Key words : Coronavirus disease 2019, Exosome, mRNA vaccine, SARS-CoV-2

Introduction

There are approximately 300 000 viruses, many of which have zoonotic potential; development of vaccines for all of these viruses is unreasonable and beyond the scope of present technology. To develop vaccines for any specific virus during an epidemic or pandemic (as was done for the severe acute respiratory syndrome coronavirus [SARS virus, ie, SARS-CoV] during the pandemic of 2002-2003) is unrealistic because of the lead times required for vaccine development, efficacy testing, credible midterm and long-term safety testing, and implementation.¹There is no such thing as a “sure thing” in vaccine development.² In 1955, tragic incidents occurred with poliovirus vaccine with 40 000 cases of severe adverse events, which included 51 cases of permanent paralysis and 5 deaths.³ In 1976, a vaccine against influenza A (H1N1) was tested in ~7000 individuals in the spring of 1976 and was initially deemed to be safe, with broad immunization starting on October 1 of that year. About 25% of the population of the United States was immunized before ~450 cases of the paralytic Guillain-Barré syndrome disease emerged, a statistically significant increase above the normal population incidence rate. This influenza immunization program was terminated in December 1976 with severe consequences, such as diminished public confidence in vaccines and the public health care system.^4,5 In 2009, there was a 13-fold higher risk of narcolepsy, an irreversible neurological disorder, in hundreds of Scandinavian and English young people aged 4 to 19 years after receiving influenza A (H1N1) adjuvant containing squalene vaccine.⁶ Last year, the phase 1/2 trial of AstraZeneca was briefly paused after a participant developed neurological symptoms that were later linked to multiple sclerosis. The phase 3 trial was also paused after a vaccine recipient developed symptoms consistent with transverse myelitis. Although the United Kingdom trial resumed shortly after the pause, as of October 5, 2020, the US trial has not yet resumed.⁷

Surprisingly, at the moment, it is not clear whether people may become immune to COVID-19 after infection, and, if they do, it is uncertain how long that immunity may last and what is the true correlate of immunity. Studies on natural herd immunity in the population that were conducted in many countries like Switzerland, Spain, the United States, and Brazil, mainly in areas with high rates of infection, revealed very low levels of herd immunity in the population, which ranged from 1% to 10% in various countries and regions.^8-11 This longitudinal assessment is relevant given that natural history studies have suggested that SARS virus and Middle East respiratory syndrome coronavirus infections, particularly in cases of mild illness, may not generate long-term antibody responses. So one may wonder, if the virus cannot induce strong natural immunity, then how would be possible to induce it artificially through a vaccine that by definition is supposed to provide safe immunity while stopping the spread of the virus?¹² None of the currently advertised vaccines have fully demonstrated success at such objectives.^13,14

By January 8, 2020, a team of Chinese scientists sequenced the genetic material of the virus, and, astonishingly, the first vaccine candidates were ready for preclinical testing in animals just weeks later. Equally alarming, some vaccines proceeded to clinical trials in human volunteers by March 2020, thereby bypassing standard animal experimentation.^1,15 By July 20 more than 200 vaccine candidates were declared to be in development, each with a specific strategy to generate immunity, despite the assertions of infectious disease experts that 18 months for a first vaccine is an incredibly aggressive schedule compared with the average 10-year development time for conventional vaccine development. It is important to note that vaccinologists have made little progress with HIV or respiratory syncytial virus, despite huge investments.

Ten vaccine candidates have already entered phase 3 clinical trials in humans.^1,7,12 These vaccines employ different technologies that include the innovations with the genetic material messenger RNA (mRNA), such as Pfizer-BioNTech’s BNT162b2 (US-Germany) and Moderna’s mRNA-1273 (US) for which the mRNA Vax is encapsulated in lipid nanoparticles and delivered to a person through a regimen of 2 injections given 3 and 4 weeks apart for the Pfizer-BioNTech and Moderna products, respectively. Others use different types of adenoviruses as vectors to deliver the spike protein: AstraZeneca, ChAdOx1 nCoV-19 with University of Oxford

(UK-US); Johnson & Johnson, Ad26.COV2.S (US); Gamaleya Research Institute of Epidemiology and Microbiology, Gam-COVID-Vac (Sputnik V), which is a vector-based combined recombinant adenovirus type 26 (rAd26) and type 5 (rAd5) that both carry the gene for SARS-CoV-2 spike glycoprotein (rAd26-S and rAd5-S) (Russia); and CanSino Biologics, nonrep­licating adenovirus type-5 (Ad5)-vectored (China); as well as inactivated viruses (traditional vaccine) developed by several Chinese pharma companies such as Sinovac Biotech or Sinopharm.

