key: cord-0718009-dljqpvyk
authors: Kostoff, Ronald N.; Kanduc, Darja; Porter, Alan L.; Shoenfeld, Yehuda; Calina, Daniela; Briggs, Michael B.; Spandidos, Demetrios A.; Tsatsakis, Aristidis
title: Vaccine- and natural infection-induced mechanisms that could modulate vaccine safety
date: 2020-10-22
journal: Toxicol Rep
DOI: 10.1016/j.toxrep.2020.10.016
sha: 2da3281c81b1bd38dfcd58424a65ed5a0a5c9e88
doc_id: 718009
cord_uid: dljqpvyk

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.

. There are a number of similarities among these three infectious diseases, including abnormal values of selected biomarkers (e.g., neutrophils, lymphocytes, albumin, CRP, TNF-alpha, etc.), pulmonary inflammation, pulmonary damage, etc. The most important similarity among these infectious diseases is the demographic affected most severely [2] . This demographic tends to be the elderly, with comorbidities and degraded/dysfunctional immune systems, and others with degraded/dysfunctional immune systems [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] . While there is some decline in the immune system with age, comorbidity is a stronger predictor of impaired immunity than chronological age in older adults [14] [15] .

There are also similarities between COVID-19 and influenza: "Both (COVID-19 and influenza) cause fever, cough, body aches and fatigue; sometimes vomiting and diarrhea; can be mild or severe, even fatal in rare cases; can result in pneumonia" [16] . Additionally, "Neither virus is treatable with antibiotics, which only work on bacterial infections; both are treated by addressing symptoms, such as reducing fever; severe cases may require hospitalization and support such as mechanical ventilation" [16, 17] . Both COVID-19 and influenza share the demographic affected most severely, as well.

The main measures being taken to control the spread of the SARS-CoV-2 coronavirus (the virus mainly associated with are conceptually those that were taken to control the spread of the SARS-CoV coronavirus in 2002-2003: good hygiene and quarantine (lockdown). The difference is the scale of these measures. Currently, many countries are on lockdown (at different levels of severity), restricting many activities and businesses that involve gatherings of large numbers of people in close proximity. As of early October, 2020, it is unknown how long these restrictions will be in place.

In addition to identifying short-term adverse vaccine effects related to the mechanisms, this paper identifies potential mid-and long-term adverse vaccine effects that cannot be identified in short-term human clinical trials characteristic of vaccine efficacy testing. To ensure vaccine safety, long-term human testing under real-life conditions (exposures to multiple toxic stimuli) is J o u r n a l P r e -p r o o f required. There is an incompatibility between the accelerated vaccine development times being pursued by government and industry and the long times required for validation of vaccine safety.

In summary, it is difficult to see how safe COVID-19 vaccines can be developed and fully tested for safety on development time scales of one or two years, as proposed presently.

The only real protection against a future COVID-19 pandemic or any other viral pandemic/outbreak is the one that was demonstrated to work in the SARS, MERS, and COVID-19 pandemics/outbreaks, and in the annual influenza pandemics/outbreaks: a healthy immune system capable of neutralizing incoming viruses as nature intended.

There are myriad efforts being pursued to develop treatments and preventative measures for COVID-19. Some of these will now be outlined.

If treatments are defined as a set of actions that improve health, then (at least) two types of treatments are possible.

The first type can be defined as positive treatments. They can be sub-divided into hightech treatments and low-tech treatments.

The high-tech are the classical treatments where drugs (or supplements) and/or radiation and/or surgery are implemented, and symptoms are alleviated. These high-tech positive treatments are basically a reactive tactical response to abnormal markers of health. They can be applied for the short-term (e.g., antibiotics for bacterial infections, antivirals for viral infections, etc.) [18, 19] , or for the long-term (e.g., statins, blood thinners, antihypertensives, etc.) [20] . The low-tech treatments involve dietary supplements or natural bioactive compounds [21] [22] [23] , sleep, and other behavioral changes shown to impact the immune system positively (see section A4-C of our previous COVID-19 monograph [13] for a bibliography of low-tech immune system strengthening factors). For long-term benefit, these low-tech treatments need to be maintained indefinitely [24] . On average, the high-tech treatments have greater risk than the low-tech treatments.

