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21/01/2022 francesoir.fr  15 min 🇬🇧 #200967

Immunity, vaccines, side effects, treatments: the analysis of Jean-Marc Sabatier

DR

What do we know about immunity? How is it activated following an infection or vaccination? What is innate non-specific immunity? What about adaptive or acquired immunity? How were the vaccines developed? Are they still effective on new variants? How dangerous is the new Omicron variant? What does ADE (Antibody Dependent Enhancement) and ERD (enhanced respiratory disease) mean? What do we know about the adverse effects of the vaccine's Spike protein? Can repeated multiple injections lead to lasting deregulation of the immune system? What role does vitamin D play in preventing infection?

Today, we are publishing the first part of this interview.

Professor Sabatier, you are Research Director at the CNRS (Centre National de la Recherche Scientifique) ; you hold a PhD in cell biology and microbiology, and are affiliated with the Institute of Neurophysiopathology at the University of Aix-Marseille. Alongside Jacques Fantini, Patrick Guérin, Nouara Yahi, Fodil Azzaz and Henri Chahinian you have worked on the new modelling studies.

Yes.

The study focused on the new variants and the vaccines' impact, as well as immune, cellular and humoral responses. In relation to the latter, we examined the balance between neutralizing antibodies and infection-facilitating antibodies, a subject that may be unfamiliar to many. When one refers to antibodies, one thinks neutralization, which may be a mistake. What happens with the different types of antibodies during an infection or after vaccination?

On injecting an antigen into a host or a vaccine designed to produce the antigen - e.g. messenger RNA or adenovirus vaccines that produce the Spike protein - the antigen, the Spike protein, is presented to the immune system. The latter then mobilises to fight that antigen, which it learns to recognize through vaccination. The immune system has two components. The first, humoral immunity, is based on antibodies, while the second is based on cellular immunity. They work together.

When the organism first encounters an antigen or virus, innate immunity gets under way. It is immediate: as soon as one come into contact with a microbe, whether a virus, a bacterium, a parasite or a fungus. Such immunity is non-specific : it is overall the same, whatever the microbe one confront. Such immunity involves various immune-system cell types, mainly circulating monocytes, macrophages, dendritic cells and granulocytes. Within the granulocytes one finds eosinophilic granulocytes, neutrophils, basophils and mast cells. Then one finds NK cells (Natural Killer cells), at the interface between innate immunity and adaptive or acquired immunity. This innate immunity is immediate and very powerful, particularly in children.

Adaptive or acquired immunity is triggered roughly 4 days after innate immunity. Adaptive immunity is specific to the microbe, and is a long-lasting process. It is based on B lymphocytes that produce antibodies (humoral immunity) when activated into plasma cells as well as on cytotoxic CD8 T lymphocytes, which express the CD8 receptor. These cells are also involved in recognising microbial antigens when the latter are expressed on the infected cells' surface, in this case the Spike protein and other viral antigens in the context of natural infection.

It seems that those who contracted Sars-CoV-1 in 2002 were still immune 17 years later.

Yes, thanks to this adaptive or acquired immunity (CD8+ T lymphocytes and B lymphocytes), whose characteristic is to be specific. It is triggered later than innate immunity, several days after one contracts the virus.

Humoral immunity, tested by serology, is the antibodies, the immunoglobulins G, A and M (IgG, IgA and IgM). It declines after a few months, hence the call for boosters. For this humoral immunity, there are three kinds of antibodies.

There are three kinds of antibodies. If one focus on humoral immunity, i.e. on the production of antibodies... When the organism perceives an antigen, it produces three types of antibodies overall. There will be neutral antibodies, able, for example, to bind to the Spike protein. A priori, they do nothing. You might think them useless. They don't protect against infection; they are produced, but are not neutralizing.

The second type of antibodies produced are neutralizing antibodies, critical to the vaccination programme, and which the manufacturers attempt to produce via the boosters. One strives for as many neutralizing antibodies as possible, since they bind to the viruses, prevent them from infecting the cells and neutralize the infection.

The third type of antibodies are facilitating antibodies, which do exactly the opposite of neutralizing antibodies. They facilitate infection by the virus and are utterly undesirable, as part of the vaccination.