Pfizer-BioNTech¹³ and Moderna¹⁴ recently publis­hed trial results from nearly 44 000 and 30 000 volunteers, respectively, randomized by half (1:1 ratio) to either receive the vaccine or the placebo. The studies are designed to test whether the vaccines are safe and can trigger an immune response that may offer adequate protection against COVID-19 but not to stop its transmission. None of the trials currently under way was designed to detect a reduction in any serious outcome such as hospital admissions, use of intensive care, or deaths. Nor are these vaccines studied for ability to interrupt transmission of the virus.¹² In fact, viral transmission may persist after vaccination. This condition will require maintenance of all standard protective measures for unvaccinated people, such as mask wearing, by vaccinated individuals until herd immunity is reached, if ever, as this outcome has yet to be proved. The achievement of herd immunity will require vaccination of 70% to 80% of the population. Both trials (Pfizer-BioNTech and Moderna) have shown efficacy of nearly 94% to 95% on a short-term basis, with more people contracting the infection in the placebo groups versus the vaccinated groups (in the Pfizer-BioNTech study, 162 in the placebo group vs 8 in the vaccine group; and in the Moderna study, 185 in the placebo vs 11 in the vaccine group).

Interestingly, in the Pfizer-BioNTech study, 10 participants developed severe clinical manifestations (severe disease) with 1/8 individuals in the vaccine group versus 9/162 in the placebo group. Severe disease was 2 times more likely to occur in those vaccinated compared with their counterparts in the placebo group (12.5% vs 5.5%). In contrast, in the Moderna trial, none of the vaccine recipients developed severe disease, and among the 30 placebo volunteers who developed severe disease, none of them died and only 0.05% (1/185 who developed COVID-19) or 0.0065 (1/15, 166 of the total placebo group) required intensive care admission, which suggests a very low level of severe disease in the placebo group that required intensive care.

Although obesity was more prevalent in the Pfizer-BioNTech trial, where 35% of the cohort were severely obese compared with only 6.7% in the Moderna trial, both trials included similar proportions of individuals with diabetes (8% and 9.8%, respectively). Obesity and diabetes mellitus are well-known predisposing factors and significant determinants of negative outcomes in COVID-19 patients. In both trials, no information was provided about participants’ application of protective measures that may affect outcomes^16,17 mainly in the setting of national and international recommendations. Adoption of such measures may change from state to state in the United States (Moderna study)¹⁴ and among different countries with different cultures and different protective measures/policies and application of these measures (Pfizer-BioNTech study),¹³ which consequently may affect outcomes by either underestimation or overestimation of COVID-19 cases in either group as a result of variable application of personal protective measures.

Surprisingly, reverse transcription-polymerase chain reaction (RT-PCR) tests were not performed systematically in those patients who developed adverse systemic events after vaccination in both studies. These adverse events that were significantly more common in the vaccine groups could be potential clinical manifestations of the disease and would be extremely difficult to distinguish between the 2 situations unless PCR tests were performed. Unfortunately, the decision for the test was left to the discretion of the investigator, a factor that may have actually underestimated the number of participants who developed the disease after vaccination.¹⁸ Moreover, participants in the phase 1/2 trials were predominantly young participants, aged 18 to 55 years, with normal body mass index (low risk group) and limited ethnic diversity, ie, White (US). Children, pregnant women, immunocompromised individuals, and elderly frail individuals with multiple comor­bidities were excluded.¹⁹ Furthermore, these studies were unable to assess durability of the immune responses, the protective effect of these antibodies, or any immunological risk (immune enhancement) associated with antibodies induced by vaccination when vaccine recipients were reexposed to the virus; these points were listed as limitations in the Moderna trial, suggested by the study investigators themselves, and rightly so.^12,14

