Toxicology Reports

Toxicology Reports 7 (2020) 1448–1458
Contents lists available at ScienceDirect
Toxicology Reports
journal homepage: www.elsevier.com/locate/toxrep
Vaccine- and natural infection-induced mechanisms that could modulate

vaccine safety
Ronald N. Kostoff a, *, Darja Kanduc b, Alan L. Porter c, d, Yehuda Shoenfeld e, f, Daniela Calina g,
Michael B. Briggs h, Demetrios A. Spandidos i, Aristidis Tsatsakis f, j
a
Research Affiliate, School of Public Policy, Georgia Institute of Technology, Gainesville, VA, 20155, USA
b
Department of Biosciences, Biotechnologies, and Biopharmaceutics, University of Bari, 70125 Bari, Italy
c
School of Public Policy, Georgia Institute of Technology, Atlanta, GA, 30332, USA
d
Search Technology, Inc., Peachtree Corners, GA, 30092, USA
e
Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer 5265601, Israel
f
I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Sechenov University, Moscow, Russia
g
Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania
h
Independent Consultant, Roscommon, MI, 48653, USA
i
Laboratory of Clinical Virology, Medical School, University of Crete, 71409, Heraklion, Greece
j
Department of Forensic Sciences and Toxicology, Faculty of Medicine, University of Crete, 71003 Heraklion, Greece
A R T I C L E I N F O A B S T R A C T
Keywords: A degraded/dysfunctional immune system appears to be the main determinant of serious/fatal reaction to viral
COVID-19 pandemic infection (for COVID-19, SARS, and influenza alike). There are four major approaches being employed or
Vaccine safety considered presently to augment or strengthen the immune system, in order to reduce adverse effects of viral
Autoimmunity
exposure. The three approaches that are focused mainly on augmenting the immune system are based on the
Molecular mimicry
concept that pandemics/outbreaks can be controlled/prevented while maintaining the immune-degrading life
Cross-Reactivity
Immune interference styles 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 summa
rizes many of those mechanisms.
1. Introduction Severe Acute Respiratory Syndrome (SARS), 2002–2003; Middle East

Respiratory Syndrome (MERS), starting in 2012; COVID-19, starting in
1.1. Background December 2019 [1]. There are a number of similarities among these
three infectious diseases, including abnormal values of selected bio
Over the past two decades, there have been at least three major markers (e.g., neutrophils, lymphocytes, albumin, CRP, TNF-alpha,
coronavirus-based infectious disease outbreaks/epidemics/pandemics: etc.), pulmonary inflammation, pulmonary damage, etc. The most
* Corresponding author.
E-mail address: [email protected] (R.N. Kostoff).
https://doi.org/10.1016/j.toxrep.2020.10.016
Received 14 October 2020; Accepted 17 October 2020
Available online 22 October 2020
2214-7500/© 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
R.N. Kostoff et al. Toxicology Reports 7 (2020) 1448–1458
important similarity among these infectious diseases is the demographic The second type can be defined as negative-negative treatments,
affected most severely [2]. This demographic tends to be the elderly, where those factors that contribute to disease are first identified and
with comorbidities and degraded/dysfunctional immune systems, and then removed. The name derives from the mathematics world, where a
others with degraded/dysfunctional immune systems [1–13]. While negative of a negative is a positive [25]. These negative-negative
there is some decline in the immune system with age, comorbidity is a treatments are basically a proactive strategic response to abnormal
stronger predictor of impaired immunity than chronological age in older markers of health, and typically involve long-term changes in lifestyle
adults [14,15]. and harmful exposures for improved health [26–29].
There are also similarities between COVID-19 and influenza: “Both
(COVID-19 and influenza) cause fever, cough, body aches and fatigue; 1.3. Tactical treatments
sometimes vomiting and diarrhea; can be mild or severe, even fatal in
rare cases; can result in pneumonia” [16]. Additionally, “Neither virus is Much of the effort to help the most vulnerable COVID-19 de
treatable with antibiotics, which only work on bacterial infections; both mographic at this time has been searching for, and experimenting with,
are treated by addressing symptoms, such as reducing fever; severe cases treatments that were/are used to combat other (mainly) viral diseases
may require hospitalization and support such as mechanical ventilation” (aka repurposed treatments). These treatments include, but are not
[16,17]. Both COVID-19 and influenza share the demographic affected limited to: Actemra/Tocilizumab; Avigan/Favipiravir; Azithromycin;
most severely, as well. Baricitinib/Olumiant;
The main measures being taken to control the spread of the SARS- Bevacizumab/Avastin; Calquence/Acalabrutinib; Chloroquine; Col
CoV-2 coronavirus (the virus mainly associated with COVID-19) are crys/Colchicine; Convalescent Plasma; EIDD-2801; Fingolimod/Gile
conceptually those that were taken to control the spread of the SARS- nya; Galidesivir; Hydroxychloroquine; Ilaris/Canakinumab; Ivermectin;
CoV coronavirus in 2002− 2003: good hygiene and quarantine (lock Jakafi/Ruxolitinib; Kaletra/Lopinavir/Ritonavir; Kevzara/Sarilumab;
down). The difference is the scale of these measures. Currently, many Kineret/Anakinra; Leronlimab; Mavrilimumab; Methylprednisolone;
countries are on lockdown (at different levels of severity), restricting Olumiant/Baricitinib; Otezla/Apremilast; Remdesivir; Tamiflu/Oselta
many activities and businesses that involve gatherings of large numbers mivir; Umifenovir/Arbidol; Xeljanz/Tofacitinib [30–34].
