THE ANTI SARS-COV-2 VACCINES AND THE QUESTIONSTHEY RAISE

Since it was first reported in late 2019, SARS-Cov-2 had a global impact on human physical and mental health, as well as on their social life and economic endeavor. In one year, the virus has infected over 115 million people, killed almost 2.6 million of them and left many others with long-term health sequelae. The SARS-Cov-2 pandemic has overwhelmed healthcare systems, interrupted routine care and prevented patients’follow-up. All these factors led to increased mortality from other chronic diseases. Further, the SARS-Cov-2 pandemic has caused an unprecedented disruption to education, economic trade, travel, social life, and has profoundly changed our way of living. In this review article we present the organization and the function of the immune system that protects us against diseases, the virology, the infection, the transmission and the pathogenesis of SARS-Cov-2, the disease Covid-19, the development of vaccines against SARS-Cov-2 and some of the questions raised by these vaccines, as well as suggested responses to them.

The SARS-Cov-2RNAgenome further encodesin the Rough Endoplasmic Reticulum (RER) for thestructural proteinsE, M and S. After modification in the RER-Golgi complexthese structural proteinsform in association with phospholipidsthe virus envelope (22). The E and M-proteins are also needed for viral assembly. The S-protein is used to attach to and to enter into the host-cell.
The N-proteincontainsN and C termini domains (NTDs and CTDs) which bind RNA molecules. It has highly conserved serine-arginine domains (SR/RS) across species and is enriched in basic ammino-acid residues. These structural attributes allow the N-protein to wrap and coil the acidicpositive senseRNA molecule into a nucleocapsid complex. This process is highly efficient and specific for positive senseRNA molecules, which have the correct sequence and size to form mature viral particles. The N-protein also interacts with the M-protein to facilitate the process of viral genomic packaging in the newly produced virions (23, 24). The S-proteinis a transmembrane glycoproteinwhich mediates the attachment, the fusion and the entrance of the virus into the cell via theAngiotensin Converting Enzyme II(ACE-2) receptor. It is made of 1273 amino acids, which assemble into a homotrimer on the surface of the virus giving it the specific decoration of Coronaviruses. The 1273 amino acid residues are organized from the N-terminal to C-terminal direction, in several domains including the peptide signal (SP), the subunit (S1) which contains 685 amino acids, the subunit (S2) which contains 588 amino acids, the Furin cleavagesite located at the S1 / S2 junction, thetransmembrane domain(TM) and the cytoplasmic tail (CT), among others.
The S1 subunit contains a Receptor Binding Domain (RBD) which uses its Receptor Binding Motif (RBM) to recognize and bind to theACE-2 receptor. The S2 subunit facilitates the fusion between the virus envelopeand the cell membrane of the host-cell (16).The surface location of the S-protein made it a main target for the host immune response. The humoralimmune response produces antibodies which recognize antigenic determinants on the Sprotein and prevent theinfection of host-cells by SARS-Cov-2, hence protection against the disease Covid-19. A study which followed 1241 seropositive patients for 127 days and 11052 seronegative patients for 188 days found zero cases of symptomatic infection and 3 cases of asymptomatic infection in the seropositive group but 89 cases of symptomatic infection as well as 79 cases of asymptomatic infection in the seronegative group (10). Another study showed that immune memory cells were detectable for up to 8 months after infection with SARS-Cov-2 (11). The conclusion is that antibodies protect against SARS-Cov-2 infection. Thus, the S-protein is the focus of vaccine 583 development against SARS-Cov-2,and a target for rational drug design to produce therapies against Covid-19.The organization of the amino-acid sequence of the S-protein is shown in Figure-2here-below.
But not all antibodies produced afterSARS-Cov-2 infection are necessarily protective. Certain non-neutralizing antibodies can complicate the immune response by facilitating the entry of the virus into target cells through a mechanism that was dubbed "Antibody-dependent Enhancement" (12). This could explain why the use of plasma from convalescing subjects as a treatment has yielded mixed results (61, 62).
The mechanism of attachment and entryof SARS-Cov2 into the host-cell requires a rearrangement of both the Sprotein and the ACE-2 receptor. SARS-Cov-2 uses its S-protein to attach to the ACE-2 receptor present on the host cell cytoplasmic membrane. Then it either fuses its membrane with the host-cell cytoplasmic membrane,or it is endocytosed via the endosomal pathway and once inside the host-cell it fuses its envelope with the endosome membrane. The Entryof SARS-Cov-2 into the host-cell via the endosomal route is mediated by acidic pH and endosomal cathepsins. The Entryof SARS-Cov2 by fusion with the host cell cytoplasmic membrane is mediated by proteases such as Transmembrane Serine Protease Type 2 (TMPRSS2) or Human Airway Trypsin (HAT), and Furin which is a membrane endopeptidasethat shuttles between the Trans-Golgi Complex and the surface of the host-cell. On the one hand TMPRSS2 cleaves the ACE-2 receptor, and on the other hand it primes the precursor of the Sprotein to assist the Furin to act on the cleavage site located at the S1 / S2 junctionand separate the S1 andS2 subunits.
In both cases, SARS-Cov-2 succeeds to release its positive senseRNA genome and its essential enzymes into the cytoplasm of the host-cell. Inside the host cell cytoplasm, the viral genome undergoes nucleocapsid uncoating to dissociate the N-proteinsfrom the RNA. The genomic RNA is then ready to be transcribed and translated. The first to be produced is a SARS-Cov-2replicase polyproteinwhich is cleaved by the viral proteases into 16 non-structural accessory proteinsthat will form the RTC. Then a negative senseRNA template is synthesized. The stage is then set for SARS-Cov-2 to hijack the cellular machineries and reproduce itself as described above. Newly produced essentialSARS-Cov-2 enzymes, S, M and E proteins, and the nucleocapsids are packaged into virions which bud into the lumen of the RER-Golgi apparatus to form mature virions which are released from the host-cell to start a new cycle of infection and propagation (22).

