The complex mechanisms of infection, the limits of vaccination, the risks of the third dose: Jean-Marc Sabatier, a doctor of cellular biology and microbiology, explains everything about Sars-CoV-2.
Can you explain how the SARS-CoV-2 virus affects our bodies?
When it is not neutralized by our immune system, the SARS-CoV-2 virus affects our bodies by disrupting a major physiological hormone system called the renin-angiotensin system (RAS). This system is responsible for the functioning of our organs and tissues. It is ubiquitous in the body as it is found in the heart, lungs, kidneys, liver, vascular system (blood vessels), pancreas, spleen, sexual organs (endometrium and testicles), intestines, skin, and even the brain. It is a very complex system that is essential for the proper functioning of the human body and mammals in general. It also controls the immune response (innate immunity) by acting directly on certain types of immune cells (monocytes, macrophages, granulocytes, dendritic cells, “killer” NK cells).
SARS-CoV-2 interferes with (and disrupts) the RAS because its spike protein -which is a viral surface protein- is able to interact with a cellular receptor (called ACE2 = angiotensin-2 converting enzyme) involved in the functioning of the RAS. This disruption of the RAS (induced by the virus) leads to an increase in the concentration of a hormone: angiotensin-2. This angiotensin-2 in excess will overactivate its own receptor which is AT1R. It is this AT1R receptor that is responsible for the Covid-19 diseases observed in people infected by the virus and developing more or less severe forms of the disease.
The deleterious effects
The overactivated AT1R receptor is very deleterious for our organism, because it has multiple activities: it is pro-hypertensive (it constricts blood vessels), pro-inflammatory (it causes inflammation and is responsible for the cytokine storm), pro-thrombotic (it causes thrombosis), pro-angiogenic (it promotes vascularization and thus tumor/cancer development), pro-oxidant (it induces a release of reactive oxygen particles that kill cells), pro-fibrosis (it causes fibrosis of organs such as the heart and lungs), pro-hypertrophy (it makes organs grow larger, including the heart and lungs), and it reduces the production of nitric oxide (NO), which is involved in inflammatory, immune and memory phenomena (memorization).
These multiple and varied deleterious effects lead directly to Covid-19 diseases. Thus, it is not the SARS-CoV-2 virus that is really responsible for Covid-19 diseases, but the malfunctioning RAS (because it is overactivated by the virus).
What is the purpose of vaccination against SARS-CoV-2?
The SARS-CoV-2 virus attacks our body and causes Covid-19 diseases. To protect ourselves from its attack and to defend our body, we must teach our immune system to defend itself against it: this is the purpose of vaccination.
To teach our body to defend itself, we must present it (before being infected by the virus) with pieces of the virus, i.e. one or more of its viral proteins. Our immune system is the protective system that helps protect us from microbial infections. To help it neutralize the SARS-CoV-2 virus, it must be taught to recognize it. This recognition is done through vaccination: one or more viral antigens are injected, or the body produces (one or more of) these antigens.
In the majority of current vaccines, the production (by our body) of the SARS-CoV-2 spike protein is targeted using mRNA vaccines (Pfizer-BioNtech or Moderna vaccines) or viral vector vaccines expressing this protein (AstraZeneca and Janssen vaccines). In the case of Chinese vaccines (e.g. Sinopharm vaccine), the entire viral particle is directly injected and its infectious power neutralized by a prior chemical treatment.
Not always harmless
The purpose of these vaccines is to mobilize the immune response to recognize and neutralize SARS-CoV-2. The vaccines used must be effective (against the virus) and harmless (to our body). The vaccines currently in use – called first generation vaccines – are not without potential side effects for those vaccinated, which means that they are unfortunately not always harmless depending on the person: this is a major problem.
On the other hand, these vaccines have lost their initial effectiveness, with the appearance over time of new “different” viruses (variants of SARS-CoV-2, including the Indian “Delta” variant). Indeed, some vaccinated persons can be infected by SARS-CoV-2 and its variants, and transmit the virus to other persons. There are therefore two major issues to be resolved at this time: increasing vaccine efficacy and safety.
How, then, can we increase the efficacy and safety of current SARS-CoV-2 vaccines?
To increase the efficacy of vaccines (2nd generation vaccines to come), it is necessary to modify the vaccine compositions since they are not satisfactory to date. It seems imperative to include in these vaccines “modified” viral antigens, or even “new” viral antigens.