of people in close proximity. As of early October 2020, it is unknown Other novel tactical treatments could be identified using our
how long these restrictions will be in place. Literature-Related Discovery and Innovation (LRDI)-based treatment
In addition to identifying short-term adverse vaccine effects related repurposing methodology [35,36].
to the mechanisms, this paper identifies potential mid-and long-term
adverse vaccine effects that cannot be identified in short-term human 1.4. Strategic treatments
clinical trials characteristic of vaccine efficacy testing. To ensure vaccine
safety, long-term human testing under real-life conditions (exposures to Strategic treatments were the focus of our previous COVID-19
multiple toxic stimuli) is required. There is an incompatibility between monograph [13]. Their identification is a two-step process. First,
the accelerated vaccine development times being pursued by govern markers of immune system health (ranging from specific biomarkers to
ment and industry and the long times required for validation of vaccine more general descriptors) are selected. Second, those substances (e.g.,
safety. smoking, excess alcohol, pesticides, etc.) behaviors (e.g., sedentary
In summary, it is difficult to see how safe COVID-19 vaccines can be lifestyle, substance abuse, etc.), and other toxic stimuli that degrade the
developed and fully tested for safety on development time scales of one levels of these markers (i.e., lead to immune dysfunction, immunotox
or two years, as proposed presently. The only real protection against a icity, immunosuppression, etc.) are then identified and recommended
future COVID-19 pandemic or any other viral pandemic/outbreak is the for elimination [37]. The strategic treatments identified in the previous
one that was demonstrated to work in the SARS, MERS, and COVID-19 monograph are those contained within the immune system core litera
pandemics/outbreaks, and in the annual influenza pandemics/out ture. Additional novel strategic treatments could also be identified using
breaks: a healthy immune system capable of neutralizing incoming vi our LRDI-based treatment repurposing methodology [35,36].
ruses as nature intended.
1.5. Reactive tactical vs proactive strategic treatments
1.2. Potential treatments
The reactive tactical treatment approach for countering infections
There are myriad efforts being pursued to develop treatments and from viral exposure improves biomarker levels and reduces symptoms
preventative measures for COVID-19. Some of these will now be (if successful), but ordinarily does little to improve the body’s resistance
outlined. to disease. For viral infections, the tactical treatments will do little to
If treatments are defined as a set of actions that improve health, then strengthen the degraded/dysfunctional immune (and other) system.
(at least) two types of treatments are possible. After tactical treatments for one viral infection, people with degraded/
The first type can be defined as positive treatments. They can be sub- dysfunctional immune systems will again be vulnerable to serious in
divided into high-tech treatments and low-tech treatments. fectious consequences from exposure to the next harmful virus they
The high-tech are the classical treatments where drugs (or supple encounter.
ments) and/or radiation and/or surgery are implemented, and symp The proactive strategic treatment approach will strengthen the im
toms are alleviated. These high-tech positive treatments are basically a mune (and other) system by removing those critical factors that
reactive tactical response to abnormal markers of health. They can be contribute to disease and a degraded/dysfunctional immune system
applied for the short-term (e.g., antibiotics for bacterial infections, an (unless irreversible damage has been done to the immune system, or
tivirals for viral infections, etc.) [18,19], or for the long-term (e.g., individuals possess congenital or other hereditary damage to their im
statins, blood thinners, antihypertensives, etc.) [20]. The low-tech mune system) [38–40]. These strategic treatments tend to require
treatments involve dietary supplements or natural bioactive com long-term adherence by their recipients. In turn, these recipients of
pounds [21–23], sleep, and other behavioral changes shown to impact strategic treatments will be less vulnerable to infection from exposure to
the immune system positively (see section A4-C of our previous the next pathogenic virus they encounter (SARS-CoV-2 or otherwise).
COVID-19 monograph [13] for a bibliography of low-tech immune Like many healthy people who were exposed to SARS-CoV and
system strengthening factors). For long-term benefit, these low-tech SARS-CoV-2, these people who follow the (typically) long-term proac
treatments need to be maintained indefinitely [24]. On average, the tive strategic treatment regimen successfully may not even be aware
high-tech treatments have greater risk than the low-tech treatments. they have been exposed to, or infected by, the coronavirus. The only
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indication of their infection will be coronavirus antibodies in their factors contributing to weakening the immune system (see section A4-A
serum. of the previous monograph [12] for a table of these contributing fac
tors), and 2) identification and addition of factors contributing to
2. Methodology strengthening the immune system (see section A4-C of the previous
monograph [12] for a bibliography of low-tech immune system
A hybrid methodology was used to identify references showing po strengthening factors). The present section addresses the second type of
tential long-term adverse effects of vaccines and vaccine/infection- strategic treatment: development and implementation of a COVID-19
induced mechanisms that could contribute to these adverse effects. vaccine. The prospects for such a vaccine will be addressed from three
Based on reading myriad vaccine adverse effects review articles, terms criteria perspectives: development time, efficacy, and safety.