SARS Cov-2 has a multiple cell tropism.
Since the ACE-2 receptor is present on cells of multiple organs, SARS-Cov-2 can infect and multiply in all these organs. This multiple cell tropism of SARS-Cov-2 and its RNA genome give it the advantage of evolving more rapidly, of crossing the species barrierand propagating in other hosts, of infecting several vital organs of the body and of expressing itself in multiple clinical forms.

Covid-19, the disease caused by SARS-Cov-2
As with many other pathogens, the clinical course of infection with SARS-Cov-2 will be dependent on the inoculum and the virulence of the viral variant circulating in the population. Generally, the following phases are distinguished:

The incubation phase:
After contracting SARS-Cov-2, the incubation phase will last about 5 days. During this phase the virus continues to multiply in the body at high speed, but the infected person has not yet developed symptoms. The amount of virus accumulated in the body reaches a maximum between the 7 th and 10 th days after infection and then begins to drop over the following days under the pressure of the immune system.

The clinical phase:
The symptomsbegin around the 6 th day after infection and will continue to develop even though the amount of the virus in the body begins to drop under the pressure from the immune system. This phase can take several forms.
In the weak or silent forms, the patient does not develop symptoms and has no idea that he had contracted SARS-Cov-2. He will only discover this fact whenhis physicianasks for anti SARS-Cov-2 antibodies in a routine laboratory blood-test examination that takes place weeks after exposure.
In the active formsthe patient begins to develop symptoms from the 6 th day after infection. The intensity of these symptoms varies from one person to another. Some patients will develop a moderate form of the disease which peaks between day 10 and 14 and then returns to normal on 15 th dayafter infection. Other patients will have their symptoms worsen with hyper-inflammation(Cytokine Storm Syndrome) requiring hospitalizationand evenadmission in the intensive care unit (ICU). Some of the critical cases will sadly end in fatality. In fact, the human body's immune response to infection with SARS-Cov-2 is a double-edged sword. By trying to protect us, our immune system will also participate in the severe complications of the disease (9).

Vaccination
The first vaccinationin human would have been a passive maternal immunity in which the first women who got pregnant was able to immunize her fetus via transplacental transport of protecting antibodies during her pregnancy.
Active vaccinationrelies on the two responses of the immune system. Humoral immunity which uses antibodies to neutralize the virus circulating in the extracellular medium, and cellular immunity which uses cytotoxic T-Lymphocytes to destroy infected cells that are resistant to antibodies.
Many technology platformswere developed to design and prepare vaccines for a variety of diseases. Several of these technologies are today being implemented to develop vaccines against SARS-COV-2. The main types are listed in Table-1shown here-below.

