Open Questions over the COVID-19 Pandemic

Brief Chronology of the First Year of COVID-19 Disease Onset

On 9^th January 2020, the WHO suspected the possible roots of what should later become the COVID-19 pandemic, stressing that the flood of pneumonia-like cases that occurred in the Chinese city of Wuhan could stem from a new coronavirus, SARS-CoV-2. There were 59 reported cases at the time, and travel precautions were taken immediately. On 20^th January 2020, the American Center for Disease Control and Prevention (CDC) announced that three American airports would start screening for the new coronavirus. The day after, the CDC confirms the first positive case of a Washington state resident returning from Wuhan. The RT-qPCR test developed by the so-called Drosden group⁶ was chosen as the SARS-CoV-2 testing method and accordingly used to confirm these cases. On the same day, Chinese scientists confirm the transmission of the disease among humans. Later the same month, the city of Wuhan with 11 million inhabitants was put under quarantine (having at that time 300 diagnosed patients). At the end of January 2020, WHO declares a global threat and global flying restrictions came into force. On 11^th March 2020, the WHO declares a pandemic. Starting from 24^th March 2020, halting of clinical trials was also recommended. On 30^th March 2020, the Food and Drug Administration (FDA) authorizes the use of hydroxychloroquine in the treatment of COVID-19. Later on, two renowned medical journals provided confounding data on this treatment asking for caution in use of hydroxychloroquine. These were the Lancet⁷ and the New England Journal of Medicine.⁸ Both these papers added confusion in development of adequate successful protocols for early treatment of COVID-19 with hydroxychloroquine, previously prescribed for coronavirus infections treatment, and were both withdrawn after the authors said they could not guarantee the data used for paper preparation. In both studies indeed, a private database of medical records from a relatively unknown company Surgisphere was used to draw conclusions on hydroxychloroquine safety. This is not the only example of the highly problematic publishing of scientific papers during “pandemics” and data accuracy related to clinical and public health management of COVID-19. This is a serious matter as scientific data should be openly and accurately published to allow the medical and scientific community in development of adequate treatments for the disease and eventual counteracting measures. Science can have difficulty performing its societal role if it does not rely on exact and confirmed data. Further, on 30^th June 2020, Antony Fauci began to openly warn the population about this new disease, and on 9^th July 2020, the WHO announced that this new respiratory disease could spread through the air. A number of epidemiologic measures that were imposed afterward to the general population, such as massive contact tracking of positive asymptomatic cases followed by isolation or quarantine were mainly based on RT-qPCR-positive cases. Clinical and symptomatic cases are exempted from this observation as these cases were clinically confirmed. It should be also noted that airborne diseases may be spread from an infected person via coughing, sneezing, laughing, and close personal contact or aerosolization of the microbe, which means that a patient infected or colonized with a certain infectious agent is required for spreading of a disease.⁹ Accordingly, a symptomatic person or a person with truly proven infectious potential is required for a respiratory disease spreading, requirements that were largely not met in the RT-qPCR testing of the global population where healthy people were involved as a majority of tested subject. Some major problems with usage of RT-qPCR test for confirmation of COVID-19 cases have indeed been seriously challenged by external independent expert scientists,¹⁰ after the original paper was published by the method developer group in 2020.⁶ Later on, the method was also questioned by WHO itself¹¹ and CDC that announced on 19^th July 2021, a recommendation for clinical laboratories and testing sites that have been using the CDC 2019-nCoV RT-qPCR assay, to consider adoption of a multiplexed method that can facilitate detection and differentiation of SARS-CoV-2 and influenza viruses.¹²

