Strategies for the Management of Spike Protein-Related Pathology

Abstract

In the wake of the COVID-19 crisis, a need has arisen to prevent and treat two related conditions, COVID-19 vaccine injury and long COVID-19, both of which can trace at least part of their aetiology to the spike protein, which can cause harm through several mechanisms. One significant mechanism of harm is vascular, and it is mediated by the spike protein, a common element of the COVID-19 illness, and it is related to receiving a COVID-19 vaccine. Given the significant number of people experiencing these two related conditions, it is imperative to develop treatment protocols, as well as to consider the diversity of people experiencing long COVID-19 and vaccine injury. This review summarizes the known treatment options for long COVID-19 and vaccine injury, their mechanisms, and their evidentiary basis.

Full text

Citation: Halma, M.T.J.; Plothe, C.;
Marik, P.; Lawrie, T.A. Strategies for
the Management of Spike
Protein-Related Pathology.
Microorganisms 2023,11, 1308.
https://doi.org/10.3390/
microorganisms11051308
Academic Editors: Keivan Zandi and
James J. Kohler
Received: 16 March 2023
Revised: 4 May 2023
Accepted: 10 May 2023
Published: 17 May 2023
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
conditions of the Creative Commons
Attribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
microorganisms
Review
Strategies for the Management of Spike Protein-Related Pathology
Matthew T. J. Halma 1, Christof Plothe 2, Paul Marik 3and Theresa A. Lawrie 1, *
1EbMCsquared CIC, 11 Laura Place, Bath BA2 4BL, UK
2Center for Biophysical Osteopathy, Am Wegweiser 27, 55232 Alzey, Germany
3
Front Line COVID-19 Critical Care Alliance (FLCCC), 2001 L St. NW Suite 500, Washington, DC 20036, USA;
pmarik@flccc.net
*Correspondence: tess@e-bmc.co.uk
Abstract:
In the wake of the COVID-19 crisis, a need has arisen to prevent and treat two related
conditions, COVID-19 vaccine injury and long COVID-19, both of which can trace at least part
of their aetiology to the spike protein, which can cause harm through several mechanisms. One
significant mechanism of harm is vascular, and it is mediated by the spike protein, a common element
of the COVID-19 illness, and it is related to receiving a COVID-19 vaccine. Given the significant
number of people experiencing these two related conditions, it is imperative to develop treatment
protocols, as well as to consider the diversity of people experiencing long COVID-19 and vaccine
injury. This review summarizes the known treatment options for long COVID-19 and vaccine injury,
their mechanisms, and their evidentiary basis.
Keywords:
long COVID; COVID-19 vaccine injury; spike protein; thrombosis; inflammation;
repurposed medication; autophagy
1. Introduction
According to available data, by 30 September 2022, 68% of the world’s population had
received at least one dose of the COVID-19 vaccine, and 12.74 billion doses had been admin-
istered [
1
]. The vaccines most commonly administered were Comirnaty (Pfizer/BioNTech),
Covishield (Astrazeneca), CoronaVac (Sinovac), Spikevax (Moderna), and Jcovden (Johnson
& Johnson) [
2
]. Of these, approximately 30% of the doses produced by 22 January 2022
were in the form of a novel vaccine with a synthetic N1-methyl-pseudoiridinylated mRNA
encapsulated in a lipid nanoparticle (LNP) [3].
LNPs are a new technology that was not used in vaccine delivery until the emergency
use authorization (EUA) of the Pfizer/BioNTech BNT162b2 and Moderna mRNA-1273
COVID-19 vaccines [
4
]. This was also unprecedented in the approval process, being the
fastest for any vaccine [
5
], leaving many concerns with regard to long-term safety [
6
], which
was difficult to evaluate due to the unblinding of the initial clinical trials [7].
Whilst the delivery technology of LNPs have previously been used to deliver small
molecules, it has only recently been used to deliver RNA. LNPs are advantageous for
targeting brain tissue, as they can cross the blood–brain barrier (BBB) [
8
,
9
]. The first
drug used and LNP to deliver RNA was a small interfering RNA (siRNA)-based drug,
known as Onpattro (Alnylam Pharmaceuticals), first approved in 2018 for the treatment of
polyneuropathies [10].
Given both the novelty of the technology and the paucity of data on which approval
was based (which was also subject to data integrity issues [
11
]), long-term effects cannot
be definitively ruled out, especially because many of the foundational claims on which
approval was based have been contested by recent experiments [
12
–
14
]. For example,
in contrast to claims that the injection stayed at the injection site [
15
], and that spike
protein would only be expressed for a short period of time (based on the lability of non-
pseudouridylated RNA [
16
]), the contents and products of the COVID-19 vaccines have
been found in the blood stream of most vaccinees studied within hours to days [12].
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Microorganisms 2023,11, 1308 2 of 26
The first claim was based on Intramuscular administration [
15
], and the second claim
was based on the lability of RNA [
17
], with a typical RNA half-life of minutes [
18
]; however,
biodistribution studies have found significant expression of spikes in other tissues and
organs [
12
], and researchers have found both vaccine mRNA and spike protein (which is
encoded by the vaccine sequence) two months post-administration [
14
], and even up to
four months post-vaccination [
13
]. One preprint study of people with SARS-CoV-2 negative
post-vaccination Long COVID-19-like symptoms showed spike protein persistence, on
average, 105 days post vaccination [
19
]. Long COVID-19 patients (post SARS-CoV-2
infection) show spike protein persistence up to 15 months [
20
]. Another study showed
spike protein persistence in the gut of long COVID-19 patients, but not in the bloodstream.
