Literature-related discovery techniques applied to ocular disease: a vitreous restoration example.

PURPOSE OF REVIEW: Literature-related discovery and innovation (LRDI) is a text mining approach for bridging unconnected disciplines to hypothesize radical discovery. Application to medical problems involves identifying key disease symptoms, and identifying causes and treatments for those symptoms from throughout the biomedical literature. LRDI has not been applied to vitreoretinal ophthalmological problems previously. This review illustrates the use of LRDI for potential restoration of degenerated vitreous. RECENT FINDINGS: Vitreous restoration literature is very small; much research is aimed at vitreous composition and degradation, improving vitrectomy, and pharmacological vitreolysis. LRDI has the potential to find ways to slow, halt, or reverse the degradation through systemic improvement and myriad local treatments, some not ordinarily used by the ophthalmology community. SUMMARY: The many potential discoveries and innovations were generated within a larger context, namely that timely healing required cause removal, healing obstacle removal, and healing acceleration (focused treatments) in an integrated manner. Although many potential causes, healing obstacles, and healing accelerations were identified strictly from the premier published literature, causes and obstacles that may have been operable but were not found in the literature were also postulated, as were gaps in the research that covered these potential causes and obstacles and unresearched treatments as well.

Modifiable contributing factors to COVID-19: A comprehensive review.

The devastating complications of coronavirus disease 2019 (COVID-19) result from an individual's dysfunctional immune response following the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS-CoV-2 exploits the dysfunctional immune system to trigger a chain of events ultimately leading to COVID-19. The current study identifies eighty immune system dysfunction-enabling toxic stressors and behaviors (hereafter called modifiable contributing factors (CFs)) that also link directly to COVID-19. Each CF is assigned to one of the five categories in the CF taxonomy shown in Section 3.3.: Lifestyle (e.g., diet, substance abuse); Iatrogenic (e.g., drugs, surgery); Biotoxins (e.g., micro-organisms, mycotoxins); Occupational/Environmental (e.g., heavy metals, pesticides); Psychosocial/Socioeconomic (e.g., chronic stress, lower education). The current study shows how each modifiable factor contributes to decreased immune system capability, increased inflammation and coagulation, and increased neural damage and neurodegeneration. It is unclear how real progress can be made in combatting COVID-19 and other similar diseases caused by viral variants without addressing and eliminating these modifiable CFs.

Literature-related discovery and innovation - update.

Literature-Related Discovery and Innovation (LRDI - formerly LRD - literature-related discovery) integrates 1) discovery generation from disparate literatures with 2) the wealth of knowledge contained in prior art to 3) potentially reverse chronic and infectious diseases and/or 4) potentially solve technical problems that appear intractable. This article describes the evolution of LRDI by the author and the insights gained/lessons learned over the past decade. To illustrate the potential power of LRDI, the article emphasizes the relationship between the results of our 2008 LRDI multiple sclerosis (MS) study and a recent demonstration of MS reversal. Lessons learned from the six LRDI medical studies done so far include:⁎The main operational problem in the author's LRDI approach is selecting the most important concepts from extremely large volumes of potential discovery retrieval. This is contrary to most published LRDI research, where the discovery focus is searching for rare events.⁎It is important to have topical specialist(s) working closely with information technologist(s); the topical specialist(s) applies judgment in selecting the most important concepts.⁎A functional form of the information retrieval query with proximity searching capability provides highly selective filtering for discovery retrieval and core prevention/treatment retrieval; the functional form of the query with proximity searching capability allows the use of full-text for discovery and core prevention/treatment.⁎Bibliographic coupling (identifying papers that share common references) combined with text-based relationships strengthens selection for potential discovery further.⁎Having 'skin-in-the-game' (being affected personally) relative to the medical outcome is a strong incentive to do whatever is necessary to solve the research problem.⁎Hormesis is critical to healing; relatively modest doses of stimuli tend to be beneficial, whereas relatively large doses may be harmful. The synergy of hormetic treatment doses produces effects larger than combinations of individual doses and requires smaller doses when combined; the synergy of hormetic doses allows conversion of megadoses of nutrients typically reported in lab/clinical studies to physiological (food-level) doses and associated increased safety.⁎Co-promoters (combinations of toxic stimuli required to produce disease symptoms) are extremely important for explaining seemingly conflicting results; if true co-promotion is present, elimination of one of the co-promoters may be adequate for removing symptoms, even though the overall problem persists.⁎Prior art (potential treatments already published in the literature but not pursued by mainline medicine) may have much to contribute to potentially solve many serious medical problems; much of prior art is overlooked, especially low-tech prior art (e.g., foods, food extracts, herbs, etc.).⁎Systemic and focused treatments are both necessary components of healing, but neither will be fully, or many times even partially, effective until the cause(s) is identified and removed. Any medical approach that involves administering treatments for chronic and infectious diseases without addressing the cause(s) results in a broad range of outcomes mainly involving substitution of one set of symptoms for another.⁎Past results of LRDI medical studies showed much overlap among preventatives/systemic treatments for different diseases. Differences will arise mainly in focused treatments, especially those involving high technology.⁎The central parameters to healing in much medical research are never identified nor reported. Many treatments require a combination of skilled practitioners, cause removal, and immune/neural/endocrine/circulatory systems to be healthy for full effectiveness, yet practitioner skill, degree of cause removal, and immune system et al. health are never reported. A lack of this information does not allow efficacy of different treatments to be compared. Reviews and meta-analyses that compare and draw conclusions about the effectiveness of these different treatments without the above critical information being reported are of extremely limited value and credibility.⁎Finally, the most important deficiency for fully reversing chronic and infectious diseases, as well as rapidly accelerating healing of injuries and wounds, is the credibility and integrity of the medical literature itself, especially in areas that concern commercial and government/political sensitivities. In the evaluation of many concepts that deviated from the norm, it was difficult to ascertain whether the difference was based on solid high-quality research, poor research, or deliberately skewed research.