Previous experience with veterinary coronavirus vaccines has raised safety concerns about the potential for vaccine-associated enhanced respiratory disease related to either increased susceptibility to antibody-dependent enhancement of replication or induction of antibodies with poor neutralizing activity.^20-22 This is an important and valid concern, especially with the emergence of the new COVID-19 variants that may limit the efficacy of the vaccine, as reported in Israel, where, after vaccination of 25% of the population with the first dose, only 30% of those vaccinated developed antibodies at 2 weeks,²³ indicating an efficacy well below the reported 52% with the Pfizer-BioNTech vaccine at 12 days after the first dose¹³ and 95.2% with the Moderna vaccine at 14 days after vaccination.¹⁴ These results may be explained by the rapid spread of the new South African variant 501Y.V2 in Israel. New reports suggest that this variant, as well as others, may cause significant reduction in the effectiveness of the Pfizer-BioNTech and Moderna mRNA vaccines, through a decline in the potency of antibodies elicited by these vaccines, because the new variant may be resistant or impermeable to many of the otherwise potent neutralizing (virus-blocking) antibodies generated by people who had received other vaccines or had recovered from infection.²⁴

In addition, one should consider the different genetic, environmental, and psychological parameters not assessed in the 2 main trials that may have considerable effects on outcomes, efficacy, and safety.²⁵ According to evidence-based medicine, factors that may be effective in one population may not apply in another population. Moreover, there are several reports from different countries about deaths of elderly and frail people shortly after vaccination, and this category was excluded in the preliminary studies. Norway has reported, so far, 33 deaths of which 13 were related to the vaccine in elderly nursing residents above 80 years of age.²⁶ The deaths occurred in people who received the Pfizer-BioNTech vaccine. Similarly, 10 cases have been reported in Germany and in a nursing home in New York state shortly after they received the vaccine. In Israel, several vaccine recipients developed idiopathic facial palsy,²³ an adverse event that was considered anecdotal, but which occurred in some participants in both trials.^13,14 Recently, through a public statement, Germany’s health minister requested AstraZeneca to retract the usage of their vaccine in people 65 years of age or older.

Scientists are apprehensive regarding the rate of progress of pharma toward approval before clinical trials end, because this rate of progress could complicate efforts to study long-term effects. Once a vaccine is granted emergency approval, developers may feel pressure to offer immunization to trial participants who received a placebo.¹⁸ Such pressure is already present, reflected by the official demands by pharma companies addressed to regulatory agencies such of the US Food and Drug Administration to provide vaccination for participants from the placebo groups on ethical grounds. However, if too many people cross over to the vaccine group, the companies may not have sufficient data to establish long-term outcomes, such as safety, duration of vaccine protection, and effectiveness against infection and not simply for the prevention of the disease.

There is limited evidence of short-term efficacy and no evidence of long-term efficacy and safety, mainly for the mRNA versions; many members of the scientific community have raised valid and serious concerns, given the lack of previous experience with such a concept in general, and in particular by some young pharma companies like Moderna, which was started as chemotherapy company with no history of vaccine manufacture. Although under apparent political and governmental pressures to conduct the necessary research and produce vaccines funded by governments in return for low-cost vaccines, pharma companies accepted the contracts in exchange for freedom and protection by law from potential legal consequences in case of any future short-term or long-term serious adverse events that may occur in vaccinated volunteers within the next 2 years. It is astonishing that pharma companies backed by physicians from the medical community refuse to handle such responsibilities despite their repeated assurances against any potential long-term adverse events. Such a stand taken by pharma, to avoid a guarantee of the safety of their own products until 2 years after its introduction as product of new and novel technologies, has generated considerable doubt and uncertainty in the minds of many potential recipients and created many legal hurdles in many countries where such permissive laws do not exist, which may delay contracts with these companies until new laws are in place to address the introduction of these vaccines in these countries.