Spike proteins can be packaged in exosomes [
13
], possibly resulting in inflammation
and immune activation [
21
,
22
] in organs and tissues distant from the injection site [
13
].
Extracellular vesicles are capable of crossing the blood–brain barrier [
23
], and LNPs, as
well as exosomes, will exchange more readily in small diameter vessels with low flow
rates (i.e., capillaries and small vessels) [
24
]. Importantly, the spike protein seems to
additionally impact blood–brain barrier permeability [
25
,
26
]. These results challenge the
initial mechanistic foundation on which the presumption of safety is contingent.
Compared with other vaccines, COVID-19 vaccines have a much higher adverse
event rate [
27
]. Histopathological findings and autopsies of those dying post-vaccination
support the causative role of the vaccine in deaths [
28
], most commonly from vascular-
related events. Pharmacovigilance programs in several countries have observed a safety
signal for myocarditis in the COVID-19 vaccinated population [
29
–
31
]. A US survey
found that 19% of myocarditis cases had not recovered at 90 days after onset [
32
]. In
addition, screening of BNT162b2 vaccine recipients among boys aged 13–18 in a Thai study
revealed that 2.3% of the boys had at least one elevated cardiac biomarker or positive
lab assessment, and 29% had at least one cardiac manifestation, such as tachycardia,
palpitation, or myopericarditis [
33
]. Given this information, and given the ubiquitous
use of COVID-19 vaccines, it is possible that widespread subclinical damage exists in the
COVID-19 vaccinated population. Structurally, the spike protein, particularly the receptor-
binding domain (RBD) of the S1 subunit, has attracted much attention, as it is the most
prominent aspect of the viral capsid [
34
] (It consists of spike (S) and nucleocapsid (N))
glycoproteins. Cell entry is mediated by the binding of Spike RBD to the Angiotensin
Converting Enzyme II (ACE2) [
35
]. Therefore, by preventing this binding through allosteric
inhibition, it is possible to prevent the entry of SARS-CoV-2 virions into the cell and
subsequent infection [36].
A strategy to inhibit S1 RBD binding to ACE2 has been employed in the development
of SARS-CoV-2 vaccines [
37
]. mRNA vaccines exclusively encode spike proteins, and
mono-antigenic targeting can create opportunities for immune escape by variants [
38
],
given that the mRNA vaccines do not halt transmission [
39
]. Positive selection pressure
is observed on residues of the spike protein because of widespread vaccination, although
these cannot be definitively related causally [40,41].
This article sets out to first describe the mechanisms of spike protein related pathology
and the factors which affect them (e.g., patient characteristics) and their relevant biomarkers
and diagnostics. The objective, then, is to introduce therapeutics with some promise, based
on either mechanistic or clinical evidence, and to summarize the evidence base for each
intervention, so that practitioners and scientists may be guided concerning therapeutic de-
velopment. Other articles cover the pathophysiology of long COVID-19, as well as provide
a list of therapeutics under investigation [
42
], and a recent review describes the similarities
between long COVID-19 and COVID-19 vaccine injury [
43
]. This review is unique in
that it provides an integrated discussion of disease mechanism for both post-COVID-19
vaccination syndrome and long COVID-19, which are difficult to distinguish in many cases,
and summarizes the treatment modalities available to those experiencing symptoms.

Microorganisms 2023,11, 1308 3 of 26
2. Methods
This review begins by summarizing the mechanisms of harm from spike protein,
either from COVID-19 illness or form COVID-19 vaccination. We also cover the clinical
aspects, which can affect the course of the disease. The review then moves to therapeutic
mechanisms, which can address the spike protein via different pathways.
For therapeutic interventions for these conditions (long COVID-19 and vaccine in-
jury) with a plausible mechanism of action against spike protein, these are shown in the
results section. Relevant clinical trials are added, and any direct evidence or proxy evi-
dence for efficacy (such as efficacy against original COVID-19 illness) is included in the
rightmost column.
Additionally, we include clinical trials on long COVID-19 and vaccine injury in Ta-
ble S1. A search for clinical trials for the condition “Long COVID OR Long COVID-19”
in ClinicalTrials.gov revealed 317 studies. A search for clinical trials on vaccine adverse
events revealed that one study used rutin and glycoside-rich mulberry juice to reduce
adverse events to C19 injection [
44
]. Other studies, while not specifically treating the
immune response, administer therapy alongside vaccination to observe changes in re-
sponse. These include spermidine [
45
], probiotics [
46
], a yeast-based supplement rich in
selenium and zinc [
47
], plant stanol esters [
48
], mushrooms [
49
], deltoid muscle exercises
(for site pain) [
50
], osteopathic manipulative treatment [
51
,
52
], metformin [
53
], iron [
54
],
ergoferon [55], ketogenic diet [56], and immunosuppressants [57,58].
It is a difficult task to assess the evidentiary basis for each type of intervention, as
few meta-analyses have been carried out. For example, a search in the Cochrane Col-
laboration Library for “Post Acute COVID-19” yields one relevant review on remedying
olfactory dysfunction, finding limited evidence for the usefulness of proposed therapies [
59
].
Furthermore, 46 relevant completed studies for the search term “Long COVID” exist on
ClinicalTrials.gov (8 January 2023). As few systematic reviews exist, we aim to summarize
the evidentiary basis of the known interventions currently in clinical trials for the treatment
of long COVID-19 and COVID-19 vaccine injury are shown in Table S1. There is a single
review on treating COVID-19 vaccine injury that could be found, which is included in
Table S1.