Retraction notice to "Why are we vaccinating children against COVID-19?" [Toxicol. Rep. 8 (2021) 1665-1684].

[This retracts the article DOI: 10.1016/j.toxrep.2021.08.010.].

Contributing factors common to COVID­19 and gastrointestinal cancer.

The devastating complications of coronavirus disease 2019 (COVID­19) result from the dysfunctional immune response of an individual following the initial severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS­CoV­2 exploits the dysfunctional immune system to trigger a chain of events, ultimately leading to COVID­19. The authors have previously identified a number of contributing factors (CFs) common to myriad chronic diseases. Based on these observations, it was hypothesized that there may be a significant overlap between CFs associated with COVID­19 and gastrointestinal cancer (GIC). Thus, in the present study, a streamlined dot­product approach was used initially to identify potential CFs that affect COVID­19 and GIC directly (i.e., the simultaneous occurrence of CFs and disease in the same article). The nascent character of the COVID­19 core literature (~1­year­old) did not allow sufficient time for the direct effects of numerous CFs on COVID­19 to emerge from laboratory experiments and epidemiological studies. Therefore, a literature­related discovery approach was used to augment the COVID­19 core literature­based 'direct impact' CFs with discovery­based 'indirect impact' CFs [CFs were identified in the non­COVID­19 biomedical literature that had the same biomarker impact pattern (e.g., hyperinflammation, hypercoagulation, hypoxia, etc.) as was shown in the COVID­19 literature]. Approximately 2,250 candidate direct impact CFs in common between GIC and COVID­19 were identified, albeit some being variants of the same concept. As commonality proof of concept, 75 potential CFs that appeared promising were selected, and 63 overlapping COVID­19/GIC potential/candidate CFs were validated with biological plausibility. In total, 42 of the 63 were overlapping direct impact COVID­19/GIC CFs, and the remaining 21 were candidate GIC CFs that overlapped with indirect impact COVID­19 CFs. On the whole, the present study demonstrates that COVID­19 and GIC share a number of common risk/CFs, including behaviors and toxic exposures, that impair immune function. A key component of immune system health is the removal of those factors that contribute to immune system dysfunction in the first place. This requires a paradigm shift from traditional Western medicine, which often focuses on treatment, rather than prevention.

Literature-related discovery: Potential treatments and preventatives for SARS.