1)Vaccines based on whole viruses,inactivated or attenuated by various mechanisms 2)Vaccines based on pathogen-protein-subunits or based on virus-like-particles (VLPs)
3)Vaccines based on replicatingor non-replicating viral vectors. This technology dates back to the 1980s. It uses non-pathogenic DNA viruses to infect the host-cells. The viral vector is genetically engineered to transport, deliver and express inside thehost-cells, genes encodingimmunogens that elicit a protective immunity in the host. However, live vaccines are risky in immuno-compromisedindividuals. 4)DNA-based vaccines. This technology dates back to the 1990s. These vaccines require the technique of electroporation to facilitate the entry of DNA into host-cells and increase its immunogenicity. 5)Vaccines based on mRNA which is non-replicating and non-self-amplified. The mRNA molecules are encapsulated in lipid nanoparticles called amphipathic micelles or LPNsfor stability and to facilitate their passage through the cell membrane. This vaccine is not stable at room temperature, hence the need to store it in a frozen form at a very low temperature. Once inside the host recipient cell, the micelles release their mRNA content into the cytoplasm of the cell where it is translated into proteins that are processed and exported to the surface of the APCs to elicit a response from the immune system (Fig-2). The translated mRNAis degraded and does not enter the nucleus of the recipient cells or integrate into their genetic material.
In asummary, mRNA constitutes a minimal genetic vector which is non-infectious, non-immunogenic by itself, non-integrative, rapidly synthesized in the laboratory, packaged and effectively delivered, stable and efficiently translated by the ribosomes in the cytoplasm of the recipient cell, and is degraded after translation.

Anti SARS-Cov-2 vaccines:
One year after the outbreak there are hundreds of vaccine projects in development, a few of which are already approved and used in vaccination campaigns, and several more are in clinical trials (Tables-1).
In this article we only discuss the mRNA vaccines encoding the S-protein of SARS-Cov-2.The mRNA is produced in vitro from a DNA template containing the open reading frame of the S-protein flanked at its 5-prime end by a Cap1 structureand an untranslated region (UTR) to confer mRNA stability, to stimulate mRNA biogenesis (splicing and transport) and to increase mRNA translation efficiency, and at its 3-prime end by an UTR and a polyA tail. The purified mRNA is encapsulated in lipid nanoparticles (LPNs) to enhance its uptake by the vaccinated cells (17-19,

Questions& Answers Why Should we develop vaccines against SARS-Cov-2?
Vaccines in general are the crown jewel of medicine. In contrast with therapeutic drugs, their use is less frequent, their protection from disease is for much longer and their cost is much lower. Vaccines are very important in supporting the economy by reducing the severity of diseases in the population and thus keeping it healthy and thriving (30). During the SARS-Covid2 pandemic an increase in all-cause mortality was reported (31). We cannot wait for mass-population immunity (herd immunity) to be achieved by natural infections as this has been shown not to be an option in certain countries (32).