The treatment options by use of existing drugs, especially after the confusion done with erroneously published hydroxychloroquine data, were put almost completely aside from the media focus and governmental policies giving large media coverage to producers of the genetic recombinant products as “vaccines” for COVID-19. Publicly released news on the effectiveness of such new “Moderna vaccine” began on 14^th July 2020 when data from phase 1/2 trials of Moderna Inc.’s COVID-19 vaccine on 15 volunteers was disclosed.¹³ This company was the first to enter large-scale human trials as well. On 20^th July 2020, in the United States, it was announced that delays in diagnostic procedures due to COVID-19 could increase cancer incidence.¹⁴ Followed by Moderna Inc.’s news, on 21^th July 2020, the optimistic results of vaccination trials were released by AstraZeneca and CanSino Biologics as well,^15,16 and on 22^nd July 2020, the contract for the distribution of Pfizer BioNTech vaccines was announced in the United States.¹⁷ It should be noted that these products aimed for COVID-19 vaccination were based on genetic constructs for the production of the coronavirus spike protein in the cells of human recipients. This technology, with the purpose of vaccination, was new to human applications and the sequences for spike proteins in these products were bioinformatically deduced and constructed, in some cases chemically modified, meaning that the final effects in a human body were mainly unknown. These effects include, for example, potential for integration in the human genome or other effects interfering with cellular biological pathways. At the end of August 2020, remdesivir, as one of the firstly pushed antiviral cure for COVID-19, was declared ineffective.¹⁸ It was announced, however, that steroids reduced mortality in severe cases of COVID-19,¹⁹ Europe also reported an increase in the number of cases, and on 23^rd September 2020, a new variant emerged. On 29^th September 2020, Regeneron reported on its website positive results from a monoclonal antibody treatment.²⁰ It became obvious that a race to find a COVID-19 treatment was reaching a mature point. Indeed, many scientific and clinical groups reported on various possible treatments for COVID-19 patients.²¹ Despite criticism toward the heavily pushed use of remdesivir, the FDA at that time gives permission for remdesivir. This remains almost unexplainable from a scientific point of view, especially due to poor clinical utility in COVID-19 treatment and considering the serious adverse effects of this drug reported in the literature.^22,23

Public announcements on dilemmas about COVID-19 vaccine products on the utility to induce true immunity against coronavirus expectedly began already on 5^th November 2020 before a mass vaccination campaign against COVID-19 started. A number of renewed scientists emphasized that immunity against a coronavirus was not achieved in previous studies on animals by this type of genetic product (i.e., mRNA-based products) and will accordingly not be easy to achieve in a human population with these new products as well. Previous studies might have been thus at least considered by regulatory agencies for cautious applications of recombinant medical products for “vaccination” purposes in massive public health decisions.^24-26 These recombinant genetic products, aimed to be used as vaccines against COVID-19, have paved their way sequentially to the public during 2020 and got the emergency use authorization by FDA firstly for Pfizer-BioNTech COVID-19 vaccine²⁷ and conditional marketing authorization by European Medicines Agency (EMA).²⁸ The documentation supplied to regulatory agencies by the producers stated only a relative efficacy of the genetic recombinant products after a rather short period of observation of the subject “vaccine” products. This was shown later to be a crucial point as massive vaccination did not prove useful for control of COVID-19 spreading, particularly to emerging virus mutants, or for disease control.^29-31 In parallel to emergency use clearance of these genetic recombinant products for COVID-19 “vaccination,” treatment options were continuously tested and developed. This was, however, not in the major spotlight of COVID-19 disease control decisions in spite of good results for some products obtained in clinical practice.^21,32 It should also be noted that some sophisticated and successful treatment options such as monoclonal antibodies, that is, bamlanivimab later on showed to be subject to coronavirus mutations escape as well.³³ In the chronology of the first year of the COVID-19 pandemic and besides the pharmacological treatment options for COVID-19 patients, two additional important categories were seemingly intentionally omitted from publicly released information. These are (a) exact incidence and (b) confirmed mortality cases from the COVID-19 disease. The reason for this is in the objective lack of scientifically precise information on these two points. Incidence of the disease was counted indeed as RT-qPCR-positive cases, which cannot, in any case, be linearly assessed without other clinical data and exact diagnostics. Mortality data were also partially erroneously counted for all RT-qPCR test positive cases and death-confirmation autopsies were almost halted. Still, even with this highly overestimated number of COVID-19 death cases, the mortality may be comparable with previous years’ seasonal flu data. Unfortunately, realistic data for these two categories will accordingly never be obtained. As just one example for the highly controversial management of public health decisions related to either vaccination or other lockdown measures, the rather robust UK statistics data may be used through the publicly available online service.³⁴ According to the last released document on COVID-19 deaths from 1^st January 2021 to 31^st October 2021, the number of deaths in unvaccinated persons was in total 35,578 and in vaccinated categories was in total 35,416. In addition, COVID-19 mass vaccination started in December 2020 with the expectation to decrease the excess death rates measured in 2020 since the pandemic’s start. Still, according to the public statistics (stated as statistics for England and Wales), cumulative excess deaths for the 5-year average was constantly increasing until 2^nd July 2021, particularly for the age-group 65 years and higher, which raises some additional questions on the health status of the population following COVID-19 measures, including mass vaccinations.