showing mechanisms were extracted (e.g., antibody-dependent Calina et al. evaluated the ongoing approaches to COVID-19 vaccine
enhancement, viral interference, route of infection, original antigenic development, and stated: “Normally, the period of development of a
sin, etc), and used as a Medline query to retrieve potentially relevant vaccine is 12‑15 years” [41]. Against this backdrop, SARS-CoV-2 vac
articles. All these retrieved articles were read, and the most relevant cines are targeted for accelerated development, safety testing,
ones extracted. Their titles were entered into the Web of Science, and the manufacturing, and distribution by an order of magnitude [42]. Each of
citation network was explored (citing papers, cited papers, papers that the accelerated steps [41] has drastically reduced the time required from
shared common references, etc). Those records were read, and the most normal development. Some of the potential adverse vaccine effects
relevant ones extracted for this monograph. shown on the right of Fig. 1 may take years to emerge, well after the
initial abbreviated vaccine safety testing period.
3. Results
3.1. Overview 3.2. Past coronavirus vaccine development history
The main body of our previous COVID-19 monograph [12] addressed There have been two prior coronavirus outbreaks in the 21 st cen
the first type of strategic treatment: 1) identification and removal of tury: SARS in 2002–2003, and MERS starting in 2012. Vaccine devel
opment for each started/accelerated during the height of each outbreak.
Fig. 1. Compares the traditional vaccine development schedule with the accelerated COVID-19 vaccine development schedule.
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What have been the results of these prior coronavirus vaccine devel one virus may enhance infection with a different virus)
opment efforts? [55–61];
According to a comprehensive 2019 article on MERS vaccine -1b) Immune Enhancement (enhancement of secondary in
development [43], “To date, there is no specific treatment proven fections via immune interactions) [62–65];
effective against this viral disease. In addition, no vaccine has been -1c) Cross-reactivity (an antibody raised against one specific
licensed to prevent MERS-CoV infection thus far … In general, the po antigen has a competing high affinity toward a different
tential vaccine candidates can be classified into six types: viral antigen.) [66,67]
vector-based vaccine, DNA vaccine, subunit vaccine, nanoparticle-based -1d) Cross-Infection Enhancement (infection enhancement of
vaccine, inactivated-whole virus vaccine and live-attenuated vaccine” one virus by antibodies from another virus) [68,69]
According to a comprehensive 2020 article on SARS and MERS 2) Vaccine-associated Virus Interference (where vaccinated in
vaccine development [44], “As of April 2020, no vaccine is commer dividuals may be at increased risk for other respiratory viruses
cially available for these coronavirus strains”. The rationale for lack of a because they do not receive the non-specific immunity associated
vaccine is given by the following: “Reasons for the lack of commercial with natural infection) [70–75];
and effective vaccines for SARS and MERS are varied. In the case of 3) Vaccine-Associated Imprinting Reduction (where vaccinations
MERS, it is likely that the vaccine development was delayed because of could also reduce the benefits of ‘imprinting’, a protection
the scarcity of suitable and cost-effective small animal models during conferred upon children who experienced infection at an early
pre-clinical experimentation. In addition, it is probable that a vaccine age) [76,77];
has not been delivered because of the low interest in investing in a 4) Non-Specific Vaccine Effects on Immune System (where previous
vaccine for a disease that has produced relatively low and geographi infections can alter an individual’s susceptibility to unrelated
cally centralized cases (compared with other more global and persistent diseases) [78,79];
infectious diseases such as influenza, HIV and tuberculosis). This last 5) Impact of Infection Route on Immune System (where immune
factor might have also contributed to the lack of a vaccine for SARS, in protection can be influenced by the route of exposure/delivery)
the sense that it was considered pointless to continue investing in a [80–82];
vaccine for a disease whose cases ceased to be reported in 2004.” 6) Impact of Combinations of Toxic Stimuli (where people are
While interest in a vaccine may have waned after the SARS exposed over their lifetime to myriad toxic stimuli that may
pandemic/outbreak seemed to have terminated, research on such a impact the influence of any vaccine) [78; 83, 84];
vaccine persisted. References in the above article showed SARS vaccine 7) Antigenic Distance Hypothesis (negative interference from prior
research continued for a decade or more after the pandemic had ended season’s influenza vaccine (v1) on the current season’s vaccine
[45,46]. (v2) protection may occur when the antigenic distance is small
Based on the experiences with SARS and MERS, successful vaccine between v1 and v2 (v1 ≈ v2) but large between v1 and the cur
development was not achieved after about a decade of research, or even rent epidemic (e) strain (v1 ∕= e).) [85–87];
more. That does not bode well for COVID-19 coronavirus vaccine 8) Bystander Activation (activation of T cells specific for an antigen
development/safety testing/distribution for the one-year timescales X during an immune response against antigen Y) [88–90];
being projected. 9) Gut Microbiota (Impact of gut microbial composition on vaccine
response) [91–95];
3.3. Challenges for successful vaccine development - overview 10) Homologous Challenge Infection Enhancement (the strain of
challenge virus used in the testing assay is very closely related to
The main challenges facing successful coronavirus vaccine devel the seed virus strain used to produce the vaccine that a subject
opment can be summarized as time to development, efficacy of the received) [96–98];
vaccine and, most importantly, safety of the vaccine. A complementary 11) Immune Evasion (evasion of host response to viral infection)
perspective on some of the problems listed in [41] can be stated as [99–102];
follows: 12) Immune Interference (interference from circulating antibody to
First, although the virus’s spike protein is a promising immunogen the vaccine virus) [103,104];
for protection, optimizing antigen design is critical to ensure optimal - 12a) Original antigenic sin (propensity of the body’s immune
immune response. Debate continues over the best approach — for system to preferentially utilize immunological memory based on
example, targeting the full-length protein or only the receptor-binding a previous infection when a second slightly different version of
domain. that foreign entity (e.g. a virus or bacterium) is encountered.)