Literature-related discovery (LRD) is the linking of two or more previously disjoint concepts in order to produce novel, interesting, plausible, and intelligible connections (i.e., potential discovery). LRD has been used to identify potential treatments or preventative actions for challenging medical problems, among myriad other applications. Severe acute respiratory syndrome (SARS) was the first pandemic of the 21st century. SARS was eventually controlled through increased hygienic measures (e.g., face mask protection, frequent hand washing, living quarter disinfection), travel restrictions, and quarantine. According to recent reviews of SARS, none of the drugs that were used during the pandemic worked. For the present paper, SARS was selected as the first application of LRD to an infectious disease. The main goal of this research was to identify non-drug non-surgical treatments that would 1) prevent the occurrence, or 2) reduce the progression rate, or 3) stop/reverse the progression of SARS. The MeSH taxonomy of Medline was used to restrict potential discoveries to selected semantic classes, and to identify potential discoveries efficiently. To enhance the volume of potential discovery, databases were used in addition to Medline. These included the Science Citation Index (SCI) and, in contrast to previous work, a full text database. Because of the richness of the full text, 'surgical' queries were developed that targeted the exact types of potential discovery of interest while eliminating clutter more efficiently.

Erratum to "Why are we vaccinating children against COVID-19?" [Toxicol. Rep. 8C (2021) 1665-1684 / 1193].

[This corrects the article DOI: 10.1016/j.toxrep.2021.08.010.].

Why are we vaccinating children against COVID-19?

This article examines issues related to COVID-19 inoculations for children. The bulk of the official COVID-19-attributed deaths per capita occur in the elderly with high comorbidities, and the COVID-19 attributed deaths per capita are negligible in children. The bulk of the normalized post-inoculation deaths also occur in the elderly with high comorbidities, while the normalized post-inoculation deaths are small, but not negligible, in children. Clinical trials for these inoculations were very short-term (a few months), had samples not representative of the total population, and for adolescents/children, had poor predictive power because of their small size. Further, the clinical trials did not address changes in biomarkers that could serve as early warning indicators of elevated predisposition to serious diseases. Most importantly, the clinical trials did not address long-term effects that, if serious, would be borne by children/adolescents for potentially decades. A novel best-case scenario cost-benefit analysis showed very conservatively that there are five times the number of deaths attributable to each inoculation vs those attributable to COVID-19 in the most vulnerable 65+ demographic. The risk of death from COVID-19 decreases drastically as age decreases, and the longer-term effects of the inoculations on lower age groups will increase their risk-benefit ratio, perhaps substantially.

Common contributing factors to COVID-19 and inflammatory bowel disease.

The devastating complications of coronavirus disease 2019 (COVID-19) result from an individual's dysfunctional immune response following the initial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Multiple toxic stressors and behaviors contribute to underlying immune system dysfunction. SARS-CoV-2 exploits the dysfunctional immune system to trigger a chain of events ultimately leading to COVID-19. We have previously identified many contributing factors (CFs) (representing toxic exposure, lifestyle factors and psychosocial stressors) common to myriad chronic diseases. We hypothesized significant overlap between CFs associated with COVID-19 and inflammatory bowel disease (IBD), because of the strong role immune dysfunction plays in each disease. A streamlined dot-product approach was used to identify potential CFs to COVID-19 and IBD. Of the fifty CFs to COVID-19 that were validated for demonstration purposes, approximately half had direct impact on COVID-19 (the CF and COVID-19 were mentioned in the same record; i.e., CF---→COVID-19), and the other half had indirect impact. The nascent character of the COVID-19 core literature (∼ one year old) did not allow sufficient time for the direct impacts of many CFs on COVID-19 to be identified. Therefore, an immune system dysfunction (ID) literature directly related to the COVID-19 core literature was used to augment the COVID-19 core literature and provide the remaining CFs that impacted COVID-19 indirectly (i.e., CF---→immune system dysfunction---→COVID-19). Approximately 13000 potential CFs for myriad diseases (obtained from government and university toxic substance lists) served as the starting point for the dot-product identification process. These phrases were intersected (dot-product) with phrases extracted from a PubMed-derived IBD core literature, a nascent COVID-19 core literature, and the COVID-19-related immune system dysfunction (ID) core literature to identify common ID/COVID-19 and IBD CFs. Approximately 3000 potential CFs common to both ID and IBD, almost 2300 potential CFs common to ID and COVID-19, and over 1900 potential CFs common to IBD and COVID-19 were identified. As proof of concept, we validated fifty of these ∼3000 overlapping ID/IBD candidate CFs with biologic plausibility. We further validated 24 of the fifty as common CFs in the IBD and nascent COVID-19 core literatures. This significant finding demonstrated that the CFs indirectly related to COVID-19 -- identified with use of the immune system dysfunction literature -- are strong candidates to emerge eventually as CFs directly related to COVID-19. As discussed in the main text, many more CFs common to all these core literatures could be identified and validated. ID and IBD share many common risk/contributing factors, including behaviors and toxic exposures that impair immune function. A key component to immune system health is removal of those factors that contribute to immune system dysfunction in the first place. This requires a paradigm shift from traditional Western medicine, which often focuses on treatment, rather than prevention.