3. Pathophysiology
3.1. Mechanisms of Harm
As mentioned previously, while it was expected that the LNP-encapsulated synthetic
mRNAs would remain at the injection site and rapidly degrade, there is substantial evidence
that they enter the bloodstream [
60
], deposit in other tissues [
61
], and even in the breast milk
of lactating mothers [
62
]. The S1 subunit of the spike protein can damage the endothelial
lining of blood vessels [
63
–
65
]. Vaccine particles in the bloodstream can cause a significant
inflammatory response in blood vessels [66].
Several hypotheses for the mechanisms of long COVID-19 exist, including immune
dysregulation, auto-immunity, endothelial dysfunction, activation of coagulation, and
latent viral persistence [
67
,
68
], though this review focuses on the elements common to
both COVID-19 infection and vaccine injury. Cardiovascular complications, particularly
microthrombus formation, feature both in the etiologies of long COVID-19 [
69
,
70
] as well
as COVID-19 vaccine injury [71].
The SARS-CoV-2 (infection or vaccine produced) spike protein can bind to the ACE2
receptor on platelets, leading to their activation [
72
], and it can cause fibrinogen-resistant
blood clots [
73
]. Spike protein fragments can also be amyloidogenic on their own [
74
].
Several reports demonstrate elevated troponin levels in cardiac symptoms following the
COVID-19 vaccine [75].
Ontologically, both infection and vaccination express the spike protein, though some
subtle differences exist between the vaccine-generated and the infection-generated spike
protein. Importantly, the spike protein encoded by vaccines is static and does not un-
dergo evolution, whereas the spike protein produced by infection evolves as the virus

Microorganisms 2023,11, 1308 4 of 26
evolves [76,77]
. There is one exception to this, and that is when the vaccine is updated, as
it is in the bivalent boosters of Pfizer and Moderna, which express the spike protein of both
the B.1.1.529 (omicron) BA.5 sublineage and the ancestral WA1/2020 strain [
78
]. The other
important distinction between vaccine spike and infection spike is the stabilized pre-fusion
state in the vaccine spike, which results in an increased ACE2 binding affinity compared to
spike proteins generated via SARS-CoV-2 infection [
79
]. The difference in the circulating (in
the population) SARS-CoV-2 spike protein to the spike protein (either vaccine or infection
generated) of one’s initial immune imprinting has important implications for immune
escape [
77
,
80
] and immune-mediated damage [
81
]. Immune escape is demonstrated in
population studies showing waning vaccine efficacy [82].
In 2021, a comprehensive investigation revealed consistent pathophysiological alter-
ations after vaccination with COVID-19 vaccines, including alterations of immune cell gene
expression [83].
3.2. Clinical Observations
Although no official definition exists for ‘post-COVID-19-Vaccine Syndrome,’ a tem-
poral correlation between receiving a COVID-19 vaccine and the beginning or worsening
of a patient’s clinical manifestations is sufficient to make the diagnosis of a COVID-19
vaccine-induced injury when the symptoms are unexplained by other concurrent causes.
It should, however, be recognized that there is a significant overlap between the symp-
toms and features of the long COVID-19 syndrome [
84
] and the post-COVID-19-Vaccine
Syndrome [
85
]. However, a number of clinical features appear to be distinctive of the post-
COVID-19 vaccine syndrome; most notably, severe neurological symptoms (particularly
small fiber neuropathy) appears to be more common following vaccination [
86
–
88
]. To
complicate matters further, patients with long COVID-19 are often vaccinated [
89
], making
the issue of definition more difficult.
Unfortunately, only post mortem examination to date can prove causal relationship
when tissues damaged demonstrate the presence of spike protein and absence of nucleo-
capsid protein (SARS-CoV-2 only) [90].
The true magnitude of post-COVID-19-Vaccine Syndrome is unknown, as data are lim-
ited to short duration clinical trials. From a survey of vaccinated individuals, approximately
1% required medical attention immediately following vaccination [
91
]. A nationwide cohort
study of U.S. veterans reported adverse reactions in 8.5% of recipients of the Pfizer vaccine
and 7.9% of those receiving the Moderna vaccine [92].
A number of factors are associated with an increased risk of adverse events;
these include:
•
Genetics: first-degree relatives of people who have suffered a vaccine injury appear
to be at a very high risk of vaccine injury. People with a methylenetetrahydrofolate
reductase (MTHFR) gene mutation [
93
] and those with Ehlers-Danlos type syndromes,
may be at an increased risk of injury. Increased homocysteine levels have been linked
to worse outcomes in patients with COVID-19 [
94
,
95
]. Increased homocysteine levels
may potentiate the microvascular injury and thrombotic complications associated with
spike protein-related vaccine injury [96,97].
•
mRNA load and quantity of spike protein produced: this may be linked to specific
vaccine lots that contain a higher concentration of mRNA due to variances in manu-
facturing quality, as well as heterogeneity within the vial [98].
•
Type and batch of vaccine: variances in the levels of adverse reactions were observed,
depending on the manufacturer of the vaccine [91].
•
Number of vaccines given: the risk of antibody enhancement (ADE) increases with
each exposure to the virus or a vaccine. A negative inverse correlation of dosages
given, as well as effectiveness, was also observed [99].