Can the foreign DNA or mRNAdelivered into the cells of the vaccinated host integrate into and modify their own genetic material?
A vaccine should be based on facts and scientific knowledge that change and evolve over time. To overcome the epidemic, we must act quickly but on solid principles. Still many uncertainties and many questions remain unanswered. The decision must be made according to the particularities of each person. As a reminder, human cells, with the exception of mature red blood cells, carnified cells of the skin, hair and nails, are nucleated eukaryotic cells.
They have their genetic material in form of DNAorganized and structured into chromosomes. The chromosomes are located in a separate compartment, the nucleus, which is surrounded by an active nuclear membrane. The communication of the nuclear membrane with the surrounding cytoplasm is highly regulated by the cell.
The human genomic DNAis made of regions calledEXONS which encode for (or are expressed into) proteins, and regions called INTRONS which are non-encoding (or not expressed, or silent, or interfering). Theintrons make up the majority of human DNA. The exons are organized into genes and regulatory sequences. The latter govern the transcription of the encoding sequences within the gene [Open Reading Frame (ORF)] into mRNA, in the nucleus.The mRNAthen leaves the nucleus to be translated into proteins by the ribosomes in the cytoplasm.
The process of protein synthesisin eukaryotic cells begin in the nucleus by transcribing the genes intoprimary mRNA moleculeswhich undergo splicing(excision of introns and connection of exons) to produce mature mRNA molecules. The latter exit the nucleus to be translated into proteins by the ribosomes in the cytoplasm.
The insertion of a DNA fragmentinto another DNA molecule may not have any consequences or may cause profound changes. Depending on the position of the insertion, it can activate a new ORF, or inactivate an existing one. For these reasons the safety of directly injected or vectorized DNA vaccines raises legitimate questions about their safety. In principle, vaccines using genetic material derived from an infectious agent should not pose a risk to the vaccinated host given the care taken in the development of such vaccines. Also, we must not losesightof the fact that even classical inactivated or live attenuated vaccines contain the entire infectious agent with its lipids, carbohydrates, proteins and of course its genetic material (DNA and RNA). Moreover, we have many years of experience with mRNA vaccines in malignant neoplasms and certain infectious diseases. In addition, mRNA is delivered into the cytoplasm of the recipient cell where it is translated by the ribosomesthen is degraded after a short life. Therefore, it should not come in contact with the nucleus of the recipientcell where the chromosomes are located. Butthe use of replicating viral vectorswhich carry DNA molecules that obey to the same enzymatic molecular transactions as the human DNAraises questions about the possible interaction and integration of the viral DNA into the genetic material of human cells, and the consequences of such event (63 -66).

Are our cells capable of degrading and recycling synthetic mRNA?
The incorporation of ribonucleotides into RNA synthesis occurs only on the 3-primecarbon of the ribose molecule in nature. However, chemically it is also possible to use 2-primecarbon. Therefore, since the mRNA vaccine is made of synthetic mRNA molecules obtained by transcription from a DNA template: 1) Does the mRNA vaccine only includemRNA molecules that have been elongated on the 3-primecarbon? 2) What was done to avoid elongation on the 2-primecarbon or to get rid of such mRNA molecules if the vaccine produced contains a mixture of C-2 prime and C-3 primemRNAmolecules? 3) The mRNA is degraded after translation. Are human cells capable of degrading mRNA synthesized by elongation on 2-prime carbon that does not occur in nature in living systems? 4) Was the transcription process used to produce the mRNA vaccine proven not to produce partially synthesized mRNA fragments? 5) Does elongation on the C-2 prime produce partially synthesized or instable full mRNA molecules? 6) Does the mRNA vaccine only include a homogeneous population of mRNA molecules which were fully transcribed from the DNA template? 7) Does the mRNA vaccine include partially synthesized mRNA molecules and if yes what was done to remove them? 8) Are the partially synthesized mRNA molecules packaged in the LPNs with the full mRNA molecules? 9) Are the partially synthesized mRNA molecules stable inside the LPNs, and inside the vaccinated host? 10) Are the partially synthesized mRNA molecules translated into shorter polypeptides in the vaccinated host? 11) What happen to the polypeptides produced from partially synthesized mRNA molecules that are stable and translated?
We haven't yet seen published studies on thesesubjects. But given the complexity and efficiency of our biochemistry it is possible that our cells can handle it. If not, would this causea long-term problem of cellular and genomic toxicity, especially if the vaccine has to be taken repeatedly? We have raised these questions before, and we are waiting for anyone with a sufficient and convincing answer (25 -28).
We suggest the following preliminary basic research experiments to answer these questions. The first type of experiments would consist of determining whether the product of an in vitro synthesis of mRNA from a DNA template without cells, contains mRNA molecules whose elongation was made on the C -2 prime carbon. If so, what proportion does this type of molecules represent in the mixture? The second type of experiments would consist of blocking the C-3 prime carbon and synthesizing an mRNA by elongation only on the C-2 prime carbon. The third type of experiments would consist of injecting this C-2 primemRNA into cell cultures and measuring its toxic effect. Radioactive labeling or tagging of C-2 prime or C-3 prime may be one way to monitor mRNA synthesis in vitro (25 -28).
The developers of mRNA vaccines and therapeutics may have already performed these studies since they should have shown biocompatibility studies to get approval from regulatory bodies. Or maybe academic and other independent groupshave conductedresearch in this field. If so, please share your findings with us.