The vaccine based on the wild Wuhan strain is problematic as the virus is constantly mutating. Significant mutations are called variants. For nigh on two years now, one finds both variants and sub-variants. Your study indicates that with the new variants, facilitating rather than neutralizing antibodies appear.

Quite. If one injects a vaccine composition as part of the mRNA or adenovirus vaccines, the cells produce Spike protein. When presented to the immune system, that protein contains a number of domains that the immune system will recognize, called epitopes.

When the immune system perceives the Spike protein, it does not recognize it in its entirety. Think of the Spike protein as a string of pearls, with each pearl being an amino acid residue; the string of 1,273 pearls corresponds to the 1,273 Spike protein's amino acid residues. However, the immune system will not recognize all the pearls in the necklace, but groups of pearls. There are roughly 20 different types of pearls forming the necklace, some of which can be modified.

Because it's a string of pearls, the immune system will recognize one area of the necklace where there are, say, six pearls, and another where there are, say, seven or eight. These domains are distributed along the necklace.

The immune system can also recognize arrangements of pearls in space, i.e. some pearls may be far apart within the necklace, but nearby in space because of the necklace's shape.

An antibody may be directed against several pearls at different places in the necklace but nearby in space. These pearls constitute a conformational epitope. With the Spike protein, there are domains called conformational epitopes that will be recognized by antibodies directed against arrangements of pearls normally far apart within the necklace.

For example, the antibody will eventually recognize a pearl in position 1, and a pearl in position 100 or a pearl in position 250. In summary, the antibody recognizes either linear epitopes, i.e. successive strings of pearls, for example, it will recognize pearls 7 to 14 (i.e. pearls 7, 8, 9, 10, 11, 12, 13, 14). There are other conformational antibodies, so directed against conformational epitopes, which might recognize, for example, pearls 10, 12, 120, 250. But do all of these occur in a very tight space? This can occur because the necklace has taken on a specific shape in space, i.e. a certain three- dimensional structure that brings the pearls together. At that point, the immune system can recognize such a domain.

Accordingly, there are regions in the Spike protein - or in other proteins - that are immune-silent, namely which the immune system fails to perceive. When the organism is made to produce Spike protein with messenger RNA (as with the Pfizer/BioNTech or Moderna vaccines), it will produce a long necklace of 1,273 pearls; the immune system will spontaneously recognize domains, i.e. groups of pearls, whether they be sequential groups (pearls that follow one another) or spatially nearby. The antibodies produced will thus recognize certain domains called B epitopes (recognized by the B lymphocytes). Those domains will generate the production of antibodies, which can be either neutral, neutralizing or facilitating.

In the aforesaid study, you state that neutralizing antibodies are recognized very randomly across variants, whereas facilitating antibodies are retained across all circulating variants. Scrolling through all the major variants' history, confronted with vaccination, up to which variant did vaccination work?

It has been a gradual drift, nor is the transition obvious. The analysis is predictive, based neither on experimentation nor on observation of facilitation phenomena found with one variant rather than another. These are predictions in relation to various antigenic sites, i.e. the different epitopes described on the variants.

For Sars-CoV-1 in the 2002 epidemic, studies have been carried out, and certain facilitating epitopes highlighted. These are regions of the Sars-CoV-1 Spike protein of the earlier Coronavirus, known to produce antibodies that will facilitate infection rather than neutralise it. These are so-called facilitating epitopes that follow the ADE phenomenon (Antibody-Dependent Enhancement), which means facilitation of infection by antibodies.

A research team member has explained the severity of the disease in Wuhan as compared to elsewhere. Sars-CoV-1 (2002-2003) has infected some in China. When sars-cov-2 arrived in Wuhan (late 2019), the infection was severer.

Put simply, if one present a virus such as the Wuhan Sars-CoV-2 to the immune system, one produces antibodies against the Wuhan Spike protein. That is the 2019 virus' structure. It has well-defined epitopes in its Spike protein, because the strain is well characterized.