The second type can be defined as negative-negative treatments, where those factors that contribute to disease are first identified and then removed. The name derives from the mathematics world, where a negative of a negative is a positive [25] . These negative-negative treatments are basically a proactive strategic response to abnormal markers of health, and J o u r n a l P r e -p r o o f for one viral infection, people with degraded/dysfunctional immune systems will again be vulnerable to serious infectious consequences from exposure to the next harmful virus they encounter.

The proactive strategic treatment approach will strengthen the immune (and other) system by removing those critical factors that contribute to disease and a degraded/dysfunctional immune system (unless irreversible damage has been done to the immune system, or individuals possess congenital or other hereditary damage to their immune system) [38] [39] [40] . These strategic treatments tend to require long-term adherence by their recipients. In turn, these recipients of strategic treatments will be less vulnerable to infection from exposure to the next pathogenic virus they encounter (SARS-CoV-2 or otherwise). Like many healthy people who were exposed to SARS-CoV and SARS-CoV-2, these people who follow the (typically) long-term proactive strategic treatment regimen successfully may not even be aware they have been exposed to, or infected by, the coronavirus. The only indication of their infection will be coronavirus antibodies in their serum.

A hybrid methodology was used to identify references showing potential long-term adverse effects of vaccines and vaccine/infection-induced mechanisms that could contribute to these adverse effects. Based on reading myriad vaccine adverse effects review articles, terms showing mechanisms were extracted (e.g., antibody-dependent enhancement, viral interference, route of infection, original antigenic sin, etc), and used as a Medline query to retrieve potentially relevant articles. All these retrieved articles were read, and the most relevant ones extracted.

Their titles were entered into the Web of Science, and the citation network was explored (citing papers, cited papers, papers that shared common references, etc). Those records were read, and the most relevant ones extracted for this monograph.

The main body of our previous COVID-19 monograph [12] addressed the first type of strategic treatment: 1) identification and removal of factors contributing to weakening the immune system (see section A4-A of the previous monograph [12] for a table of these contributing factors), and 2) identification and addition of factors contributing to strengthening the immune system (see section A4-C of the previous monograph [12] for a bibliography of low-J o u r n a l P r e -p r o o f tech immune system strengthening factors). The present section addresses the second type of strategic treatment: development and implementation of a COVID-19 vaccine. The prospects for such a vaccine will be addressed from three criteria perspectives: development time, efficacy, and safety.

Calina et al. evaluated the ongoing approaches to COVID-19 vaccine development, and stated: "Normally, the period of development of a vaccine is 12-15 years" [41] . Against this backdrop, SARS-CoV-2 vaccines are targeted for accelerated development, safety testing, manufacturing, and distribution by an order of magnitude [42] . Each of the accelerated steps [41] has drastically reduced the time required from normal development. Some of the potential adverse vaccine effects shown on the right of Figure 1 may take years to emerge, well after the initial abbreviated vaccine safety testing period. According to a comprehensive 2020 article on SARS and MERS vaccine development [44] , "As of April 2020, no vaccine is commercially available for these coronavirus strains".

The rationale for lack of a vaccine is given by the following: "Reasons for the lack of commercial and effective vaccines for SARS and MERS are varied. In the case of MERS, it is likely that the vaccine development was delayed because of the scarcity of suitable and costeffective small animal models during pre-clinical experimentation. In addition, it is probable that a vaccine has not been delivered because of the low interest in investing in a vaccine for a disease that has produced relatively low and geographically centralized cases (compared with other more global and persistent infectious diseases such as influenza, HIV and tuberculosis).