•
Sex: the majority of vaccine-injured people are female [
100
], and vaccines historically
have sex-specific effects [101].

Microorganisms 2023,11, 1308 5 of 26
•
Underlying nutritional status and comorbidities: certain preexisting conditions may
likely have primed the immune system to be more reactive after vaccination [
102
].
This includes those with preexisting autoimmune disorders [103].
4. Therapeutic Interventions
There are several non-specific means of counteracting the effects of long-COVID-19 and
post-COVID-19 vaccine injury. These include nutritional support for general immune regula-
tion and for overall health [104], as well as more specific, spike protein-specific therapeutics.
Non-specific therapeutic moieties include nutritional optimization, as diet-related
pathologies, including obesity [
105
] and type 2 diabetes [
106
], were associated with worse
outcomes from COVID-19 infection. Additionally, high blood glucose facilitates several
steps of the viral lifecycle and infection progression [
107
], motivating the reduction in
sugar and refined carbohydrate intake, which are associated with increases in blood sugar.
Furthermore, adoption of a whole-food, plant-based diet is associated with decreased
oxidative stress and inflammation [
108
] and better cardiovascular conditions. These posi-
tive impacts are attributed to their nutrient profiles, consisting of antioxidants, vitamins,
minerals, and phytochemical-containing phenolic compounds, which can exert antioxidant,
anti-inflammatory, and other beneficial effects [109,110].
The microbiota plays a fundamental role in the induction, training, and function of
the host’s immune system and thus shape the responses to its challenges [
111
]. Gut micro-
biome composition was significantly altered in patients with COVID-19 compared with
non-COVID-19 individuals, irrespective of whether patients had received medication [
112
].
The researchers said patients with severe illness exhibit high blood plasma levels of inflam-
matory cytokines and inflammatory markers. Additionally, given altered gut microbiota
composition in SARS-CoV-2 infected subjects, there is substantial involvement of the GI
tract during infection. These results suggest that gut microbiota composition is associated
with the magnitude of immune response to COVID-19 and subsequent tissue damage and
thus could play a role in regulating disease severity. The scientists also found that, because
a small subset of patients showed gut microbiota dysbiosis, or imbalance, even 30 days
after recovery, this could be a potential explanation for why some symptoms persist in long
COVID-19 [113].
Given the intricate influence of gut microbiota (GM) on host immune effectors and
subsequent inflammatory profile, GM composition and function might contribute to ex-
plaining the individual resilience/fragility with respect to COVID-19 and/or the response
to therapeutics (vaccines), which deserve further research [
114
]. Microbial diversity can be
improved by consuming many prebiotics and probiotics, such as sauerkraut and kimchi.
The design and discovery of spike protein inhibitors have followed a typical drug
repurposing process. Given the structural similarity of the SARS-CoV-2 spike protein
to other coronaviruses [
115
,
116
], compounds that work for these could potentially be
repurposed for SARS-CoV-2 spike inhibition.
Typically, once a prospective compound for repurposing has been identified, it is
tested using a ligand-binding assay (LBA) [
117
]. These assays can provide information
on binding affinity and kinetics, as well as binding stoichiometries and even cooperative
effects [117].
The next level of verification may be an
in vitro
assay for viral inhibition in cell culture,
where cells are infected with a virus, and viral levels or titre (concentration) are measured by
counting viral plaques [
118
] or measuring viral nucleic acid (NA) levels [
119
]. Control cells
are compared with treated cells. Though the approach has limitations, in not considering
the whole-body dynamics of a virus [120], it can serve as a useful starting point.
In vivo
studies are a further level of verification, which show the impact of the inter-
vention in an animal model. Beyond
in vivo
studies, there are clinical studies, which are
typically of two design types: observational and randomized control trials (RCTs) [121].
To date, little to no guidance has been provided by health authorities on how to manage
spike protein related disease, leaving it up to independent scientists and doctors to develop.

Microorganisms 2023,11, 1308 6 of 26
Regarding the COVID-19 Vaccine induced Thrombotic Thrombocytopenia Syndrome (TTS),
a 2021 review made suggestions on management, including intravenous immunoglob-
ulin, anticoagulants, and plasma exchange in severe cases [
122
]. These compounds are
nutritional supplements and natural products, with some repurposed pharmaceuticals
(Tables 1and 2).
This list points to the available evidence on each therapy and advances them for
further investigation. The following therapeutics work through different mechanisms, but
we largely focus on those proteins that bind directly with the spike protein for improved
clearance. Here, we summarize studies with different levels of evidence for their respective
efficacies, from in silico predictions, which can be based on binding predictions or systems
biological associations, to those showing activity in an
in vitro
or cell-free assay,
in vivo
studies, and any clinical or epidemiological evidence.
Given the many uncertainties around the duration of spike protein production and
the variables determining production, adopting a preventive approach seems sensible,
provided the proposed interventions are safe. It remains unknown whether full recovery
from COVID-19 Vaccine Injury is possible. However, we suggest targeting several different
processes to reduce symptoms associated with both vaccine injury and long COVID-19.