Second, preclinical experience with vaccine candidates for SARS and [105–108];
the Middle East respiratory syndrome (MERS) have raised concerns 13) Prior Influenza Infection/Vaccination (effects of prior influenza
about exacerbating lung disease, either directly or as a result of infection/vaccination on severity of future disease symptoms)
antibody-dependent enhancement. Such an adverse effect may be [109–116];
associated with a type 2 helper T-cell (Th2) response. Hence, testing in a 14) Timing between Viral Exposures (elapsed time between viral
suitable animal model and rigorous safety monitoring in clinical trials exposures) [117–120];
will be critical” [47]. 15) Vaccine-Associated Enhanced Respiratory Disease (where vacci
nation enhances respiratory disease) [121–123];
3.4. Vaccine mechanisms with uncertain consequences 16) Chronic Immune Activation (continuous innate immune re
sponses) [124–126].
Numerous mid- and longer-term potential issues concerning vaccines
have been identified. Their themes are summarized initially, followed by 3.5. Vaccine effectiveness
excerpts from specific cited references.
The previous section addressed mechanisms that could potentially
1) Antibody-Dependent Enhancement (where enhanced virus entry enhance infections, rather than attenuate or prevent them. The present
and replication in a number of cell types is enabled by antibodies) section addresses empirical findings of low vaccine effectiveness, where
[47–54]; mechanistic explanations may or may not have been offered. Because of
-1a) Intrinsic Antibody-Dependent Enhancement (where non- similarities between influenza and COVID-19, and space limitations, the
neutralizing antibodies raised by natural infection with focus will be on the influenza vaccination experience. Significant
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influenza VE could not be demonstrated for any season, age, or setting Pilgrim Healthcare, Inc, reported that fewer than 1% of vaccine adverse
after adjusting for county, sex, insurance, chronic conditions recom events are reported. In other words, the actual numbers of adverse re
mended for influenza vaccination, and timing of influenza vaccination. actions to vaccines are one to two orders of magnitude higher than those
[127]. We found a threefold increased risk of hospitalization in subjects reported in VAERS!
who did get the TIV vaccine [128]. The methodology used by Harvard Pilgrim Healthcare. Inc, for
Using data from traditional control subjects, VE for those seasons was obtaining this result was as follows: Every patient receiving a vaccine
estimated to be 5 % (95 % CI, − 52 % to 40 %), 11 % (95 % CI, − 96 % to was automatically identified, and for the next 30 days, their health care
59 %), and 37 % (95 % CI, − 10 % to 64 %), respectively; confidence diagnostic codes, laboratory tests, and medication prescriptions are
intervals included 0 [129]. Participants reporting pH1N1-related ILI evaluated for values suggestive of an adverse vaccine event. When a
during the period 1 April through 5 June 2009 were more than twice as possible adverse event was detected, it was recorded, and the appro
likely to report having previously received seasonal influenza vaccine priate clinician was to be notified electronically.
[130]. Unvaccinated children had more flu-specific CTLs than vacci Thus, these adverse events that were identified are single-visit short-
nated children with CF [131]. term adverse events (within thirty days of the vaccination). They do not
Following 2009 H1N1 vaccination, subjects previously given a sea reflect the results of vaccination combinations administered over a
sonal influenza virus vaccination exhibited significantly lower antibody longer period than thirty days, and they do not reflect results of vacci
responses, as determined by hemagglutination inhibition assay, than nations of any type in the mid-or long-term [139].
subjects who had not received the seasonal influenza virus vaccination If fewer than 1% of vaccine adverse events are reported, how well
[132]. Our study confirms the results from our previous interim report, does this sample reflect the total number of adverse events actually
and other studies, that failed to demonstrate benefit or harm from experienced? This is not a randomly-selected sample, as would be
receipt of seasonal influenza vaccine in patients with confirmed infec required for a statistically-valid result. Thus, even analyses of short-term
tion with pandemic influenza H1N1 2009. [133]. Influenza vaccination adverse effects based on VAERS data are severely flawed. And, if fewer
seemed to be associated with an increased risk of non-influenza respi than 1% of these short-term adverse events are reported, what fraction
ratory virus infections, which is consistent with temporary nonspecific of longer-term adverse events (where the connection between the
immunity. [134]. A potential doubling of pandemic infection risk among adverse event and the vaccination becomes more tenuous as time pro
prior seasonal vaccine recipients could be disastrous in the event of a ceeds) would be reported? One can only conclude that a negligible
more severe pandemic involving a higher per-case fatality risk” [135]. fraction of long-term adverse events is reported in a passive monitoring
system like VAERS.