This last factor might have also contributed to the lack of a vaccine for SARS, in the sense that it was considered pointless to continue investing in a vaccine for a disease whose cases ceased to 

The main challenges facing successful coronavirus vaccine development can be summarized as time to development, efficacy of the vaccine and, most importantly, safety of the vaccine. A complementary perspective on some of the problems listed in [41] can be stated as follows:

First, although the virus's spike protein is a promising immunogen for protection, optimizing antigen design is critical to ensure optimal immune response. Debate continues over the best approachfor example, targeting the full-length protein or only the receptor-binding domain.

Second, preclinical experience with vaccine candidates for SARS and the Middle East respiratory syndrome (MERS) have raised concerns about exacerbating lung disease, either directly or as a result of antibody-dependent enhancement. Such an adverse effect may be associated with a type 2 helper T-cell (Th2) response. Hence, testing in a suitable animal model and rigorous safety monitoring in clinical trials will be critical" [47] .

Numerous mid-and longer-term potential issues concerning vaccines have been identified. Their themes are summarized initially, followed by excerpts from specific cited references. 

The previous section addressed mechanisms that could potentially enhance infections, rather than attenuate or prevent them. The present section addresses empirical findings of low vaccine effectiveness, where mechanistic explanations may or may not have been offered.

Because of similarities between influenza and COVID-19, and space limitations, the focus will be on the influenza vaccination experience. Significant influenza VE could not be demonstrated for any season, age, or setting after adjusting for county, sex, insurance, chronic conditions recommended for influenza vaccination, and timing of influenza vaccination. [127] . We found a threefold increased risk of hospitalization in subjects who did get the TIV vaccine.

[128].

Using data from traditional control subjects, VE for those seasons was estimated to be 5% (95% CI, -52% to 40%), 11% (95% CI, -96% to 59%), and 37% (95% CI, -10% to 64%), respectively; confidence intervals included 0 [129] . Participants reporting pH1N1-related ILI during the period 1 April through 5 June 2009 were more than twice as likely to report having previously received seasonal influenza vaccine [130] . Unvaccinated children had more flu-specific CTLs than vaccinated children with CF [131] .

Following 2009 H1N1 vaccination, subjects previously given a seasonal influenza virus vaccination exhibited significantly lower antibody responses, as determined by hemagglutination inhibition assay, than subjects who had not received the seasonal influenza virus vaccination [132] . Our study confirms the results from our previous interim report, and other studies, that failed to demonstrate benefit or harm from receipt of seasonal influenza vaccine in patients with confirmed infection with pandemic influenza H1N1 2009. [133] . Influenza vaccination seemed to be associated with an increased risk of non-influenza respiratory virus infections, which is consistent with temporary nonspecific immunity. [134] . A potential doubling of pandemic infection risk among prior seasonal vaccine recipients could be disastrous in the event of a more severe pandemic involving a higher per-case fatality risk" [135] . -Influenza Vaccine FLUARIX QUADRIVALENT has not been evaluated for carcinogenic or mutagenic potential or male infertility in animals.

-DTAP Vaccine INFANRIX has not been evaluated for carcinogenic or mutagenic potential or for impairment of fertility.

-HPV Vaccine (137) GARDASIL 9 has not been evaluated for the potential to cause carcinogenicity, genotoxicity or impairment of male fertility.

Long-term safety studies of vaccines are rare. The typical vaccine study is aimed at efficacy.

Such studies tend to be a few months long, and the main evaluation criterion is titers of antibody in the serum.

Vaccines, especially childhood vaccines, are administered according to a schedule, which now comprises about seventy+ doses covering about sixteen vaccines. The schedule-based combination effects of these seventy+ vaccine doses have not been tested, and, therefore, adverse effects due to real-life vaccine synergies are unknown. Such vaccine combination experiments cannot be limited to the pristine environment of the laboratory, but require testing in humans who are exposed to myriad toxic stimuli that could impact vaccine combination synergies.