There are domains that are facilitating, neutralizing and neutral; one will therefore have both B epitopes that are neutral, B epitopes that will be neutralizing and B epitopes that will be facilitating. The immune system responds in the usual way and no specific problem arises at this stage. One may arise later on infection by another viral serotype, i.e. by another Sars-CoV-2 variant which will follow the ADE phenomenon, i.e. for which the ADE phenomenon of facilitation by antibodies exists. At that point, one finds antibodies facilitating the infection. Thus, where those injected with a vaccine based on the original Sars-CoV-2 virus, the Wuhan virus, are subsequently infected by a variant (Delta, Omicron or other), they may develop severer disease, precisely because of the facilitating antibodies: the latter will attach to the new variant/serotype. The complexes between the new virus and the facilitating antibodies will be recognized by innate immunity cells, notably monocytes, macrophages and dendritic cells, because these cells on their surface a receptor called Fc-gamma R2A (or even another receptor, Fc-gamma R2B), which recognises the constant fraction of antibodies.

Antibodies have a schematic Y-shaped structure. At the tip of the Y's two bars appear the paratopes. The latter are identical and recognize the epitopes, i.e. the Spike protein regions against which they are directed. The Y bar, the constant fraction of the antibody, will be recognized by the Fc-gamma R2A (or even Fc-gamma R2B) receptor. Thus, cells of the innate immune system (monocytes, macrophages, dendritic cells) that express these receptors will recognize the binary complexes of the antibody facilitating the virus, and will phagocytose these complexes to neutralize the virus. In so doing, the cells infect themselves with the new Sars-CoV-2 variant.

In other words, these facilitating antibodies do the opposite of the neutralizing antibodies: they help the virus to infect these immune system cells and foster infection of dendritic cells, monocytes, and macrophages. All this further extends the virus' cellular tropism, since the ADE phenomenon also helps the virus infect new cell types. The phenomenon makes the virus more dangerous as it facilitates infection.

Let us assume for the moment that the wild strain and perhaps certain variants may be defeated by vaccination. But what of the latest variants?

The balance of neutralizing and facilitating antibodies was favourable for the Alpha and Beta variants of Sars-CoV-2. For the latest variants, including Gamma, Delta, Lambda and Mu, one finds the opposite trend, namely an unfavourable balance of neutralizing and facilitating antibodies. The balance has thus become more favourable to facilitating than to neutralising antibodies; initially it had been very favourable to the latter; the vaccine was thus effective in terms of neutralisation. The trend is now towards an unfavourable antibody balance.

With multiple boosters (third, fourth, even fifth...), the risk/benefit ratio will become increasingly unfavourable. In striving to over-protect by producing neutralizing antibodies, one achieves the opposite and increases the proportion of facilitating antibodies in relation to neutralizing antibodies. Rather than vaccine protection one ends up with vaccine facilitation, alongside facilitated cellular infection. Those infected with the new variants may consequently develop severer disease than the unvaccinated. Fortunately, the highly contagious Omicron variant, now spreading worldwide, has a lethality is 7 times lesser than the Delta variant (still the most prevalent), itself 4 times less lethal than the original Wuhan strain. The emergence of ever-less lethal Sars-CoV-2 variants, despite their being more contagious, makes the ADE phenomenon less problematic.

Given the notable efficacy and safety issues with the current vaccines, your research team has decided to publish a pre-print study, in view of promptly adapting the vaccine.

In attempting to jack up immunity to Sars-CoV-2 with boosters based on the Spike protein from the original Wuhan strain, obsolete for nearly 18 months, one succeeds only in making people more vulnerable. Those infected with certain variants may more readily develop severe or lethal forms.

Given the properties of a rapidly mutating virus, is vaccination really appropriate? Even if one speedily creates a new vaccine via the messenger RNA technology, will rapid mutation not defeat vaccination?

The answer is twofold. With Sars-CoV- 2, one has a (relative) opportunity. This is the classic evolution in virology, as a virus becomes ever more infectious and ever less noxious. The latest variants (Delta, Omicron) infect cells more readily and therefore spread faster, being both highly contagious as they evolve but ever less virulent and lethal, e.g. Omicron. The variants appear ever faster too, due to selection pressure exerted by vaccination, particularly during a pandemic.

Delta was much more contagious. Relying upon Professor Jacques Fantini's index for Omicron, the latter appears to be 3 times less contagious than Delta. If less contagious, does that mean more dangerous? For the moment, it would not seem so. Prof. Fantini's latest study indicates that Omicron will likely be dominant only in certain regions, while overall, Delta will remain dominant with its T-Index of 10.67 (3.90 for Omicron). That is however a few days old while the picture changes quickly. For Professor Bernard La Scola a virus such as Delta starts out by being highly contagious and gradually winds down. By now, many have caught Delta.