3.6. Potential short- and long-term diseases resulting from vaccines
3.7. Diseases triggered by vaccines
- Tracking Deficiencies for Vaccine Adverse Effects
A brief analysis was performed of the vaccine biomedical literature
While the efficacy issues for a COVID-19 vaccine have been to identify diseases potentially triggered by vaccination, especially in
enumerated extensively in recent reviews [49,54], more emphasis needs the long-term. It should be noted the biomedical literature is very sparse
to be placed on ensuring mid- and long-term safety are achieved. Vac with studies on long-term vaccine effects, especially long-term adverse
cines do not appear to have the same safety requirements as many drugs. effects. Large numbers of people and long periods of time are required to
For example, consider the following excerpts from selected vaccine in identify such adverse events, and draw statistically-valid connections
serts relative to safety [136]: between vaccinations and disease. These efforts would be very resource-
intensive, and there appears to be little motivation among the vaccine
- MMR Vaccine: M-M-R II has not been evaluated for carcinogenic or producers and regulators to make these resources available for such
mutagenic potential, or potential to impair fertility. Animal repro studies. Thus, the following examples reflect the extremely small tip of
duction studies have not been conducted with M-M-R II.; an extremely large iceberg of long-term adverse vaccine effects.
- Influenza Vaccine FLUARIX QUADRIVALENT has not been evaluated The two main categories of diseases reported in the biomedical
for carcinogenic or mutagenic potential or male infertility in literature triggered by vaccinations are Autoimmune (e.g., Systemic
animals. Lupus Erythematosus, Psoriasis, Arthritis, Multiple Sclerosis, Hepatitis,
- DTAP Vaccine INFANRIX has not been evaluated for carcinogenic or Uveitis, Pseudolymphoma, Guillain-Barre Syndrome, Thrombocyto
mutagenic potential or for impairment of fertility. penic Purpura, etc.) and Neurological (e.g., Central Demyelinating
- HPV Vaccine [137] GARDASIL 9 has not been evaluated for the Diseases, Developmental Disability, Febrile seizures, Narcolepsy,
potential to cause carcinogenicity, genotoxicity or impairment of Encephalomyelitis, Autonomic Dysfunction, etc.). Others include Dia
male fertility. betes, Gastrointestinal, Joint-related, Necrobiotic Granuloma, Neu
tropenia, Pulmonary Fibrosis, etc.
Long-term safety studies of vaccines are rare. The typical vaccine Main syndromes associated with systemic toxicity of adjuvanted
study is aimed at efficacy. Such studies tend to be a few months long, and vaccine: acute phase response (APR), hypersensitivity reactions, in
the main evaluation criterion is titers of antibody in the serum. duction or worsening of autoimmune diseases, modification of drug
Vaccines, especially childhood vaccines, are administered according hepatic metabolism, vascular leak syndrome (VLS), oral immunosup
to a schedule, which now comprises about seventy + doses covering pression or tolerance post vaccination [140].
about sixteen vaccines. The schedule-based combination effects of these Vaccinations may also contribute to the mosaic of autoimmunity.
seventy + vaccine doses have not been tested, and, therefore, adverse Evidence for the association of vaccinations and the development of
effects due to real-life vaccine synergies are unknown. Such vaccine these diseases is presented in this review. Infrequently reported post-
combination experiments cannot be limited to the pristine environment vaccination autoimmune diseases include systemic lupus erythemato
of the laboratory, but require testing in humans who are exposed to sus, rheumatoid arthritis, inflammatory myopathies, multiple sclerosis,
myriad toxic stimuli that could impact vaccine combination synergies. Guillain-Barre syndrome, and vasculitis [141].