Much of the published data for vaccine adverse events (at least in the USA) originates from the Vaccine Adverse Event Reporting System (VAERS) database. VAERS is a passive monitoring system, and, like all similar systems, suffers from substantial under-reporting of adverse events [138] . A groundbreaking study [139] , performed by Harvard Pilgrim Healthcare, Inc, reported that fewer than 1% of vaccine adverse events are reported. In other words, the actual numbers of adverse reactions to vaccines are one to two orders of magnitude higher than those reported in VAERS! The methodology used by Harvard Pilgrim Healthcare. Inc, for obtaining this result was as follows: Every patient receiving a vaccine was automatically identified, and for the next 30 J o u r n a l P r e -p r o o f days, their health care diagnostic codes, laboratory tests, and medication prescriptions are evaluated for values suggestive of an adverse vaccine event. When a possible adverse event was detected, it was recorded, and the appropriate clinician was to be notified electronically.

Thus, these adverse events that were identified are single-visit short-term adverse events (within thirty days of the vaccination). They do not reflect the results of vaccination combinations administered over a longer period than thirty days, and they do not reflect results of vaccinations of any type in the mid-or long-term [139] .

If fewer than 1% of vaccine adverse events are reported, how well does this sample reflect the total number of adverse events actually experienced? This is not a randomly-selected sample, as would be required for a statistically-valid result. Thus, even analyses of short-term adverse effects based on VAERS data are severely flawed. And, if fewer than 1% of these shortterm adverse events are reported, what fraction of longer-term adverse events (where the connection between the adverse event and the vaccination becomes more tenuous as time proceeds) would be reported? One can only conclude that a negligible fraction of long-term adverse events is reported in a passive monitoring system like VAERS. Immunization with pediatric vaccines increased the risk of insulin diabetes in NOD mice…..Exposure to HiB immunization is associated with an increased risk of IDDM. NOD mice can be used as an animal model of vaccine induced diabetes. [144] .

As the above results have shown, vaccines can have long-term impacts on the immune system (positive and negative), and short and long-term effects on other diseases. The effects of vaccines can vary according to route of infection, prior history of vaccinations, and, as stated by Benn et al above, administration "with other vaccines, drugs, or micronutrients and in different sequences. [78] . To accelerate the time required to demonstrate long-term safety, laboratory experiments are usually done using animals with relatively short lifespans whose responses to myriad toxic stimuli are similar to that of human beings. The other alternative is to perform these safety studies with human beings. For long-term safety studies (e.g., potential vaccine effects on initiating cancer or Alzheimer's Disease), decades could be required for credible results. Thus, there is a major disconnect between the time required for credible safety studies of a COVID-19 vaccine and the one-year or less vaccine commercialization being propounded by decision-makers and the media today.

The above analyzed COVID-19 vaccine safety considerations become even more cogent in light of the fact that cross-reactivity might represent the mechanism underlying the immunopathology and the disease multitude associated with the coronavirus infection [145] . The rationale is that the sharing of peptides between SARS-CoV-2 and human proteins might trigger immune responses hitting not only the virus but also the human proteins, with consequent autoimmune pathologies in the human host [146] . Hence, the massive viral vs. human peptide J o u r n a l P r e -p r o o f commonalities described since 2000 [147, 148] clearly explain how the protective anti-viral antibody immune response can become a pathogenic autoimmune attack against the human organism, thereby addressing the issue of why SARS-CoV-2 attacks the respiratory system so heavily [149] . The scientific cross-reactivity context and the clinical data showing that immunization with SARS-CoV antigens causes severe pneumonia [150] suggest a prominent pathogenic role of anti-SARS-CoV antibodies in COVID-19. In fact, emerging reports show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection precedes the appearance of various autoimmune and autoinflammatory diseases, including pediatric inflammatory multisystemic syndrome or multisystem inflammatory syndrome in children [151, 152] . Simply put, the current race for obtaining a highly immunogenic anti-SARS-CoV-2 vaccine might actually equate to a race for producing a highly lethal vaccine also in light of the fact that adjuvanted anti-SARS-CoV-2 would have a higher immunogenicity and autoimmune pathogenicity when compared to SARS-CoV-2 infection. This risk of cross-reactivity further increases when considering that it cannot be estimated with the current vaccine pre-clinical tests [153, 154] . Indeed, the level of peptide sharing is highest between pathogens and human, murine, and rat proteomes, and is lowest (or absent) with proteomes from nonhuman primates such as gorilla, chimpanzee, and rhesus macaque. That is, from the genetic point of view, primates are unreliable animal models for revealing potential autoimmune cross-reactions in preclinical testing of immunotherapies since, obviously, no crossreactions can occur in primates in absentia of shared sequences.