The Delta variant, still very present worldwide, is being replaced by Omicron.

The latest data strongly suggest that Omicron will supplant Delta in the near future; its prevalance is increasing sharply in several countries, especially in those with very high vaccination rates. Omicron is notably resistant to vaccines; its mucosal tropism for the upper airways makes it both less accessible to the immune system, less dangerous and more contagious than other variants.

Omicron's T-index is 3.90. This is much lower than Delta's T-index of 10.67, which is almost three times more contagious. However, since Delta has been present for months world over, might Delta be winding down? Will Omicron become dominant?

Yes, Omicron, less dangerous than Delta and of course much less dangerous than the original Wuhan strain, will likely replace Delta. Delta is about four times less dangerous than the Wuhan strain, which vanished about 18 months ago. The Omicron variant does not appear to be especially lethal, inducing only mainly mild forms of Covid-19. Detected months ago, it has been spreading rapidly in recent weeks.

Now, the more one vaccinates and the more boosters be given, the more one selects for vaccine-resistant variants - variants that will emerge from the vaccination. Since Omicron is not especially noxious, this is not really a problem.

What is however most disturbing with vaccination is not ADE in the immediate future, but the vaccine Spike protein's toxicity. A good vaccine should be effective against the relevant microbe - in this case it must neutralise Sars-CoV-2, as well as neutralise the cellular infection and block transmission of the virus from an infected person to a non-infected one. And the vaccine must be safe, harmless to the organism that receives it, free from adverse effects. That cannot be said of these vaccines.

Instances of myocarditis, pericarditis, Guillain-Barré syndrome have occured in the vaccinated...

Thrombosis, thrombocytopenia, myocarditis and pericarditis, autoimmune disease such as diabetes, acquired haemophilia, Hashimoto's thyroiditis, multiple sclerosis, scleroderma, rheumatoid arthritis, and others. Many autoimmune diseases may appear or worsen. The same goes for cancers and neurological disorders.

Type 2 diabetes is due to glucose intolerance, while type 1 is autoimmune in origin. Both are now appearing. I have been warning of the emergence of all these diseases.

These multiple boosters are a serious health threat -whether in the short-, medium- or long term. Because the vaccines are virtually obsolete, while the visible as well as the yet-invisible harmful effects of the Spike protein are very much present, and worsen with each booster. While the vaccine did initially neutralize the virus, its efficacy is breaking down. By now, its true effectiveness represents a mere 20 to 30%. Within in a few short months, it will be close to nil, protecting neither from infection nor contagion. This is already clear. Although the vaccine is said to ward off severe or lethal forms of the disease, which may be true, that protection vanishes over time.

In their clinical trials, Pfizer reports deaths neither in the placebo group nor in the vaccinated group. In epidemiology, severe forms are defined in relation to deaths. How can one claim that the vaccine protects against severe forms?

Unclear! Recently, I learnt that in the trials there were deaths in both groups. The trials take some time; as there were elderly individuals and/or some with comorbidities, one would expect deaths. Apparently, there were a few more deaths amongst the vaccinated than amongst the unvaccinated. Strangely, Pfizer went on to vaccinate all the non-vaccinated, the control group! Pfizer claims they had to protect the unvaccinated, but thereby skewed the trials! As a result, one cannot formally compare the vaccinated cohorts to the unvaccinated, Pfizer having chosen to vaccinate the entire group at the end of the day! Personally, I believe this was deliberate because you can't go back on it. The trial becomes meaningless, worthless to study.

If true, it's somehow fraudulent. In any case, with this vaccine, there is a great deal of unclarity. Faced with all the reported adverse effects, never would there have been authorisation to launch and then pursue worldwide, mass vaccination plus multiple boosters. Under normal circumstances these vaccines would have been pulled from the market, given their adverse effects, which stand at a rate 10 times greater than any previous vaccine. A ten-fold increase compared to conventional vaccines in use for 20 or 30 years, whereas this crop of vaccines was launched in late 2020! Moreover, the adverse effects of vaccination are doubtless greatly underestimated. There is a real and potential danger, particularly for the innate immunity of those vaccinated.

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