Can a genetic vaccine induce or exacerbate autoimmune diseases?
Yes, it is possible, but such complications would not only be seen with genetic vaccines. In theory,they can happen with any vaccine. For a vaccine to elicit or exacerbate an autoimmune response, it must confuse our immune system and cause it to fail in distinguishing between its own normal cells, and foreign antigens or self-abnormal cells.
Autoimmune diseases develop when autoreactiveT-Cells can make it through all the multilayer maturation processes and further escape the suppressionby the immune system (29).However, many studieshave shownthe presence of autoantibodiesin the sera of patients who were infected with SARS-Cov-2 (70 -84). Some of these antibodies and the diseases they are associated with are listed in Table-2 shown here-below.

Can the vaccine cause autoimmune diseases similar to those caused by the natural infection?
Vaccines directed against SARS-Cov-2 proteins such as the S-protein cause the production of antibodies which block the peptide domain used by the S-proteinto anchor itself to the cytoplasmic membrane of the host-cells, at the ACE-2 receptor. In addition, these vaccines activate subclasses of T-Lymphocytes which confer a cellular immune response. There is a need to investigate whether the antibodies produced, or the T-cell subclasses activatedby these vaccines, do or do not cross react with the peptide domains of angiotensin-2 and therefore block italso? If such a possibility exists, even at a minimal level, the consequences for our health would be very serious given the important role of angiotensin-2 in our physiology. The same question can be extended to all other vaccines using other SARS-Cov-2 proteins such as the M-protein, and to all known human proteins.
We propose the following preliminary experiments in basic research to try to answer these questions. From the SARS-Cov-2 genome, we can deduce the amino acid sequences of all of its proteins such as the S-protein whose mRNA is used in vaccines already available on the market. The amino acid sequences of many human proteins can also be obtained from the Human Genome Project database.Therefore, it is easy to determine the degree of homology between SARS-Cov-2 proteins and known human proteins. It is also known that the immune response generated by the natural SARS-Cov-2 infection, or elicited by the vaccine, is both humoral and cellular.
Rapid experiments would consist of determining whether the sera of patients who have contracted the natural infection or who have been vaccinated react with human proteins which have homologies with the proteins of SARS-Cov-2. More detailed and laborious experiments would first consist of isolating and cataloging the antibodies produced as well as the subclasses of activated T-Lymphocytes, from naturally infected patients as well as from vaccinated patients. Second, the antigenic domains recognized respectively by these antibodies and these activated T-Lymphocyte subclasses are mapped on the SARS-Cov-2 proteins. We could then investigate whether these recognized antigenic domains also existed on human proteins and if they were also recognized. Cross-reaction against human proteins would suggest the possibility of autoimmune reactions (25 -28).
As we explained above RNA viruses mutate frequently. This process can generate mutants that are more infectious, more virulent, more resistant to treatments, more evading to vaccines, more deceiving and confusing to the immune system, and possibly more lethal. Several investigators have reported the detection of autoantibodies in naturally infected patients (49 -60, 70 -84). Would the vaccines cause autoimmune disorders by eliciting autoantibodies and/or cross-reactive T-Cell subclasses? Only time will tell.
The developers of mRNAvaccines and therapeutics, and the regulatory bodies may have alreadyasked themselves the same questions and probably have some confidential answers. The bottom line is it comes down to trusting the scrutinizing process of the multilayered system on the benefit/risk ratio of getting vaccinated.

Will vaccines have long-term consequences on our health?
mRNA used in the vaccine is synthesized in vitro rather than being biologically produced. Therefore, it is much quicker to produce than conventional vaccines. mRNA vaccine technology is not new. It was in the development for decades. Since the mRNA degrades easily at ambient temperature, the progress was very slow. In 2005 researchers discovered that packaging the mRNA into small lipid particles called LPNs or micelles increases its stability. Thus, the use of mRNA in vaccine development became an achievable goal. Micelles can fuse with the cell membrane of the host-cell and the endosome membrane to release their mRNA content in the cytoplasm of the host-cells where the mRNA is translated by the cell machinery to produce the protein encoded by the mRNA (Fig-2). The questions we asked at this level have been detailed above and elsewhere. (25 -28) What dothe proponents say about the safety of the mRNA vaccines?
The security is the first concern in the mind of many including health professionals (34). Therefore, the issue of safety was analyzed, investigated and scrutinized. The arguments presented in favor of the safety of SARS-Cov-2mRNA vaccines include past experience with this type of vaccines (39 -41), the careful testing of the vaccine following all required steps in clinical trials (17), enrollment of large numbers of individuals in the clinical trials, setting short time intervals for the manufacturers to report their data to regulating bodies, and continuous monitoring for side effects in vaccinated individuals (36). Further, the relatively short time spent to develop these vaccines was due to the type of technologies used and in no way was due to skipping safety steps or lack of vaccino-vigilance or pharmaco-vigilance. (35). Moreover, the vaccine is synthetized in vitro without cell culture and therefore is free from cellular contaminants and does not cause more allergies (42). Finally, animal studies have shown that mRNA is quickly degraded (37) and remains localized in the area where it is injected (38).