On the whole, the data exposed above open new scenarios in vaccinology by confirming the basic concept first stated in 2000 [147] and then illustrated repeatedly [155] [156] [157] [158] , according to which only peptide sequences derived from pathogens and absent in the human proteome, i.e., 'non-self' peptides', can lead to safe and efficacious immunotherapies.

The issues discussed previously can be viewed as micro-level issues. The focus is at the cellular-virus-antibody level. These micro-level issues need to be understood within the larger context of macro-level issues. Two of these macro issues will be discussed in the present section. 

In the evolution of COVID-19, 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 the disease. A person with such a degraded immune system is more vulnerable to infections and other health assaults.

Assume that person is given a vaccine to 'protect' against a specific virus. How does it perturb the immune system?

The vaccination is designed to provide a local optimization; it is not designed to provide a global optimization. A successful vaccine may offer some increased protection against the specific viral strain in the vaccine, ranging from one season to a lifetime. What protection does it offer against other strains of the same virus, or other viruses? Does it enhance or decrease protection against other challenges, such as the rapid cell increases characteristic of cancer?

One of the mechanisms examined previously is vaccine-Associated Virus Enhancement (where vaccinated individuals may be at increased risk for other respiratory viruses because they do not receive the non-specific immunity associated with natural infection). This phenomenon doesn't always happen, but it can happen. Its occurrence would strengthen the argument for local optimization, where protection is increased against one viral strain at the expense of reduced protection against another viral strain. Given that (on average) measures are not being taken to reverse the immune system degradation in parallel with administering a vaccine, adding a vaccine may improve one type of protection but degrade another type. The immune system remains degraded, and it will express its limitations against other challenges. Considering the military logistics analogy of the immune system, forces/supplies are being withdrawn from one Front to increase defensive capabilities on another Front. Since overall forces or supplies have not been increased, net overall capabilities have not increased, and, to first order, the vacated Front becomes more vulnerable.

As mentioned previously, many (if not all) vaccine inserts state that the vaccine has not been tested for carcinogenicity (and mutagenicity and fertility) impacts. Such carcinogenicity testing would require long-term tracking and establishing a credible link between the vaccine administered long ago and the onset of cancer. There are few incentives for the developers and J o u r n a l P r e -p r o o f regulatory agencies (who tend to be vaccine promoters, especially for a COVID-19 vaccine) to conduct such safety tests; finding e.g. a vaccine-cancer or vaccine-fertility or vaccine-AD link would present major problems. But, if the local/global optimization concept is correct, such a link may be possible, or even greater than possible. Unless the immune system is intrinsically strengthened, it is difficult to see how its operations can be improved in one sector without reducing performance in another sector. Otherwise, vaccines could be developed against every conceivable challenge, and compensate for the degraded immune system.

There is a more fundamental problem with vaccines and other members of the vast armamentarium employed by most of modern-day medicine to treat chronic and infectious diseases. Assume that one of the main operational functions of the body (not subjected to hereditary-based dysfunctions or autoimmune dysfunctionality) is to heal itself continuously.