For example, the current spike protein (from the original Wuhan strain in 2019 which is now in a very small minority) could be “changed” by that of the Indian “Delta” variant (or a sub-variant of the “Delta” virus) which is prevalent in the world.
It is also possible to add one or more other viral antigens, such as core protein N, envelope protein E, membrane protein M, and/or hemagglutinin esterase. Nucleocapsid protein N is a particularly interesting target because it has the advantage of being highly non-variable (it could theoretically confer protective immunity to the vaccinee against almost all variants of SARS-CoV-2).
Inactivated virus vaccines could also undergo an “optimized” inactivation treatment to maintain the structure and integrity of its constituent proteins as well as possible, which should lead to a better neutralization of the infectious agent and a higher efficiency of the neutralizing immune response.
Two problems to solve
To increase the safety of 2nd generation vaccines, there are two major problems to be solved (without considering the adjuvants of these vaccines which are of great importance and which can also be optimized -in terms of adjuvant combination- or replaced by other molecules).
In the case of spike-based vaccines, it is necessary that the spike proteins produced are not able to bind to their ACE2 receptor in order not to trigger a physiological response that would be an overactivation of the “deleterious” AT1R receptor (by hindering the degradation of angiotensin-2 by the ACE2 receptor). Indeed, this overactivation of the AT1R receptor mediated indirectly by the vaccine spike protein is at the origin of the Covid-19 diseases (e.g. thrombosis, myocarditis, pericarditis, etc.) observed in some vaccinated persons. Fortunately, this phenomenon is very rare. For this, it is essential to modify the structure of the vaccine spike protein.
The second problem to be solved is related to the “ADE” (Antibody-dependent enhancement) and “ERD” (Enhanced respiratory diseases) phenomena.
ADE and ERD facilitate the infection of cells by SARS-CoV-2, which is obviously not desirable in the context of vaccination. During an “ADE” phenomenon, anti-spike protein antibodies are produced, but these facilitate the infection (they are called “facilitating” antibodies, in contrast to the other antibodies produced, which are called “neutralizing” antibodies). ADE” is closely associated with the “ERD” phenomenon corresponding to antibody-independent facilitation of cellular infection with SARS-CoV-2, e.g. induction of a highly deleterious cytokine storm, or an exacerbated cellular immune response that is also deleterious (cell-mediated immunopathology).
In order to avoid the “ADE” (or even “ERD”) phenomenon, it is necessary to remove -as far as possible- the domains of the vaccine spike protein that make our immune system produce such “facilitating” antibodies. The production of “neutralizing” antibodies will of course be largely favored (as opposed to the production of “facilitating” or “neutral” antibodies).
Are you in favor of a third (booster) dose of vaccine for the most vulnerable people, including the elderly?
The purpose of this third (or even fourth) vaccine dose is to increase the production of “neutralizing” antibodies. These antibodies are able to neutralize the virus and are therefore protective. However, it is likely that multiple booster vaccinations increase -in parallel- the proportion of “facilitating” antibodies (these antibodies do not protect and facilitate the infection of target cells by a new variant of SARS-CoV-2), adversely modifying the benefit/risk ratio of “neutralizing” antibodies to “facilitating” antibodies. This would lead to an opposite effect to the one sought, with vaccinated individuals more susceptible to subsequent infection with SARS-CoV-2 (“Delta” variant?) and to its deleterious or lethal effects. The said “cure” could therefore lead to more serious effects on people vaccinated and then infected by a new SARS-CoV-2 variant.
The indispensable vitamin D
In conclusion, it is important to remember that during vaccination (before, during and after), it is essential to have an appropriate level of circulating vitamin D (ideally between 40 and 60 ng of calcidiol per ml of blood), as it allows our immune system to function optimally, whether it is innate immunity (monocytes, macrophages, dendritic cells, “natural killer” cells, granulocytes) or adaptive/acquired immunity (B- and T- lymphocytes).
All of these immune system cells have receptors for vitamin D (calcitriol) which is the “fuel” that allows them to function properly. At the same time, a satisfactory blood level of vitamin D will protect (partially) against SARS-CoV-2 infection (thanks to the optimal functioning of the immune system), and will avoid the development of severe – even fatal – forms of Covid-19 in case of SARS-CoV-2 infection.
*Jean-Marc Sabatier is Director of Research at the CNRS and holds a PhD in Cell Biology and Microbiology, affiliated with the Institute of Neuro-Physiopathology (INP), at the University of Aix-Marseille.