Much of the published data for vaccine adverse events (at least in the Toplak et al. reported the production of autoantibodies (such as
USA) originates from the Vaccine Adverse Event Reporting System antinuclear and antiphospholipid antibodies) in 92 healthy medical
(VAERS) database. VAERS is a passive monitoring system, and, like all workers up to 6 months after influenza vaccination. Other studies have
similar systems, suffers from substantial under-reporting of adverse demonstrated a latency period of years between HiB vaccination and
events [138]. A groundbreaking study [139], performed by Harvard diabetes mellitus, and between HBV vaccination and demyelinating
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events. In conclusion, latency periods can range from days to years for human host [146]. Hence, the massive viral vs. human peptide com
postinfection and postvaccination autoimmunity [142]. monalities described since 2000 [147,148] clearly explain how the
Adults receiving HBV had significantly increased odds ratios (OR) for protective anti-viral antibody immune response can become a patho
multiple sclerosis (OR = 5.2, p < 0.0003, 95 % Confidence Interval (CI) genic autoimmune attack against the human organism, thereby
= 1.9–20), optic neuritis (OR = 14, p < 0.0002, 95 % CI = 2.3–560), addressing the issue of why SARS-CoV-2 attacks the respiratory system
vasculitis (OR = 2.6, p < 0.04, 95 % CI = 1.03–8.7), arthritis (OR = 2.01, so heavily [149]. The scientific cross-reactivity context and the clinical
p < 0.0003, 95 % CI = 1.3–3.1), alopecia (OR = 7.2, p < 0.0001, 95 % CI data showing that immunization with SARS-CoV antigens causes severe
= 3.2–20), lupus erythematosus (OR = 9.1, p < 0.0001, 95 % CI = pneumonia [150] suggest a prominent pathogenic role of anti-SARS-CoV
2.3–76), rheumatoid arthritis (OR = 18, p < 0.0001, 95 % CI = antibodies in COVID-19. In fact, emerging reports show that severe
3.1–740), and thrombocytopenia (OR = 2.3, p < 0.04, 95 % CI = acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection pre
1.02–6.2) in comparison to the TCV group. Minimal confounding or cedes the appearance of various autoimmune and autoinflammatory
systematic error was observed [143]. diseases, including pediatric inflammatory multisystemic syndrome or
The difference in cumulative incidence between those receiving 4 multisystem inflammatory syndrome in children [151,152]. Simply put,
doses and those receiving 0 doses is 54 cases of IDDM/100,000 (P = the current race for obtaining a highly immunogenic anti-SARS-CoV-2
0.026) at 7 years, (relative risk = 1.26). Most of the extra cases of IDDM vaccine might actually equate to a race for producing a highly lethal
appeared in statistically significant clusters that occurred in periods vaccine also in light of the fact that adjuvanted anti-SARS-CoV-2 would
starting approximately 38 months after immunization and lasting have a higher immunogenicity and autoimmune pathogenicity when
approximately 6–8 months. Immunization with pediatric vaccines compared to SARS-CoV-2 infection.
increased the risk of insulin diabetes in NOD mice…..Exposure to HiB This risk of cross-reactivity further increases when considering that it
immunization is associated with an increased risk of IDDM. NOD mice cannot be estimated with the current vaccine pre-clinical tests [153,
can be used as an animal model of vaccine induced diabetes [144]. 154]. Indeed, the level of peptide sharing is highest between pathogens
and human, murine, and rat proteomes, and is lowest (or absent) with
3.8. Time required for credible COVID-19 vaccine safety studies proteomes from nonhuman primates such as gorilla, chimpanzee, and
rhesus macaque. That is, from the genetic point of view, primates are
As the above results have shown, vaccines can have long-term im unreliable animal models for revealing potential autoimmune
pacts on the immune system (positive and negative), and short and long- cross-reactions in preclinical testing of immunotherapies since, obvi
term effects on other diseases. The effects of vaccines can vary according ously, no cross-reactions can occur in primates in absentia of shared
to route of infection, prior history of vaccinations, and, as stated by Benn sequences.
et al. above, administration “with other vaccines, drugs, or micro On the whole, the data exposed above open new scenarios in vac
nutrients and in different sequences [78]. To accelerate the time cinology by confirming the basic concept first stated in 2000 [147] and
required to demonstrate long-term safety, laboratory experiments are then illustrated repeatedly [155–158], according to which only peptide
usually done using animals with relatively short lifespans whose re sequences derived from pathogens and absent in the human proteome, i.
sponses to myriad toxic stimuli are similar to that of human beings. e., ‘non-self’ peptides’, can lead to safe and efficacious
One major difference between these animal experiments and the immunotherapies.
human model is that the laboratory experiments are usually performed
with the administration of a single toxic stimulant, or maybe two, while 3.10. Macro-level considerations
the human model lives in a sea of toxic stimuli. Also, it is not always
clear which animal model simulates the human model best for response The issues discussed previously can be viewed as micro-level issues.
to vaccination. The focus is at the cellular-virus-antibody level. These micro-level issues
There are many examples in the biomedical literature where com need to be understood within the larger context of macro-level issues.
bined exposures to toxic stimuli showed adverse effects whereas expo Two of these macro issues will be discussed in the present section.
sures to the same stimuli in isolation (at the same dosages) showed no The first issue examines the role of vaccines from a larger systemic
adverse effects [83,84]. Thus, unless these laboratory experiments are perspective, especially whether the vaccine target is based on local or
performed with a range of combinations of associated immunomodu global optimization. The second issue relates to the objectivity of the
lators, they would not be credible for safety assessment purposes. Such published vaccine effectiveness studies, and how the results are open to
experiments would require enormous amounts of financial and time bias due to conflicts of interest with research sponsoring agencies.
resources.