These include:
(1)
Establishing a healthy microbiome
(2)
Inhibiting spike protein cleavage and binding (stopping ongoing damage)
(3)
Clearing the spike protein from the body (clearing the damaging agents)
(4)
Healing the damage caused by the spike protein (restoring homeostasis and boosting
the immune system)
These categories are not clearly separate, as compounds binding to the spike can both
inactivate it by preventing its binding to ACE2, as well as aid in its clearance. There are
many biological pathways through which a given effect can occur. To inhibit the harmful
effects of the spike protein, it is possible to target the furin cleavage, either by directly
binding to the furin cleavage site itself [
123
–
125
] or by interfering with the serine protease
reaction [
126
–
128
] to block the interaction by binding to ACE2 [
129
], downregulating ACE2
expression [
130
], inhibiting the transition to the active conformation of S protein [
131
], or
binding the RBD of spike protein and allosterically inhibiting interaction with ACE2 [
132
]
(Figure 1). Clearing of spike proteins can also be accomplished by increasing autophagy,
which clears proteins and recycles their amino acids [133].
Microorganisms 2023, 11, x FOR PEER REVIEW 6 of 27
In vivo studies are a further level of verification, which show the impact of the inter-
vention in an animal model. Beyond in vivo studies, there are clinical studies, which are
typically of two design types: observational and randomized control trials (RCTs) [121].
To date, lile to no guidance has been provided by health authorities on how to man-
age spike protein related disease, leaving it up to independent scientists and doctors to
develop. Regarding the COVID-19 Vaccine induced Thrombotic Thrombocytopenia Syn-
drome (TTS), a 2021 review made suggestions on management, including intravenous im-
munoglobulin, anticoagulants, and plasma exchange in severe cases [122]. These compounds
are nutritional supplements and natural products, with some repurposed pharmaceuticals
(Tables 1 and 2).
This list points to the available evidence on each therapy and advances them for fur-
ther investigation. The following therapeutics work through different mechanisms, but
we largely focus on those proteins that bind directly with the spike protein for improved
clearance. Here, we summarize studies with different levels of evidence for their respec-
tive efficacies, from in silico predictions, which can be based on binding predictions or
systems biological associations, to those showing activity in an in vitro or cell-free assay,
in vivo studies, and any clinical or epidemiological evidence.
Given the many uncertainties around the duration of spike protein production and
the variables determining production, adopting a preventive approach seems sensible,
provided the proposed interventions are safe. It remains unknown whether full recovery
from COVID-19 Vaccine Injury is possible. However, we suggest targeting several differ-
ent processes to reduce symptoms associated with both vaccine injury and long COVID-
19. These include:
(1) Establishing a healthy microbiome
(2) Inhibiting spike protein cleavage and binding (stopping ongoing damage)
(3) Clearing the spike protein from the body (clearing the damaging agents)
(4) Healing the damage caused by the spike protein (restoring homeostasis and boosting
the immune system)
These categories are not clearly separate, as compounds binding to the spike can both
inactivate it by preventing its binding to ACE2, as well as aid in its clearance. There are
many biological pathways through which a given effect can occur. To inhibit the harmful
effects of the spike protein, it is possible to target the furin cleavage, either by directly
binding to the furin cleavage site itself [123–125] or by interfering with the serine protease
reaction [126–128] to block the interaction by binding to ACE2 [129], downregulating
ACE2 expression [130], inhibiting the transition to the active conformation of S protein
[131], or binding the RBD of spike protein and allosterically inhibiting interaction with
ACE2 [132] (Figure 1). Clearing of spike proteins can also be accomplished by increasing
autophagy, which clears proteins and recycles their amino acids [133].
Figure 1. The process of spike protein cleavage into S1 and S2 subunits and subsequent binding of
the S1 receptor binding domain (RBD) to the angiotension converting enzyme2 (ACE2) receptor on
Figure 1.
The process of spike protein cleavage into S1 and S2 subunits and subsequent binding of
the S1 receptor binding domain (RBD) to the angiotension converting enzyme2 (ACE2) receptor on
host cells. Each of the different subprocesses present opportunities for interference in spike binding
to ACE2, as well as a potential means of treating spike protein related pathology.

Microorganisms 2023,11, 1308 7 of 26
4.1. Establishing a Healthy Microbiome
The state of the microbiome is an essential criterion for the progression of acute COVID-
19 infection, long COVID-19, and post vaccine syndrome [
134
–
138
]. Patients with post-
vaccine syndrome classically have a severe dysbiosis with loss of
Bifidobacterium [139–141]
.
A whole-food, plant-based diet may improve outcomes in COVID-19 [
142
–
144
], and people
following plant-based diets, on average, experienced less severe COVID-19 symptoms [
145
].
Dietary sources of probiotics include fermented dairy [
146
], chia seeds [
147
], glucoman-
nan [148,149], and supplements [150].
Microbiome diversity and richness can be improved through a diet rich in prebi-
otic fiber and probiotics, particularly fermented foods, which can subsequently lower
inflammation [151].
4.2. Preventing Spike Protein Damage
Inhibiting Spike Protein Cleavage
The furin cleavage site on SARS-CoV-2 has been suggested as a reason for its increased
infectivity relative to SARS-CoV [
152
], which had a higher fatality rate, which was much
less infectious [
153
]. Cleavage of the full-length spike protein into S1 and S2 subunits
is essential for SARS-CoV-2 entry into human lung cells [
126
,
154
–
156
]. The full-length
spike is present in both SARS-CoV-2 infection, as well as vaccination, and it is the only
protein common to SARS-CoV-2 infection and vaccination (it is the only protein present in
vaccination) [157].