RT-qPCR Test for COVID-19 Cases Identification

Mass testing of the population with the RT-qPCR test since the proclamation of the COVID-19 pandemic comprised a large portion of healthy people and was done by modified RT-qPCR method based on the bioinformatics premise of the newly published SARS-CoV-2 viral genetic sequence. Among other things, such massive testing contributed largely to the emergence of the so-called “test-pandemic.” Indeed, RT-qPCR detection of SARS-CoV-2 RNA does not necessarily mean that a viable virus is present in the tested sample and a final diagnostic decision should be guided by the clinical signs and the patient’s epidemiologic history. Problematic aspects of the RT-qPCR method, including problems with contamination, false positive or negative results, are also described in the literature.^30,35-40 Asymptomatic individuals should not be tested by this method and the CDC recently acknowledged that the spread of COVID-19 disease has not yet been proven for asymptomatic cases. This also seriously challenges any strict lockdown decision or testing measures for healthy people. For example, a study from 2020 was conducted on more than 10 million Wuhan inhabitants that were screened for asymptomatic positive cases in the post-lockdown period. The study showed no evidence that the identified asymptomatic COVID-19-positive cases were infectious.⁴¹ Similarly, a more recent study presents a case of an asymptomatic COVID-19 patient and the clinical characteristics of its 455 contacts, with the aim to evaluate the potential infectivity of asymptomatic carriers. The computed tomography images of the contacts showed no sign of COVID-19 infection and they all tested negative for SARS-CoV-2 by nucleic acid test.⁴² Moreover, a recent paper by Lee et al. pointed out flaws in both RT-qPCR assay design and handling of the “bulk” material in the first test lot of the 2019-nCoV real-time RT-qPCR diagnostic panel.⁴³ RT-qPCR test is generally a highly specific molecular method. In other words, if someone does not have an infection, there is a high probability that the person in question will be negative. The test is also extremely sensitive. Despite the high specificity, there is a chance that someone who does not have the infection will be positive (false positive reaction). Some reasons for false positive results are laboratory errors and off-target reactions. The latter means that the test cross-reacting with something that is not SARS-CoV-2 may occur. Among the laboratory errors, the most common are handling errors, testing of the wrong sample, cross-contamination, and problems with chemicals, enzymes, and dyes. False positive can also include a recovered patient from the disease so that fragments of nucleic acid that cannot cause the disease remain present in the sample. Most importantly, RT-qPCR method used to count COVID-19 positive cases has been used without a validated and fixed number of PCR cycles (Ct) under 30 leading to an incredibly high number of positive cases. Moreover, the PCR products of this method have not been validated at a molecular level which means the method becomes useless as a highly-specific diagnostic tool to identify the SARS-CoV-2 virus. An open question also remains in the whole COVID-19 diagnostic procedure by molecular testing as majority of clinical centers and test centers did not perform a differential procedure of testing for other common respiratory viruses as well (i.e., influenza).

Face Masking as a Public Health Measure

Face masking mandates in community settings, often outdoors, during the COVID-19 pandemic management has been a matter of major controversy, especially in applications for children. We will not discuss herein the mask-wearing mandate in clinical environments and clinical institutions or in specific situations as this is a separate matter to be discussed within the medical community according to professional standards and facts. We will focus on in-community setting mandates as these have major health, psychological, and environmental consequences that seem to outweigh the envisioned benefits of such measures. Accordingly, we will start with the premise of “targeted masking” instead of mandating universal face masking to the public. Indeed, a case for mandating masks in community settings such as outdoor spaces and uncrowded environments where normal distancing and ventilation are possible does not exist rationally. Particularly, society should have enough information of true benefits as well as potential problems arising from mask-wearing before any measure related to mask-wearing is suggested widely to the population. Scientific studies dealing with the research on efficiency of mask-wearing in control of disease spreading or as part of work safety control were conducted in specific, limited conditions and for assessing types of risks other than COVID-19. Currently, there is no scientific basis to justify the community settings mandate as no clear benefits were assessed in previously published studies^44-48 as well as during the COVID-19 pandemic course.^49-53 The long mask-wearing may pose a number of other health risks and the precautionary principle that stays for preventing researchers and policymakers from neglecting potentially-harmful side effects of interventions has been completely neglected in the COVID-19 pandemic. The risks include, for example, a false sense of security of the mask wearer, exhalation of the air into the eyes, hampered breathing and oxygenation, contamination of masks with diverse microbes, etc.⁵⁴ Continuous mask-wearing may be especially dangerous for children as they block the normal oxygen flow which may have serious consequences for brain injuries or brain development of children and adolescents. A recent German study, even if preliminary,⁵⁵ found health consequences in 68% of masked children that were forced to wear a face covering for an average of 4.5 hours per day. The study comprised 17,854 health complaints that were submitted by parents as well. The health issues found in the study include increased headaches (53%), difficulty concentrating (50%), drowsiness or fatigue (37%), malaise (42%), and sleep issues in a third of children. Moreover, 29.7% of children reported shortness of breath, 26.4% reported dizziness, and many children experienced accelerated respiration, tightness in chest, weakness, and short-term impairment of consciousness. The psychological effects of massive mask-wearing mandates are also serious.