Whether public pressure exists, such as the stress generated by the pandemics through intense and focused media coverage and the consequent disastrous sanitary and socio-economical outcomes,²⁷ and in the absence of any proven treatment (apart from some vitamins and steroids in moderate to severe cases), governments have strangely accepted the legal responsibility for these programs. Currently, taxpayer money (1) has funded the research and the production of many of the current vaccines, (2) has paid for the vaccines, and (3) will be used by governments to cover future compensation in case of future medical harms attributed to the vaccines. In return, pharma companies (1) have accepted the money and have delivered (or will deliver) the vaccines as expected, (2) will receive dividends from public and private sectors in return for the purchase of the vaccines, and (3) have successfully liberated themselves from any potential future legal responsibilities. All of this was conceived and achieved under Emergency Utilization Authorization to combat the COVID-19 pandemic for which health care providers (governments) instead of the vaccine suppliers (pharma companies) bear the medico-legal liability of a product with limited short-term evidence and unknown information on long-term safety. It is surprising to observe this global apathy despite the emerging scientific data about a hopeful low-cost drug (ivermectin) discovered in 1975 as an antiparasitic agent and awarded the 2015 Nobel Prize for its global effect on many parasitic diseases such as onchocerciasis (river blindness), lymphatic filariasis, and scabies in many endemic areas around the world, by its massive reduction of morbidity and mortality rates in many low-income and middle-income countries. Recently, the US Food and Drug Administration approved ivermectin as a potent inhibitor of SARS-CoV-2 in vitro.²⁸ A recent meta-analysis,29 which included a total of 7300 patients from 24 controlled studies (15 randomized control trials; n = 3080), with 12 reports published in peer-reviewed journals that included 4054 patients, has revealed new evidence that demonstrates the effectiveness of ivermectin not only in vitro and in animal models but also its efficacy and safety, as well as its anti-inflammatory effect, in many clinical trials involving thousands of patients in many countries around the world, which strongly support its immediate use on a risk/benefit calculation in terms of prophylaxis and antiviral effect at different stages of the disease. Surprisingly, despite the well-established safety profile of ivermectin, governments remain silent and inactive in sponsoring new clinical trials, as was done with the newly advertised vaccines, to prove or disprove the efficacy and the safety of this well-known drug that has been used in several regions of the world and is listed by the World Health Organization as an “essential medicine.”

Hopefully, ivermectin would not be subjected to the same discrediting scenario as hydroxychloroquine, which after a published study in the medical journal The Lancet was retracted shortly after its publication because of inaccuracy in data reporting and an obvious conflict of interest with one of the authors who owned the company that provided the published findings.³⁰ Unfortunately, this retracted publication led immediately to the discontinuation of several ongoing randomized control trials to assess the efficacy and safety of hydroxychloroquine by the World Health Organization and in different countries, long before scientists had the time to review the retracted study.

Many members from the scientific community have stipulated that the mRNA vaccine may not be considered a vaccine and should not be perceived as such. It is possible that the imprecise use of the word “vaccine” for these new technologies may provide a method to bypass standard rigor from which true vaccines are exempt. These mRNA-based technologies are designed to stimulate a human cell to become a pathogen-manufacturing site. Under the legal definition, a vaccine must create safe immunity and also to disrupt viral transmission, something that mRNA vaccine companies are clearly admitting is not the case for their products.^13,14 So these new mRNA vaccines may be considered, in fact, nanoparticle-based medical devices containing mRNA packaged in fat, which use nanotechnology to deliver a synthetic pathogen that drives human cells to become a pathogen-producing machine to induce immune response but without the ability to disrupt viral transmission.¹² These nanoparticles may be considered exosomes, which are extracellular vesicles released from various types of cells that contribute to intercellular communication via delivering biomolecules like nucleic acids, proteins, and lipids to recipient cells.31 Exosomes are small phospholipid membrane-enclosed entities that can carry mRNAs.³² Exosomes may also have a potential role in vaccine preparations, and the ability of exosomes to deliver molecules to recipient cells raises the possibility of use for drug therapy/delivery.³³ In the same manner by which exosomes can strengthen innate and specific immune responses against the invading microbes, exosomes are also capable of immunosuppression during pathogen infection.³⁴

Reportedly, 50% to 80% of the people who are exposed to the COVID-19 virus have no symptoms at all. In contrast, 50% to 80% of the people who will be receiving the vaccine will develop various degrees of local and/or systemic clinical adverse events, as shown in the 2 above-mentioned trials. For these vaccination trials, healthy recipients are injected by a medical device containing chemical substances to induce illness, which stimulates the body to produce immunity. According to the recently published Pfizer-BioNTech study, up to 83% of recipients developed some kind of mild to moderate local events, more prevalent in young (78%-83%) than in elderly participants (66%-71%), and experienced some kind of systemic adverse manifestations, again predominantly in the young (47%-59%) compared with the older participants (34%-51%). Vaccine recipients were 2 times more likely to develop a severe disease than the nonvaccinated participants, as mentioned above (12.5% in the vaccinated group vs 5.5% in the placebo group). Given the fragility of the genetic material (mRNA), many of these vaccines require refrigeration between -70 °C (Pfizer-BioNTech) and -20 °C (Moderna), which renders the logistics of transport, handling, and storage extremely costly and complicated and could be problematic for use in resource-limited countries.