Improved strategies to counter the COVID-19 pandemic: Lockdowns vs. primary and community healthcare.

COVID-19 pandemic mitigation strategies are mainly based on social distancing measures and healthcare system reinforcement. However, many countries in Europe and elsewhere implemented strict, horizontal lockdowns because of extensive viral spread in the community which challenges the capacity of the healthcare systems. However, strict lockdowns have various untintended adverse social, economic and health effects, which have yet to be fully elucidated, and have not been considered in models examining the effects of various mitigation measures. Unlike commonly suggested, the dilemma is not about health vs wealth because the economic devastation of long-lasting lockdowns will definitely have adverse health effects in the population. Furthermore, they cannot provide a lasting solution in pandemic containment, potentially resulting in a vicious cycle of consecutive lockdowns with in-between breaks. Hospital preparedness has been the main strategy used by governments. However, a major characteristic of the COVID-19 pandemic is the rapid viral transmission in populations with no immunity. Thus, even the best hospital system could not cope with the demand. Primary, community and home care are the only viable strategies that could achieve the goal of pandemic mitigation. We present the case example of Greece, a country which followed a strategy focused on hospital preparedness but failed to reinforce primary and community care. This, along with strategic mistakes in epidemiological surveillance, resulted in Greece implementing a second strict, horizontal lockdown and having one of the highest COVID-19 death rates in Europe during the second wave. We provide recommendations for measures that will reinstate primary and community care at the forefront in managing the current public health crisis by protecting hospitals from unnecessary admissions, providing primary and secondary prevention services in relation to COVID-19 and maintaining population health through treatment of non-COVID-19 conditions. This, together with more selective social distancing measures (instead of horizontal lockdowns), represents the only viable and realistic long-term strategy for COVID-19 pandemic mitigation.

The highly cited SARS research literature.

A chronically weak area in research papers, reports, and reviews is the complete identification of important background reference documents that formed the building blocks for the research. A method for systematically determining these important references is presented. Citation-Assisted Background (CAB) is based on the assumption that important documents tend to be highly cited. Application of CAB to the field of Severe Acute Respiratory Syndrome (SARS) research is presented. While CAB is a highly systematic approach for identifying highly cited references, it is not a substitute for the judgment of the researchers, and serves as a supplement.

Treatment repurposing for inflammatory bowel disease using literature-related discovery and innovation.

Inflammatory bowel disease (IBD) incidence has been increasing steadily, most dramatically in the Western developed countries. Treatment often includes lifelong immunosuppressive therapy and surgery. There is a critical need to reduce the burden of IBD and to discover medical therapies with better efficacy and fewer potential side-effects. Repurposing of treatments originally studied in other diseases with similar pathogenesis is less costly and time intensive than de novo drug discovery. This study used a treatment repurposing methodology, the literature-related discovery and innovation (LRDI) text mining system, to identify potential treatments (developed for non-IBD diseases) with sufficient promise for extrapolation to treatment of IBD. By searching for desirable patterns of twenty key biomarkers relevant to IBD (e.g., inflammation, reactive oxygen species, autophagy, barrier function), the LRDI-based query retrieved approximately 9500 records from Medline. The most recent 350 records were further analyzed for proof-of-concept. Approximately 18% (64/350) met the criteria for discovery (not previously studied in IBD human or animal models) and relevance for application to IBD treatment. Many of the treatments were compounds derived from herbal remedies, and the majority of treatments were being studied in cancer, diabetes, and central nervous system disease, such as depression and dementia. As further validation of the search strategy, the query identified ten treatments that have just recently begun testing in IBD models in the last three years. Literature-related discovery and innovation text mining contains a unique search strategy with tremendous potential to identify treatments for repurposing. A more comprehensive query with additional key biomarkers would have retrieved many thousands more records, further increasing the yield of IBD treatment repurposing discovery.