The precautionary analysis of unwanted side effects in everyday use of face masks and potential dangers remains vital and has not been performed so far. This is at a best odd and merits further evaluation. Many countries have indeed mandated mask-wearing in public places to combat SARS-CoV-2 without proper risk analysis or follow-up risk-benefit evaluation. In a recent paper, for example,⁵⁶ the authors tested, evaluated, and compiled scientifically proven related side effects of wearing masks. Forty-four mostly experimental studies were referenced for quantitative assessment, and 65 publications were found for content assessment. The literature revealed the relevant detrimental effects of masks including mental and physical deterioration, as well as several symptoms described due to their consistent, repetitive, and uniform presentation from different disciplines such as mask exhaustion syndrome. The authors objectified the findings with evidence of changes in respiratory physiology of mask wearers with a significant correlation of O₂ decline and fatigue, group co-occurrence of respiratory damage and O₂ decline (67%) and CO₂ increase, headache, respiratory damage and fever, but also temperature and humidity masks. Prolonged wearing of masks by the general population could accordingly lead to a variety of unwanted health problems.

Recombinant Genetic Products Used for COVID-19 Vaccination

Recombinant genetic products used for COVID-19 “vaccination” have been heavily pushed on the global population and are accompanied from one side by excitement, and on the other side by numerous controversies and resistance. The relevant question in this matter is how much do the media, the Internet, and social networks contributed to information or misinformation circulating about these products and the so-called COVID-19 “vaccination” mass campaigns. One of the reasons for confusion and hesitancy may be in a more relaxed procedure of “vaccines” approval for marketing in comparison with drugs. The FDA or EMA approval for the recombinant genetic products used for COVID-19 “vaccination” was primarily based on supplied manufacturer’s data which was explained in more detail in a recent article in the British Medical Journal.⁵⁷ The emergency use in the USA or conditional marketing authorization in the EU has been granted accordingly. The central media, that played a central role in shaping public opinion on this group of products, played a somewhat negative role from a scientific point of view as facts were neglected from the public communication and propaganda was installed instead of a critical approach toward the “unknown.” The enforcing of this “vaccination” measure with an experimental product by use of methods of psychological pressure was witnessed in the public communication and political space. Regulatory agencies that granted permission for these products are often co-owners of patents or have disclosed or undisclosed conflicts of interest with producers. For example, private fees and payments, including those from pharmaceutical industry, support around 86% of the budget of the EMA agency while public financing accounts for only 15% of the total funding.⁵⁸ How can these agencies’ decisions on any product, especially a new recombinant genetic product aimed for COVID-19 “vaccination,” be mandated to the population or used for restrictions on human rights? Many media covered this topic but were not allowed to reach a wide audience (just an example is given in Ref.⁵⁹). The warnings and criticism of independent scientists and/or experts without conflict of interests were not respected and were heavily censored or put in shameful spotlight by media. Who decides on which scientist is right and which is not? Science operates through confrontation of facts and opinions. These cannot especially be done by mass media or social media as the consequences for science and the whole society may be detrimental.⁶⁰ Some physicians and medical doctors promoted “vaccination” due to lack of molecular knowledge or simply ignored the problem of using an experimental medical product due to fear or pressure. At the same time, a high number of physicians and medical doctors oppose this procedure pointing that a medical justification to use an experimental, potentially harmful product for a disease whose mortality rate is almost equal to the flu does not merit such attention (a careful statistic is done, for example, in the UK⁶¹). Some doctors have recently refused to vaccinate patients possibly due to the increase in so-called sudden deaths or severe reactions. The papers bringing criticisms on this matter do not make it through the peer review process or are retracted (e.g., Ref.⁶²). Many scientific papers report on severe cardiovascular and neurological effects and here it should be noted that this is not anyhow a “normal outcome” of vaccination. Adverse events of special interest for COVID-19 vaccines—background incidences vary by sex, age, and time period and are affected by the pandemic.