The other alternative is to perform these safety studies with human 3.11. Local vs global optimization
beings. For long-term safety studies (e.g., potential vaccine effects on
initiating cancer or Alzheimer’s Disease), decades could be required for In the evolution of COVID-19, the impact of real-life exposures to
credible results. Thus, there is a major disconnect between the time multiple toxic stressors degrading the immune system is followed by the
required for credible safety studies of a COVID-19 vaccine and the one- SARS-CoV-2 virus exploiting the degraded immune system to trigger a
year or less vaccine commercialization being propounded by decision- chain of events ultimately leading to the disease. A person with such a
makers and the media today. degraded immune system is more vulnerable to infections and other
health assaults. Assume that person is given a vaccine to ‘protect’ against
3.9. Molecular mimicry and the invalid genetic basis of vaccine pre- a specific virus. How does it perturb the immune system?
clinical tests: the new vaccinology scenario for designing safe and effective The vaccination is designed to provide a local optimization; it is not
vaccines designed to provide a global optimization. A successful vaccine may
offer some increased protection against the specific viral strain in the
The above analyzed COVID-19 vaccine safety considerations become vaccine, ranging from one season to a lifetime. What protection does it
even more cogent in light of the fact that cross-reactivity might represent offer against other strains of the same virus, or other viruses? Does it
the mechanism underlying the immunopathology and the disease enhance or decrease protection against other challenges, such as the
multitude associated with the coronavirus infection [145]. The rationale rapid cell increases characteristic of cancer?
is that the sharing of peptides between SARS-CoV-2 and human proteins One of the mechanisms examined previously is vaccine-Associated
might trigger immune responses hitting not only the virus but also the Virus Enhancement (where vaccinated individuals may be at increased
human proteins, with consequent autoimmune pathologies in the risk for other respiratory viruses because they do not receive the non-
1453
specific immunity associated with natural infection). This phenomenon 1986 passed by Congress. So, the financial motivation for thorough
doesn’t always happen, but it can happen. Its occurrence would testing does not exist for vaccines. Additionally, vaccines are not tested
strengthen the argument for local optimization, where protection is for enhancement or stimulation of serious diseases, as stated previously.
increased against one viral strain at the expense of reduced protection Literature surveys show that vaccines are rarely tested for mid-term
against another viral strain. Given that (on average) measures are not adverse effects, and certainly not tested for long-term adverse effects.
being taken to reverse the immune system degradation in parallel with They are not tested for combinations as administered over time on a
administering a vaccine, adding a vaccine may improve one type of prescribed schedule, and they are not laboratory-tested in combination
protection but degrade another type. The immune system remains with other toxic substances. There appears to be little interest from the
degraded, and it will express its limitations against other challenges. manufacturers or researchers in discovering/identifying these adverse
Considering the military logistics analogy of the immune system, forces/ effects. This disinterest is most pronounced in the present efforts to have
supplies are being withdrawn from one Front to increase defensive ca a COVID-19 vaccine on the market, perhaps made mandatory, within a
pabilities on another Front. Since overall forces or supplies have not year after starting development. There cannot be any credible safety
been increased, net overall capabilities have not increased, and, to first testing under such a schedule [161]. There are many potential adverse
order, the vacated Front becomes more vulnerable. health effects that can result from vaccine-induced mechanisms, as our
As mentioned previously, many (if not all) vaccine inserts state that present study has shown, and these effects could emerge in the
the vaccine has not been tested for carcinogenicity (and mutagenicity near-term or the long-term. To require the young people (who are not at
and fertility) impacts. Such carcinogenicity testing would require long- risk from the most serious consequences of COVID-19) to take such
term tracking and establishing a credible link between the vaccine vaccines with potential serious long-term consequences is unjustifiable.
administered long ago and the onset of cancer. There are few incentives
for the developers and regulatory agencies (who tend to be vaccine 3.12. Objectivity of vaccine effectiveness studies
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 The following is focused on the USA experience, and probably is
would present major problems. But, if the local/global optimization relevant to most other countries. Most of the vaccine research and
concept is correct, such a link may be possible, or even greater than development studies published in the biomedical literature (especially
possible. Unless the immune system is intrinsically strengthened, it is the journals with reasonable Impact Factor threshold values) are spon
difficult to see how its operations can be improved in one sector without sored by the pharmaceutical industry and the Federal government, with
reducing performance in another sector. Otherwise, vaccines could be some funds coming from Foundations. In the USA, the government
developed against every conceivable challenge, and compensate for the promotes vaccinations for myriad diseases. It provides funds to the CDC
degraded immune system. for distributing vaccines, while at the time gives the CDC responsibility
There is a more fundamental problem with vaccines and other for safety monitoring of vaccines. In essence, the Federal government
members of the vast armamentarium employed by most of modern-day (through different branches) that promotes vaccines also sponsors vac
medicine to treat chronic and infectious diseases. Assume that one of the cine research, approves vaccines, distributes vaccines, and monitors the
main operational functions of the body (not subjected to hereditary- safety of vaccines. These intertwining responsibilities open the door for
based dysfunctions or autoimmune dysfunctionality) is to heal itself conflicts-of-interest.