One of the healing mechanisms is signaling when the body is being exposed to harmful substances or harmful behaviors, in order to motivate the elimination of these harmful inputs.

Since the body can't speak vocally, it communicates through the language of symptoms. Rather than listen to the symptoms and take steps to eliminate the offending substances/behaviors, modern medicine uses the approaches of drugs/radiation/surgery and other therapies to attenuate the symptoms. Since the fundamental problem has not been eliminated by the symptomsuppression treatment(s), the body is forced to increase signaling through stronger symptoms, which may emerge short-term or long-term, and could range from modest to lethal. It is inconceivable how such an approach can lead to true healing/disease reversal.

As an example, the first author's group did a study to develop a protocol that would prevent and reverse Alzheimer's disease (AD) [159] . As part of the study, Dr. Dale Bredesen, a neurologist who had developed an AD reversal approach, was referenced and quoted as follows:

"In the case of Alzheimer's disease, there is not a single therapeutic that exerts anything beyond a marginal, un-sustained symptomatic effect, with little or no effect on disease progression. Furthermore, in the past decade alone, hundreds of clinical trials have been conducted for AD, at an aggregate cost of billions of dollars, without success. This has led some to question whether the approach taken to drug development for AD is an optimal one [160] ." That statement could apply in different degrees to myriad chronic diseases. In fact, it is challenging to identify a chronic disease to which that statement does not apply! J o u r n a l P r e -p r o o f

The situation may even be worse with vaccines. Most drugs and other therapies are required to undergo modest short-, mid-, and long-term testing for myriad adverse health effects.

One motivator for this range of testing is that the manufacturers/vendors of these therapies can be held liable for damage suffered as a result of their products. Vaccine manufacturers today have waivers from these liabilities (at least in the USA) because of the National Childhood Vaccine Injury Act (NCVIA) of 1986 passed by Congress. So, the financial motivation for thorough testing does not exist for vaccines. Additionally, vaccines are not tested for enhancement or stimulation of serious diseases, as stated previously.

Literature surveys show that vaccines are rarely tested for mid-term adverse effects, and certainly not tested for long-term adverse effects. They are not tested for combinations as administered over time on a prescribed schedule, and they are not laboratory-tested in combination with other toxic substances. There appears to be little interest from the manufacturers or researchers in discovering/identifying these adverse effects. This disinterest is most pronounced in the present efforts to have a COVID-19 vaccine on the market, perhaps made mandatory, within a year after starting development. There cannot be any credible safety testing under such a schedule [161] . There are many potential adverse health effects that can result from vaccine-induced mechanisms, as our present study has shown, and these effects could emerge in the near-term or the long-term. To require the young people (who are not at risk from the most serious consequences of COVID-19) to take such vaccines with potential serious longterm consequences is unjustifiable.

The following is focused on the USA experience, and probably is relevant to most other Local governments, dissenting voices have to make themselves heard through venues other than peer-reviewed publications in mainline journals .This is a perversion of the scientific process, which requires that all knowledgeable voices be heard, and results in a published literature of questionable credibility.

Four types of treatments are being used in different degrees to help counter the COVID-19 pandemic: reducing viral transmission (quarantine, face masks, social distancing, use of sanitizers, etc); treatments (mainly repurposed anti-viral drugs); vaccines (under development);

immune system strengthening (eliminating immune degrading toxic stimuli; adding immune enhancing behaviors/substances). The first three types can be viewed as immune-augmenting; the last type is immune-strengthening.