What do the critics say about SARS-Cov-2 Vaccines?
Many groups are against vaccination in general. They claim that vaccines cause chronic disorders such as autism,diabetes, asthma, allergies and multiple autoimmune diseases.They criticize the way clinical trial are designed, performed, and analyzed. They believe that vaccine products are tested on small non representative groups of volunteers, that the safety data is collected over a short period of time which does not allow for the detections of slow developing side effects such as chronic autoimmune and degenerative diseases. They insist that a proper clinical trial should include no less than 500.000 patients and a follow up for side effects of no less than 7 years.
A recent article published by a well-known criticof vaccination suggests that the mRNA molecules used in recently approved anti SARS-Cov-2 vaccines contain sequences which can be recognized by intrinsic proteins such as TAR-DNA-binding-Protein-43 (TDP-43) and Fused in sarcoma protein (FUS). This interactionwould then convertTDP-43 and FUS to assume their prion-disease causing state. Further, it was theorized that if the anti SARS-Cov-2 mRNA vaccine induces TDP-43 and FUS to aggregate in their prion-based conformations, this will lead to neurodegenerative illnesses such as Alzheimer and Amyotrophic Lateral Sclerosis (ALS) diseases. Furthermore, it was theorized that the binding of SARS-Cov-2 S-protein to the ACE-2 receptor would cause the Zinc-containing Angiotensin Converting Enzyme 2 to unload its Zinc molecules which in turn will cause the TDP-43 to assume its pathologic prion state. Moreover, the author touches on the controversy surrounding the origin of SARS-Cov-2 andsuggested that if SARS-Cov-2was a man-made biological weapon, then vaccinating with the S-protein would put the humanity in danger in the case of a second attack using a pathogen guided by the S-protein used in vaccination. Finally, the author warns that whatever the natural infection may cause would be of no comparison to any serious illness that may be caused by a vaccine administered to a much larger number of people, globally (48).

Are the anti SARS-Cov-2 vaccines going to protect against all the viral mutants?
It's possible because SARS-Cov-2 genetic variability is much lower than in other viruses for which we already have effective vaccines such as Influenza virus, Measle, Hepatis B virus,Mumps,Ebola etc.(33). Moreover, the vaccine will lower the transmission of mutants in the population. However, there are also published reports which show that Pfizer/BioNTech vaccineBNT162b2 elicitstwo-third less neutralizing antibodies against a laboratory mutant mimicking the South African B. Such a task would be quickly accomplished by the pharmaceutical industry because the technology involved is easily adaptable and rapidly implemented. The quote part of each type of mRNA molecules in the vaccine mixture would be optimized to elicit a protective immunity against SARS-Cov-2 wild type and its mutants (68).

Will the vaccine solve all the problems?
No. The vaccine already protects against severe forms of SARS-Cov-2 infections and this is already a big step forward. But the vaccine will not solve everything for everyone right away. First, the vaccines were only tried on adults and not children.Second, it is not known whether the vaccines will prevent the transmission of infection, and whether they will confer herd immunity.We do not know the impact of different pathologies and treatments on the immune response to vaccines and we do not know their effectiveness in older people.
The solution may be in the development of therapeutic antibodies that both neutralize the circulating virus and stimulate immune cells to phagocytize the virus and produce a protective immunity (14) Do we have to continue safety precautions after vaccination?
Yes. The vaccine protects against the severe forms of the infection but does not stop re-infection or transmission of the virus.