Vaccine-produced spike has an important difference as compared to the SARS-CoV-
2 spike—the inclusion of two proline mutations to stabilize the pre-fusion state of the
spike protein. These are related to Pfizer’s BNT162b2 [
158
], Moderna’s mRNA-1273 [
159
],
Johnson & Johnson’s Ad26.COV2.S [
160
], and NovaVax’s NVAX-CoV2373 [
161
]. This was
first discovered in the context of MERS [
162
]. Other vaccines apparently encode the full-
length, wild-type spike protein, including AstraZeneca’s ChAdOx1 [
163
] and SinoVac’s
CoronaVac [164].
These dual proline mutations featured in the mRNA vaccines stabilize the pre-fusion
state, though some cleavage still occurs [
162
,
165
,
166
], and, interestingly, the mutations
produce an unknown cleavage product of 40 kDa, where typical cleavage products for the
wild-type spike protein are 80 kDa [
166
]. As such, targeting the cleavage of spike protein
is likely to make a difference in long COVID, as well as vaccine injury from the vaccines
encoding the full-length wild-type spike protein (AstraZeneca, SinoVac and others), though
this may have less of an impact in vaccines encoding the pre-fusion-stabilized spike protein
(Pfizer, Moderna, Johnson & Johnson, NovaVax and others).
Notably, targeting cleavage has also been identified as a therapeutic modality in
the context of acute COVID-19 [
167
,
168
], which can take place via at least three distinct
pathways: cleavage by furin, trypsin, or trans-membrane serine protease [167–169].
4.3. Inhibiting Spike Protein Binding
One of the most direct therapeutic mechanisms is to seek compounds which disrupt
the ACE2/Spike interface, either through binding ACE2 or spike in isolation, or disrupting
the interface itself. This problem is a steric and conformational problem, for which computa-
tional prediction using structural models is highly amenable. A great many computational
studies of the spike protein and ACE2 binding compounds have been performed, and some
of these hits have further been developed through LBAs,
in vitro
studies,
in vivo
studies in
animal models, and, lastly, clinical trials with human subjects. Few of the compounds reach
the final stage, though several with this mechanism of action have been investigated. Most
promising were ivermectin and quercetin, as computational prediction showed these bind
to the spike. If the spike is bound in the receptor binding domain (RBD), the interaction
with ACE2 receptors, by which spike protein exerts its inflammatory effect, is also inhibited.
Similarly, compounds which bind to the ACE2 receptor can also antagonistically
compete with the spike protein for a limited number of receptor sites. For example,

Microorganisms 2023,11, 1308 8 of 26
the diabetes medication metformin has been identified as a potential long COVID-19
therapeutic agent due to this mechanism of action. Decreasing the level of spike actively
binding to ACE2 has therapeutic implications.
4.4. Clearing Spike Protein
So far, we have discussed ways to inhibit the impacts of the spike protein on the host’s
system. Importantly, to progress beyond this, it is necessary to clear out the spike protein.
This can be accomplished through upregulation of the protein degradative pathways in the
body through upregulation of autophagy. Autophagy can be upregulated by fasting [
170
]
and calorie restriction [
171
], especially if protein is reduced [
172
]. Autophagy in many
instances does not require the complete cessation of food intake (protocols are available
at https://COVID19criticalcare.com/treatment-protocols/, accessed on 15 April 2023).
Sharply decreasing protein intake can upregulate autophagy pathways [
173
], and this can
be accomplished while still eating, which makes this more approachable as a protocol.
Regular fasting was also associated with better outcomes from acute COVID-19 [174].
Spermidine, a polyanion compound found in high concentrations in wheat germ [
175
],
can potently stimulate autophagy [
176
]. Other factors which influence autophagy are acute
heat exposure, as one would experience in a sauna [
177
,
178
], flavonoid consumption [
179
],
phenolic compounds [
180
,
181
], and coffee [
182
]. Resveratrol can also induce fasting, as it
acts as a protein restriction mimetic [
183
], and metformin, a diabetes medication, can influ-
ence autophagy signaling [
184
]. Surprisingly, cold exposure, in addition to heat exposure,
also increases autophagy [
185
,
186
]. Hyperbaric oxygen [
187
] and ozone therapy [
188
] may
also stimulate autophagy.
4.5. Healing the Damage
After the damage process has been attenuated, it is necessary to heal the damage
that has occurred. The healing stage requires normalizing the immune response, reducing
lingering inflammation (such as by targeting interleukin 6 [
189
]), and addressing any acute
damage in affected tissues, particularly cardiovascular damage [
69
–
71
]. Damage reduction
may also mean reducing the level of blood clotting if clotting is present and repairing any
organ damage, if relevant. The stage of healing requires normalizing the immune response,
reducing lingering inflammation (such as by targeting interleukin 6 [
189
]), and addressing
any acute damage in whatever affected tissues, which, for our purposes, includes blood.
Micro-clots are a possible etiological factor in long COVID-19 [
190
–
192
], as well as COVID-
19 vaccine injury [
193
]. Damage reduction may also mean reducing the level of blood
clotting if clotting is present, and repairing any organ damage, if relevant. Sufferers of
long COVID-19 have been found to have a higher inflammatory response to the initial
COVID-19 infection than those who recover completely from COVID-19 [
194
], so anti-
inflammatory and immunomodulatory medications have been identified as potential long
COVID-19 therapeutics.
Anti-coagulant medication, such as aspirin, can be useful in alleviating the cardiovas-
cular complications of COVID-19 [
195
,
196
], as they have a long history of use in improving
blood flow and reducing coagulopathies [197–199].
Another useful compound for breaking up blood clots is nattokinase, which is a fibri-
nolytic found in fermented soybeans (bacterial species Bacillus subtilis var.
natto) [200,201]
.
