before it becomes widespread? It is therefore important to determine whether having T lymphocytes reactive against structural and non-structural proteins could have a beneficial impact in the event of infection with SARS-CoV-2. It now remains to quickly conduct similar studies in Western countries, or even in different regions of the same country.

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