Setting safer exposure limits for toxic substance combinations.

Toxic stimuli (stressors) exposure limits are typically based on single toxic stimuli experiments, but are presently used for both toxic stimuli in isolation and in combination with other toxic stimuli (simultaneous co-exposure or exposures separated in time). In the combination case, typically less of each constituent of the combination is required to cause damage compared to the amount determined from single stressor experiments. Thus, exposure limits based on single toxic stimulus experiments are inadequate for setting limits for stressor combinations. This article presents a recommended simplified approach to improving regulatory exposure limits for toxic stimuli combinations, and a more expansive and expensive alternative to the recommended simplified approach. The recommended approach will partially compensate for the enhanced adverse effects of toxic stimuli combinations relative to adverse effects of toxic stimuli in isolation. The approach covers myriad categories of toxic stimuli reflective of real-life exposures due to lifestyle, iatrogenic, biotoxin, occupational/environmental, and psychosocial/socioeconomic conditions. The proposed approach 1) assumes that all potential toxic stimuli to which an individual might be exposed have the same mechanisms/modes of action on biological mechanisms, and are, thus, indistinguishable by the impacted organism; 2) normalizes the myriad stimuli by converting the doses of toxic stimuli exposures to the respective toxicity reference values (TRV) fractions; 3) sums all the TRVs fractions from these toxic stimuli exposures; and 4) divides all the single substance TRVs by the sum of fractions. While it is an additive approach conceptually, it differs from other additive approaches in the breadth of its inter-category coverage, in order to reflect true inter-category real-life simulation. The newly posited approach does not account for hormetic, antagonistic, or synergistic effects of toxic stimuli in combination. It does not adjust for 1) low-dose toxicants with adverse effects that have been under-reported, or 2) exposure limits like the Occupational Safety and Health Administration - Permissible Exposure Limits (OSHA PELs) that are orders of magnitude above levels shown by published single toxic stimuli studies to have caused adverse effects. Practical considerations for the application of this approach are presented.

Adverse health effects of 5G mobile networking technology under real-life conditions.

This article identifies adverse effects of non-ionizing non-visible radiation (hereafter called wireless radiation) reported in the premier biomedical literature. It emphasizes that most of the laboratory experiments conducted to date are not designed to identify the more severe adverse effects reflective of the real-life operating environment in which wireless radiation systems operate. Many experiments do not include pulsing and modulation of the carrier signal. The vast majority do not account for synergistic adverse effects of other toxic stimuli (such as chemical and biological) acting in concert with the wireless radiation. This article also presents evidence that the nascent 5G mobile networking technology will affect not only the skin and eyes, as commonly believed, but will have adverse systemic effects as well.

[Comment] COVID­19 vaccine safety.

In response to the SARS­CoV­2 outbreak, and the resulting COVID­19 pandemic, a global competition to develop an anti­COVID­19 vaccine has ensued. The targeted time frame for initial vaccine deployment is late 2020. The present article examines whether short­term, mid­term, and long­term vaccine safety can be achieved under such an accelerated schedule, given the myriad vaccine­induced mechanisms that have demonstrated adverse effects based on previous clinical trials and laboratory research. It presents scientific evidence of potential pitfalls associated with eliminating critical phase II and III clinical trials, and concludes that there is no substitute currently available for long­term human clinical trials to ensure long­term human safety.

Vaccine- and natural infection-induced mechanisms that could modulate vaccine safety.