Do all vaccines in development produce the same effect?
No. An experimental studyhas shown that mice vaccinated with mRNAproduced a more robust immune response in terms of long-lived B-memory immune cells and neutralizing antibodiesthanmice vaccinated with the S-proteinplus adjuvant. It also appears that vaccines based on mRNA or genetically modified viruses induce protective humoral and cellular immune responses against severe forms of SARS-Cov-2 infection (95% and 90% of efficacy), unlike vaccines based onproteins and adjuvants (13).

How does the mRNA vaccine look like?
The vaccine does not come as a single dose in a pre-filled syringe like other vaccines you use to take. The mRNAbased SARS-Cov-2 vaccines are supplied in multidose vials. A dose of 0.5 ml contains, according to the producers, from 30 to 100 μg of single-stranded mRNA which encodes for the S-protein of SARS-Cov-2. The mRNA was synthesized in vitro from a DNA matrix, without cells, and encapsulated into lipid nanoparticles (LPNs), then added to a suspension of phospholipids, cholesterol, polyethylene glycol, trometamol, acetic acid, sodium acetate, sucrose and water.
Are there any immediate side effects?
Yes, but at low frequency. Those vaccinated mostly reported fatigue, headache, nausea, muscle and joint pain, pain and / or swelling and / or itching at the injection site and fever or chills. These side effects were more severe in young patients than in the elderly, and after the second injection than the first one (15). Other side effects have also been reported such as: syncope, shortness of breath, change in heart rate, swelling of the lips or face, discomfort in the throat, rash, hives, stomach pain and vomiting. Rare effects reported include facial paralysis, hypersensitivity to the vaccine, and severe allergic reactions (anaphylaxis).

Should patients who have a special condition receive the mRNA vaccine?
The Center for Disease Control and Prevention (CDC) has issued on February 10, 2021interim considerations for the use of mRNA vaccines currently authorized in the US (69). These considerations are summarized in (Table-3) shown here-below. The reader is advised to consult the CDC website for updates, and the local authorities in his country for specific instructions on the use of mRNA vaccines.

Is a second dose of the vaccine necessary to have a stronger immunity?
592 for his health and his body. On the other hand, if the vaccine prevents contagion and we cannot otherwise control the spread of the virus, mandatory vaccination becomes an option.

Should a vaccination card be issued to the vaccinated?
Yes. Proof of being vaccinated against certain diseases is already an obligation to travel to certain countries. But none of these situations quite compare to that of SARS-Cov-2 which affects the whole planet. There is therefore a conflict between the right to freedom of choice and the obligations that may be imposed depending on our type of work, our travel habits and our social activities profile etc. These fears are likely to motivate many of us to take the vaccine, even though being vaccinated does not mean being immune from getting the infection. For those of us who cannot get the vaccines due to severe health conditions,maybe isolation and quarantine are the solution.
Are all these questions about SARS-Cov2 vaccines justified and why do we have to scrutinize the vaccines when the virus is doing worse during the natural infection?
In one year, SARS-Cov-2 has infected almost 115million and killed almost2.6million, globally. Although these numbers are devastating, they respectively represent 1.44% and 0.0325% of the world population estimated at 8 billion. Therefore, a vaccine that is supposed to be administered to 70 to 80% of the world population in order to bring SARS-Cov-2 under control must be highly scrutinized because any serious error could cause harm that by far surpasses what SARS-Cov-2 can do through natural infection.
We arean enthusiastic supporter of vaccination which is the crown jewel of modern medicine. We have spent several years of our life conducting research in this field (1 -3). However, even if the questions are annoying, they should be answered in a thoughtful manner. Questions about the safety of the SARS-Cov2 vaccination can be resolved scientifically without indulging in unwarranted speculation. This can be answered by conducting basic research in immunology, cellular and molecular biology, microbiology and biochemistry. Our role as scientists and practitioner of the healing art is to openly debate the issues in a free academic environment. The pharmaceutical industry and regulatory agencies may then be interested in funding this type of research. It is not acceptable that drugs designed for use in humans become like other technological products which are sold to consumers before correcting their design flaws and then delegating the management of those problems to a customer service.
The pharmaceutical industry is a major player in health care. We have no doubt that its scientists conduct their research and development with diligence and ensure that their products are safe and effective.