Experiments have demonstrated that it potently degrades spike protein [
202
,
203
], which is
an added benefit in addition to its fibrinolytic and anti-coagulant properties [204].
4.6. Potential Therapeutics
In Table 1, we grouped the therapeutics by mechanism and stage (as per our above
definitions) and included information on their origins. Our categorization for sources is
based on the classification of natural products (NP) or pharmaceutical drugs (PD). For
natural products, we included the most common source organism(s) based on its scientific
name for consistency.

Microorganisms 2023,11, 1308 9 of 26
The pharmaceutical compounds with plausible applicability for the treatment of long
COVID-19 and post-vaccine syndrome are listed in Table 1.
Table 1.
Pharmaceutical compounds with plausible mechanisms of action against spike protein-
related pathologies.
Compound Mechanism Reference Clinical Trials Results
Ivermectin
Multiple
Binding of spike
protein
[205–209]
Corticosteroids
Reducing inflammatory
response [210,211] NCT05350774 Proxy: significant decrease in
breathlessness [212]
Antihistamines Reduced inflammation [213–215]
Aspirin Anti-coagulant [216]
Low Dose Naltrexone
(LDN) Immunomodulatory [217,218]NCT05430152
NCT04604704 Significant improvement [218]
Colchicine Reduces inflammation [219–221]
Reduced myocardial infarction,
stroke and cardiovascular death
(non-COVID-19 or vaccine
related) [222]
Metformin Several [223] NCT04510194
An amount of 42% relative decrease
in long-COVID incidence after
treatment of initial C19 infection [
224
]
Likewise, natural compounds and supplements with plausible applicability for the
treatment of long COVID-19 and post-vaccine syndrome are listed in Table 2.
Table 2.
Natural compounds and supplements with plausible mechanisms of action against spike
protein-related pathologies.
Compound Mechanism Reference Clinical Trials Evidence Summary
Vitamin D Immunomodulatory [225] NCT05356936 Proxy (C19 severity) [226]
Vitamin C Immune support,
antioxidant [227] NCT05150782
Reduction in fatigue (not
long-COVID-19 related) [227]
improved oxygenation, decrease in
inflammatory markers, and a faster
recovery were observed in initial
COVID-19 infection (proxy
measure for long-COVID-19) [228]
Improvement in general fatigue
symptoms when combined with
L-arginine [229]
Significant improvement [230]
Vitamin K2 Immunomodulatory [231] NCT05356936 Proxy evidence (severity of
COVID-19 infection) [231]
N-Acetyl Cysteine
(NAC)
Antioxidant,
anti-inflammatory, cellular
metabolism,
blocks S-ACE2 interface
(IS [232])
[233–236]NCT05371288
NCT05152849
Proxy evidence (severity of
COVID-19 infection) [234]
Glutathione
Antioxidant,
anti-inflammatory, cellular
metabolism
[237–239] NCT05371288 Proxy (severity of COVID-19
infection) [239,240]

Microorganisms 2023,11, 1308 10 of 26
Table 2. Cont.
Compound Mechanism Reference Clinical Trials Evidence Summary
Melatonin
Antioxidant,
anti-inflammatory, cellular
metabolism
[241]
Proxy (higher rate of recovery,
lower risk of intensive care unit
admission) [242]
Quercetin
Anti-inflammatory
spike-ACE2 interaction
[243,244]
[243,245–247]
Proxy (faster time to negative PCR
test when combined with Vitamin
D and curcumin) [248]
Emodin Blocks spike-ACE2
interaction [249][249]
Black cumin seed
extract
(nigella sativa)
Anti-inflammatory [250–252]
Resveratrol Anti-inflammaotry,
anti-thrombotic [253–255]Proxy (lower rates of
hospitalization) [256]
Curcumin
Inhibits spike–ACE2
interaction,
inhibits virus
encapsulation [257], binds
SC2 proteins (IS) [258]
[259–261] NCT05150782 Proxy (lowers inflammatory
cytokines) [261,262]
Magnesium Multifactorial, nutritional
support [263,264]
Proxy (low magnesium–calcium
ratio associated with higher C19
mortality [265], low magnesium
associated with higher risk of
infection [266])
Zinc Nutritional support [267–269] NCT04798677 *
Proxy (possibe better acute C19
outcomes [
270
], other meta-analysis
did not confirm efficacy [271])
Nattokinase Anti-coagulant,
degrades spike (IVT) [
203
]
[202,203]Proxy: degrades spike protein
in vitro [203]
Fish Oil Anti-coagulant [272–274] NCT05121766 Proxy (lowered hospital admission
and mortality [272])
Luteolin Decreases inflammation
[275][275–277] NCT05311852
Faster recovery of olfactory
dysfunction when combined with
ultramicronized
palmitoylethanolamide and
olfactory training [278]
St. John’s Wort Decrease inflammation
[279][279,280]
Fisetin
Senolytic [281]
Binds SARS-CoV-2 main
protease (IS) [282]
Binds spike protein
(IS) [283]
[281,283,284]
Frankincense Binds to Furin [285] NCT05150782 Positive impact [286]
Apigenin
Binds SARS-CoV-2 spike
(IS [244]),
antioxidant [287]
[288,289]
Nutmeg Anti-coagulant [290]
Sage Inhibits replication (IVT)
[291][291,292]

Microorganisms 2023,11, 1308 11 of 26
Table 2. Cont.