Reducing viral transmission may offer some benefit, but has proven to be damaging psychologically and economically. Anti-viral treatments have had mixed results, and none have achieved consensus within the medical community. Vaccines are under accelerated development. Lifestyle and regulatory changes to strengthen the immune system have been minimal Vaccines are being promoted by the healthcare industry, politicians, decision-makers, and the mainstream media as the best hope for containing the COVID-19 pandemic, and this is reflected in the funding their accelerated development is receiving (Moderna, a leading COVID-19 vaccine contender, has "scored $2.48 billion in R&D and supply funding from the U.S. government for its program" [161] ). The goal appears to be initial vaccine distribution by around end of 2020, although it is questionable whether such an accelerated vaccine development program would include adequate mid-term and long-term safety testing [161] . The present study examined many viral mechanisms that could lead to vaccines exacerbating rather than attenuating viral infection, based on findings from [162] . Generically, the main problem is that prior viral exposure (vaccine-induced or wild/natural) could impact future viral exposure (vaccine-induced or wild/natural) positively or negatively. Years could be required to determine which outcome would result, both in the short-term and in the long-term.

Additionally, many chronic diseases have been shown to result from viral exposure, and years of tracking in human trials could be required to determine which, if any, of these diseases would result from a COVID-19 vaccine. Possibly safer (non-autoimmunity-inducing) vaccines could result using peptide sequences derived from pathogens and absent in the human proteome, although the degree of safety enhancement might require years of tracking to determine.

Conceptualization: RNK, ALP and MBB; validation, research, resources, data reviewing, and writing: RNK, DK, ALP, YS, DC, MBB, DAS, AT; review and editing: DC, YS, DK, AT, and RNK. All authors contributed equally, read and approved the final manuscript.

No funding was received.

Not applicable.

The authors declare no conflict of interest. 

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AIDS vaccination studies using an ex vivo feline immunodeficiency virus model: failure to protect and possible enhancement of challenge infection by four cell-based vaccines prepared with autologous lymphoblasts

FIV vaccine with receptor epitopes results in neutralizing antibodies but does not confer resistance to challenge

Innate immune evasion strategies of influenza viruses

Regulation and evasion of antiviral immune responses by porcine reproductive and respiratory syndrome virus

Complement Evasion Strategies of Viruses: An Overview. Frontiers in microbiology

Modulation of the immune response by Middle East respiratory syndrome coronavirus

Reduction of anti-HIV-1 Gag immune responses during co-immunization: immune interference by the HIV-1 envelope

Immune interference after sequential alphavirus vaccine vaccinations

Pre-existing yellow fever immunity impairs and modulates the antibody response to tick-borne encephalitis vaccination

Combined single-clade candidate HIV-1 vaccines induce T cell responses limited by multiple forms of in vivo immune interference

Original Antigenic Sin: How First Exposure Shapes Lifelong Anti-Influenza Virus Immune Responses

Original antigenic sin: A comprehensive review

The impact of vaccination on influenzarelated respiratory failure and mortality in hospitalized elderly patients over the 2013-2014 season. The open respiratory medicine journal

Prior infection with influenza virus but not vaccination leaves a long-term immunological imprint that intensifies the protective efficacy of antigenically drifted vaccine strains

Negative impact of prior influenza vaccination on current influenza vaccination among people infected and not infected in prior season: A test-negative case-control study in Japan

Clinical infectious diseases: an official publication of the Infectious Diseases Society of America

Impact of repeated vaccination on vaccine effectiveness against influenza A(H3N2) and B during 8 seasons

The Effect of

Influenza Vaccination History on Changes in Hemagglutination Inhibition Titers After Receipt of the 2015-2016 Influenza Vaccine in Older Adults in Hong Kong. The Journal of infectious diseases

Influenza vaccination in the elderly: 25 years follow-up of a randomized controlled trial. No impact on long-term mortality

Clinical infectious diseases: an official publication of the Infectious Diseases Society of America

Innate and secondary humoral responses are improved by increasing the time between MVA vaccine immunizations

Decline in influenza vaccine effectiveness with time after vaccination, Navarre, Spain, season 2011/12. Euro surveillance: bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin

Dose-Dependent Negative Effects of Prior Multiple Vaccinations Against Influenza A and Influenza B Among Schoolchildren: A Study of Kamigoto Island in Japan During the

Change in the efficacy of influenza vaccination after repeated inoculation under antigenic mismatch: A systematic review and meta-analysis. Vaccine

Vaccine-induced anti-HA2 antibodies promote virus fusion and enhance influenza virus respiratory disease

Influenza A virus hemagglutinin protein subunit vaccine elicits vaccine-associated enhanced respiratory disease in pigs

Heterologous challenge in the presence of maternally-derived antibodies results in vaccine-associated enhanced respiratory disease in weaned piglets

Chronic Immune Activation in TB/HIV Co-infection

HIV-associated chronic immune activation

2 influenza seasons: a case-cohort study. Archives of pediatrics & adolescent medicine

Effectiveness of trivalent inactivated influenza vaccine in influenza-related hospitalization in children: a case-control study. Allergy and asthma proceedings

Effectiveness of inactivated influenza vaccines varied substantially with antigenic match from the 2004-2005 season to the 2006-2007 season. The Journal of infectious diseases

Seasonal influenza vaccine and increased risk of pandemic A/H1N1-related illness: first detection of the association in British Columbia, Canada. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

Annual influenza vaccination affects the development of heterosubtypic immunity

Reduced antibody responses to the pandemic (H1N1) 2009 vaccine after recent seasonal influenza vaccination

Pandemic influenza H1N1 2009 infection in Victoria, Australia: no evidence for harm or benefit following receipt of seasonal influenza vaccine in 2009

Seasonal Influenza Vaccination and the Heightened Risk of Coronavirus and Other Pandemic Virus Infections: Fact or Fiction? Indian pediatrics

Evidence in a Cluster Randomized Controlled Trial of Increased 2009 Pandemic Risk Associated With 2008-2009 Seasonal Influenza Vaccine Receipt

Package Inserts and Manufacturers for some US Licensed Vaccines and Immunoglobulins. Institute for Vaccine Safety

Human papilloma virus: Apprehending the link with carcinogenesis and unveiling new research avenues (Review)

Relative trends in hospitalizations and mortality among infants by the number of vaccine doses and age, based on the Vaccine Adverse Event Reporting System (VAERS)

Electronic Support for Public Health-Vaccine Adverse Event Reporting System (ESP:VAERS)

Systemic immunotoxicity reactions induced by adjuvanted vaccines

Vaccines and autoimmune diseases of the adult

Vaccines and autoimmunity

A case-control study of serious autoimmune adverse events following hepatitis B immunization

Clustering of cases of insulin dependent diabetes (IDDM) occurring three years after hemophilus influenza B (HiB) immunization support causal relationship between immunization and IDDM

From Anti-SARS-CoV-2 Immune Responses to COVID-19 via Molecular Mimicry

Peptide cross-reactivity: the original sin of vaccines

Computer assisted analysis of molecular mimicry between human papillomavirus 16 E7 oncoprotein and human protein sequences

Massive peptide sharing between viral and human proteomes

On the molecular determinants of the SARS-CoV-2 attack

Autoimmune and inflammatory diseases following COVID-19

Covid-19 and autoimmunity

Molecular mimicry between SARS-CoV-2 spike glycoprotein and mammalian proteomes. Implications for the vaccine

Medical, genomic, and evolutionary aspects of the peptide sharing between pathogens, primates, and humans

Self-nonself" peptides in the design of vaccines

The self/nonself issue: A confrontation between proteomes

Immunogenicity, Immunopathogenicity, and Immunotolerance in One Graph

Anti-cancer agents in medicinal chemistry

From HBV to HPV: Designing vaccines for extensive and intensive vaccination campaigns worldwide

Prevention and reversal of Alzheimer's disease: treatment protocol. Georgia Institute of Technology

Reversal of cognitive decline: a novel therapeutic program

COVID-19 vaccine safety