Concerns have been raised about the risk of immunogenicity of the vaccine. Despite the considerable knowledge accumulated over the last year, mysteries persist about the disease, such as the reason for the steady clinical progression despite SARS-CoV-2 clearance and the causes of the extended multiorgan damage that may last for months after hospital discharge in some patients. In a recent review in Nature,³⁵ the authors state that there are a growing number of studies that converge in their conclusions that these mysteries could be partly explained by autoimmunity, that is, the immune system mistakenly turns against the self and attacks specific proteins either circulating or expressed on specific cells belonging to different organs, mainly those most affected by the virus, such as the vessels, lung, heart, intestine, kidney, and brain. It is well established that pathogens may trigger autoimmunity (production of autoantibodies) if a part of these (epitopes) resemble epitopes of similar structure expressed on human cells as is the case with many postinfectious diseases that trigger many of the well-known autoimmune diseases. This process is likely in the context of genetic predisposition, such as the HLA-DQB1 gene,³⁵ which is strongly suspected to be the cause of the narcolepsy that occurred in hundreds of children6 after their vac­cination against the novel influenza A (H1N1)pdm09 virus (“swine flu”), a vaccine that was later discontinued. Narcolepsy is thought to result from an autoimmune attack on the neurons in the brain. This process is known as molecular mimicry. A recent publication revealed frequent similarities between numerous short sequences from the SARS-CoV-2 spike protein, which the virus uses to enter the cell, and human proteins.³⁶ Presently, the mRNA vaccines are designed to stimulate a human cell to become a pathogen-manufacturing site in which the cell produces the spike protein that ultimately will trigger the immune system to produce neutralizing antibodies against the spike protein.

Given the recently reported similarities between numerous short sequences in the viral spike proteins and the human proteins, an autoimmune reaction could be triggered at any time following the vaccination, which could lead to severe reactions ranging from anaphylactic shock in the short-term (as has been reported to occur in some recipients) to autoimmune disease or even cancer on the long-term (as yet unconfirmed). Another concern, in case of a switch in the immune system and in people with genetic predisposition, is the risk of the continuous production of the spike protein and corresponding antibodies that may lead to a state of chronic inflammation.

Finally, concerns have been expressed regarding the fact that the genetically based vaccines use either DNA or mRNA and that there may be associated risks to transform our genome and therefore the expression of our genes.³⁷ Theoretically, with the mRNA, this risk is minimal if not impossible, according to the dogma of molecular biology. However, this risk may become real in the presence of an enzyme, such as reverse transcriptase, present in retroviruses such as HIV and perhaps in other viruses, which may put HIV patients and others at high risk of genomic transformation if vaccinated. Reverse transcriptase is used in the RT-PCR test to transform the retrieved RNA specimen into DNA so that the machine may amplify this into billions of DNA copies, thereby facilitating the diagnosis. One may wonder, if this can be done artificially, then why is this not a phenomenon found in the natural world, given its billions of years of resilience and adaptive experience?

Many provocative questions and genuine concerns persist, such as the possibly short duration of efficacy and safety of follow-up, the lack of an identified correlate of protection, the morbidity and mortality reported to occur shortly after vaccination, the uncertainty of the risk of enhanced disease on exposure to the virus in the long-term, the possibility of viral transmission after vaccination, the reported reduced efficacy of these vaccines against new variants, the efficacy and safety of these vaccines in the previously excluded subgroups (such as children, pregnant women, frail and elderly high-risk popu­lations, and immunocompromised individuals), the unknown risk of immunogenicity and its association with autoimmune diseases, cancer, and state of chronic inflammation, the risk of genome transformation, mainly in the presence of reverse transcriptase, and finally the potential coercion that may be imposed by either public or private sectors to convince citizens to receive the vaccine. Many plausible questions are apparent, with no clear and convincing answers. As someone once said: “What all the leaders have to do, is tell the people that they have something to fear. Point out the source of their fear and you can get human beings to do whatever you want.”

While awaiting and monitoring for the short-term and long-term results of these trials and the upcoming trials from other pharma companies in the context of the newly emerging variants from different regions, the debate should continue in the medical community and not be suppressed or banned, as is currently practiced by some media and some governments. Such free and open debate will empower society to proceed with educated policy decisions, to ensure that vaccination programs proceed on a voluntary basis without coercion from the public or private sectors, as recently stipulated by the Resolution 2361 adopted on January 27, 2021, by the Council of Europe in Articles 7.3.1 and 7.3.2: it must be established that “vaccination is NOT mandatory,” and we must “ensure that no one is discriminated against for not having been vaccinated, due to possible health risks or not wanting to be vaccinated.”³⁸

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