A degraded/dysfunctional immune system appears to be the main determinant of serious/fatal reaction to viral infection (for COVID-19, SARS, and influenza alike). There are four major approaches being employed or considered presently to augment or strengthen the immune system, in order to reduce adverse effects of viral exposure. The three approaches that are focused mainly on augmenting the immune system are based on the concept that pandemics/outbreaks can be controlled/prevented while maintaining the immune-degrading lifestyles followed by much of the global population. The fourth approach is based on identifying and introducing measures aimed at strengthening the immune system intrinsically in order to minimize future pandemics/outbreaks. Specifically, the four measures are: 1) restricting exposure to virus; 2) providing reactive/tactical treatments to reduce viral load; 3) developing vaccines to prevent, or at least attenuate, the infection; 4) strengthening the immune system intrinsically, by a) identifying those factors that contribute to degrading the immune system, then eliminating/reducing them as comprehensively, thoroughly, and rapidly as possible, and b) replacing the eliminated factors with immune-strengthening factors. This paper focuses on vaccine safety. A future COVID-19 vaccine appears to be the treatment of choice at the national/international level. Vaccine development has been accelerated to achieve this goal in the relatively near-term, and questions have arisen whether vaccine safety has been/is being/will be compromised in pursuit of a shortened vaccine development time. There are myriad mechanisms related to vaccine-induced, and natural infection-induced, infections that could adversely impact vaccine effectiveness and safety. This paper summarizes many of those mechanisms.

The under-reported role of toxic substance exposures in the COVID-19 pandemic.

Coronavirus disease 2019 (COVID-19) and previous pandemics have been viewed almost exclusively as virology problems, with toxicology problems mostly being ignored. This perspective is not supported by the evolution of COVID-19, where the impact of real-life exposures to multiple toxic stressors degrading the immune system is followed by the SARS-CoV-2 virus exploiting the degraded immune system to trigger a chain of events ultimately leading to COVID-19. This immune system degradation from multiple toxic stressors (chemical, physical, biological, psychosocial stressors) means that attribution of serious consequences from COVID-19 should be made to the virus-toxic stressors nexus, not to any of the nexus constituents in isolation. The leading toxic stressors (identified in this study as contributing to COVID-19) are pervasive, contributing to myriad chronic diseases as well as immune system degradation. They increase the likelihood for comorbidities and mortality associated with COVID-19. For the short-term, tactical/reactive virology-focused treatments are of higher priority than strategic/proactive toxicology-focused treatments, although both could be implemented in parallel to reinforce each other. However, for long-term pandemic prevention, toxicology-based approaches should be given higher priority than virology-based approaches. Since current COVID-19 treatments globally ignore the toxicology component almost completely, only limited benefits can be expected from these treatments.

[Editorial] COVID­19: Post­lockdown guidelines.

Since March, 2020, in response to the COVID­19 pandemic, many countries have been on lockdown (at different levels of severity), restricting many activities and businesses that involve gatherings of large numbers of people in close proximity. Currently (early June, 2020), countries across the globe are in different stages of easing lockdown restrictions. Public policies for behaviors and actions during this transition period vary widely across countries and within country jurisdictions. The present editorial will address potential policies that could minimize resurgence of the present pandemic (the 'second­wave') and reduce the likelihood and severity of similar future pandemics.

COVID­19 in Northern Italy: An integrative overview of factors possibly influencing the sharp increase of the outbreak (Review).

Italy is currently one of the countries seriously affected by the COVID­19 pandemic. As per 10 April 2020, 147,577 people were found positive in a total of 906,864 tests performed and 18,849 people lost their lives. Among all cases, 70.2% of positive, and 79.4% of deaths occurred in the provinces of Northern Italy (Lombardi, Emilia Romagna, Veneto and Piemonte), where the outbreak first started. Originally, it was considered that the high number of positive cases and deaths in Italy resulted from COVID­19 initially coming to Italy from China, its presumed country of origin. However, an analysis of the factors that played a role in the extent of this outbreak is needed. Evaluating which factors could be specific for a country and which might contribute the most is nevertheless complex, with accompanying high uncertainty. The purpose of this work is to discuss some of the possible contributing factors and their possible role in the relatively high infection and death rates in Northern Italy compared to other areas and countries.

Towards effective COVID­19 vaccines: Updates, perspectives and challenges (Review).

In the current context of the pandemic triggered by SARS-COV-2, the immunization of the population through vaccination is recognized as a public health priority. In the case of SARS­COV­2, the genetic sequencing was done quickly, in one month. Since then, worldwide research has focused on obtaining a vaccine. This has a major economic impact because new technological platforms and advanced genetic engineering procedures are required to obtain a COVID­19 vaccine. The most difficult scientific challenge for this future vaccine obtained in the laboratory is the proof of clinical safety and efficacy. The biggest challenge of manufacturing is the construction and validation of production platforms capable of making the vaccine on a large scale.