^63-65 One of the main explanations for pushing the mass “vaccination” with recombinant genetic products used as “vaccines” against COVID-19 toward the public is the alleged pressure to the health system due to the spread of the COVID-19 infection. This is often publicly communicated as one of the main justifications for unprecedented restrictions of human rights and freedoms. This is witnessed through introduction of the so-called COVID-19 certificates and in its true essence almost mandatory vaccinations. For those who are faced with losing jobs, education rights, freedom of movement, etc. this is indeed a mandatory request. For example, Croatian experts and physicians clearly stated that the health system overload has not been reached in any period from the proclamation of the COVID-19 pandemics because most COVID-19 patients do not need hospital treatment at all. A similar picture may be seen in other EU countries. Then, what the restrictions are about? Why such strong unilateral support of the main media is necessary to push such impositions in the medical field? If a medical product works fine and has a medical justification, no propaganda is necessary to spread the good information. The case is obviously different. When it comes to mRNA or adenoviral vectors-based recombinant genetic products containing genetically engineered and/or chemically modified nucleic acid sequences for production of the spike protein within the host human cell, consequences may be grave and have been described so far in the scientific and medical literature (Table 2). Some consequences include the following side effects of such medical procedure: Guillain–Barré syndrome, acute disseminated encephalomyelitis, encephalitis/myelitis/encephalomyelitis/meningoencephalitis/meningitis/encephalopathy, convulsions/seizures, stroke, anaplasia, narcolepsy and narcolepsy, myocarditis/pericarditis, autoimmune disease, impact on pregnancy outcome and childbirth, non-anaphylactic allergic reactions, thrombocytopenia, disseminated intravascular coagulation, venous thromboembolism, arthritis and arthralgia/joint pain, Kawasaki disease, so-called multisystem inflammatory syndrome in children, exacerbation of the disease caused by this so-called vaccine, and death. Quite enough for serious concern. Before the COVID-19 pandemic, such list of unwanted effects for any tested medical product would immediately lead to halting of the clinical testing and further product development. Now, this is not the case. Why is this list so large and why are the reports in pharmacovigilance bases so high? After injection of the recombinant genetic products aimed for COVID-19 “vaccination,” in an ideal scenario, human cells use the instructions either in the form of DNA or mRNA to make copies of the viral spike protein. This protein is afterward presented to immunological system on the cell surface and is recognized as a foreign antigen that triggers an immune response in the form of antibody production. This process allows a fragment of the particular viral strain spike protein to form. Accordingly, these products can only trigger a rather specific but in a long-term weak or ineffective protective immune response that will not be efficient toward mutated forms, which is highly relevant for the mutating coronaviruses. Moreover, these genetic constructs may enter the nucleus and be either integrated in the human genome or impair other vital biological processes such as V(D)J recombination and DNA repair (Table 2). These risks are so high for the future health of the recipients that a massive application may lead to a massive increase in malignant diseases and other public health conditions. This is why the coronavirus-directed vaccines in general have not been developed successfully so far. A number of biological and health problems were observed with similar products in the preclinical stages of development, especially in terms of effectiveness and safety.^25,66,67 Rushing into massive programs of injecting recombinant genetic products used for COVID-19 vaccination without a clear safety frame and especially in light of failure in protecting the population in the spreading of COVID-19 and hospitalizations, is at best irresponsible, and at worst dangerous for the whole population. So far, the majority of people successfully acquired the most valuable natural immunity against the virus. Particularly, each person should decide alone whether to receive or not an experimental medical product for an experimental medical procedure as it is done for any other product or procedure. At last, we conclude this section with the list of recorded adverse events after injection of the recombinant genetic products used for COVID-19 “vaccination” publicly disclosed in many pharmacovigilance databases such as VAERS and EudraVigilance. These bases are known to report for only a few percent of really occurring adverse effects. For example, it has been found that serious adverse events post-vaccination are underreported in the VAERS system by a factor of 8.3,⁶⁸ the reported number of unwanted effects for recombinant genetic products used for COVID-19 vaccination are already so high that mass injection of these products should be immediately halted and reevaluated by the scientific and medical community. These numbers include 20,622 deaths, 108,572 hospitalized, 107,860 urgent care, 153,971 doctor office visits, 8590 anaphylaxis, 12,317 Bell’s palsy, 3365 miscarriages, 10,429 heart attacks, 201,560 myocarditis/pericarditis, 34,615 permanently disabled, 4907 thrombocytopenia and low platelet, 23,405 life-threatening reactions, 35,997 severe allergic reactions, and 11,292 shingles.⁶⁹