continuously. One of the healing mechanisms is signaling when the body It is in the interests of the Federal government that approved vac
is being exposed to harmful substances or harmful behaviors, in order to cines have high Vaccine Effectiveness (VE), and a reading of the VE
motivate the elimination of these harmful inputs. Since the body can’t literature for the VE section contained in this paper shows clearly the
speak vocally, it communicates through the language of symptoms. emphasis by the sponsored research community (at least in the High
Rather than listen to the symptoms and take steps to eliminate the Impact Factor journals) to emphasize high VE for the vaccines examined.
offending substances/behaviors, modern medicine uses the approaches For the COVID-19 vaccines under development, and the COVID-19
of drugs/radiation/surgery and other therapies to attenuate the symp emergency measures being taken by Federal, State, and Local govern
toms. Since the fundamental problem has not been eliminated by the ments, dissenting voices have to make themselves heard through venues
symptom-suppression treatment(s), the body is forced to increase other than peer-reviewed publications in mainline journals. This is a
signaling through stronger symptoms, which may emerge short-term or perversion of the scientific process, which requires that all knowledge
long-term, and could range from modest to lethal. It is inconceivable able voices be heard, and results in a published literature of questionable
how such an approach can lead to true healing/disease reversal. credibility.
As an example, the first author’s group did a study to develop a
protocol that would prevent and reverse Alzheimer’s disease (AD) 4. Conclusions
[159]. As part of the study, Dr. Dale Bredesen, a neurologist who had
developed an AD reversal approach, was referenced and quoted as fol Four types of treatments are being used in different degrees to help
lows: "In the case of Alzheimer’s disease, there is not a single therapeutic counter the COVID-19 pandemic: reducing viral transmission (quaran
that exerts anything beyond a marginal, un-sustained symptomatic ef tine, face masks, social distancing, use of sanitizers, etc); treatments
fect, with little or no effect on disease progression. Furthermore, in the (mainly repurposed anti-viral drugs); vaccines (under development);
past decade alone, hundreds of clinical trials have been conducted for immune system strengthening (eliminating immune degrading toxic
AD, at an aggregate cost of billions of dollars, without success. This has stimuli; adding immune enhancing behaviors/substances). The first
led some to question whether the approach taken to drug development three types can be viewed as immune-augmenting; the last type is im
for AD is an optimal one [160]." That statement could apply in different mune-strengthening.
degrees to myriad chronic diseases. In fact, it is challenging to identify a Reducing viral transmission may offer some benefit, but has proven
chronic disease to which that statement does not apply! to be damaging psychologically and economically. Anti-viral treatments
The situation may even be worse with vaccines. Most drugs and other have had mixed results, and none have achieved consensus within the
therapies are required to undergo modest short-, mid-, and long-term medical community. Vaccines are under accelerated development.
testing for myriad adverse health effects. One motivator for this range Lifestyle and regulatory changes to strengthen the immune system have
of testing is that the manufacturers/vendors of these therapies can be been minimal
held liable for damage suffered as a result of their products. Vaccine Vaccines are being promoted by the healthcare industry, politicians,
manufacturers today have waivers from these liabilities (at least in the decision-makers, and the mainstream media as the best hope for con
USA) because of the National Childhood Vaccine Injury Act (NCVIA) of taining the COVID-19 pandemic, and this is reflected in the funding their
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CRediT authorship contribution statement
bacterial pathogens among hospitalised patients with severe invasive infections,
Exp. Ther. Med. 16 (6) (2018) 4499–4510, https://doi.org/10.3892/
Conceptualization: RNK; Data curation: DK, ALP, YS, MBB; Valida etm.2018.6737. Dec.
[20] R. Cioboată, A. Găman, D. Traşcă, A. Ungureanu, A.O. Docea, P. Tomescu,
tion, Writing - all authors, Supervision, writing - review & editing: RNK,
F. Gherghina, A.L. Arsene, C. Badiu, A.M. Tsatsakis, D.A. Spandidos, N. Drakoulis,
YS, DC, DAS, AT. All authors contributed equally, read and approved the D. Călina, Pharmacological management of non-alcoholic fatty liver disease:
final manuscript. atorvastatin versus pentoxifylline, Exp. Ther. Med. 13 (5) (2017) 2375–2381,
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[21] B. Salehi, A. Rescigno, T. Dettori, D. Calina, A.O. Docea, L. Singh, F. Cebeci,
Declaration of Competing Interest B. Özçelik, M. Bhia, A. Dowlati Beirami, J. Sharifi-Rad, F. Sharopov, W.C. Cho,
N. Martins, Avocado-Soybean Unsaponifiables: A Panoply of Potentialities to Be
Exploited, Biomolecules 10 (1) (2020) 130, https://doi.org/10.3390/
The authors report no declarations of interest. biom10010130. Jan 13.
[22] B. Salehi, J. Sharifi-Rad, F. Cappellini, Ž Reiner, D. Zorzan, M. Imran, B. Sener,
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Toxicology Reports 7 (2020) 1448–1458

Contents lists available at ScienceDirect

Vaccine- and natural infection-induced mechanisms that could modulate

1. Introduction Severe Acute Respiratory Syndrome (SARS), 2002–2003; Middle East

3.1. Overview 3.2. Past coronavirus vaccine development history

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