Compound Mechanism Reference Clinical Trials Evidence Summary
Rutin Binds spike [293] [294] NCT05387252 †
Limonene Anti-inflammatory [295]Antiviral in in vitro assays as
whole bark product [296]
Algae Immunomodulatory [297] [298–300]NCT05524532
NCT04777981
Dandelion leaf
extract
Blocks S1–ACE2
interaction (IS + IVT [301][301]
Proxy (reduction in sore throat in
combination with other extracts
[302]
Cinnamon Immunomodulatory
[303,304][305,306]
Milk thistle extract
(Silymarin)
Antioxidant,
anti-inflammatory [307]
Endothelial protective
(IVO [308])
Blocks spike [308]
[308]Evidence for mechanism, but not
treatment, as of October 2022 [307]
Andrographis
Binds ACE2 (IVT),
reduction in viral load
(IVT) [309]
[310,311]Proxy (no decrease in C19 severity
[312]
prunella vulgaris Blocks spike [313] [313]
Licorice Immunomodulatory,
anti-inflammatory [314][315–318] Proxy (inhibits virus in vitro [319])
Cardamom Anti-inflammatory (IVO
[320][320]Proxy (lowers inflammatory
markers) [320]
Cloves
Antithrombotic,
anti-inflammatory [321],
Blocks S1–ACE2
interaction (IS, CFA) [
322
],
stimulates
autophagy [323]
[321]Prevents post-COVID-19 cognitive
impairment [324]
Ginger Unknown Proxy. Reduced the hospitalization
period in SC2 infection [325]
Garlic Immunomodulatory [326] [326–328]Proxy (faster recovery from C19)
[329]
Thyme Antioxidant, nutrient rich,
anti-inflammatory [330][331]Positive impact on energy levels
[289]
Propolis
ACE2 signalling pathways
(IS [332], IVT, IVO)
[333,334]
Immunomodulation [335]
[333,336,337]
Meta-analysis reveals propolis and
honey could probably improve
clinical COVID-19 symptoms and
decrease viral clearance time [332]
Clinical trials were conducted for a long period, unless otherwise stated. Clinical trials are for long COVID-19,
unless otherwise stated. * Vaccine immune response.
†
Adverse reactions to vaccination adverse reaction. Under
mechanism. IS: in silico. IVT: in vitro. IVO: in vivo.
5. Discussion
The amelioration of symptoms and recovery of large numbers of people worldwide
from both long COVID and post-vaccine syndrome and injury requires the use of non-
invasive, integrative therapies that can be scaled and administered in a decentralized
fashion. It is important to disseminate this knowledge to the lay public so that they
can mitigate their individual risks and those of their loved ones. While it is difficult to
enumerate the true scale of post-vaccination or post-COVID clotting disorders, there has
been an appreciable rise in cardiac incidents [
29
], strokes (inter-cerebral hemorrhages [
338
]),

Microorganisms 2023,11, 1308 12 of 26
and non-COVID excess mortality [
339
,
340
]. A significant increase in total mortality due to
a vaccine is not unprecedented, as the DTP vaccine administered in Guineau-Bissau in the
1980s increased child mortality by four times compared to unvaccinated mortality [341].
While the magnitude of the impact of both long COVID-19 and post-COVID-19 Vaccine
Syndrome or injury is unclear, it is important to prepare for the potential consequences by
having information ready for dissemination, as well as to perform research on promising
therapeutics to relieve the damage caused by spike protein and other potential mechanisms
of harm, such as DNA integration [
342
]. One limitation of this study is that it focuses
on spike-protein related pathology and can leave out other possibilities, such as allergies
to vaccine components, or other disease etiologies. Long COVID-19 and post-COVID-
19 vaccine syndrome are multifaceted disorders, with highly varied manifestations; as
such, the development of objective diagnostics is important in treating patients. The
therapies discussed in this review have a varying evidentiary basis and may serve as
starting points for the development of therapies to relieve spike protein-related pathologies
in the coming years.
Further research requires validating the treatments outlined in this review by ran-
domized control trial (RCT), observational studies, and laboratory studies of biological
mechanism. Furthermore, integration of the current research on spike-protein related
disorders is helpful. One possibility is the application of systems biology tools to describe
the perturbations to different biological pathways influenced by the spike protein. When
such a model exists, it is possible to treat the acute manifestations of the disease while still
clearing spike protein form the body.
Governments and national health services are beginning to come to terms with the
sheer magnitude of the task in front of them. This review outlines some of the most
promising therapies form an evidentiary and biological mechanistic perspective. We hope
that this article be used in the construction of treatment protocols to treat these highly
related conditions in their many disease manifestations, prioritizing not only safety and
efficacy, but cost and availability to large numbers of people.
Supplementary Materials:
The following supporting information can be downloaded at: https:
//www.mdpi.com/article/10.3390/microorganisms11051308/s1, Table S1: Overview of Clinical
Trials for Long-COVID and COVID-19 vaccine injury.
Author Contributions:
Conceptualization, M.T.J.H.; methodology, M.T.J.H.; investigation, M.T.J.H.,
C.P., P.M., and T.A.L.; writing—original draft preparation, M.T.J.H.; writing—review and editing,
M.T.J.H., C.P., P.M., and T.A.L.; supervision and project administration, M.T.J.H.; funding acquisition,
T.A.L. All authors have read and agreed to the published version of the manuscript.
Funding:
This article was crowd-funded by public donations to the World Council for Health initiative.
Data Availability Statement:
Publicly available datasets were analyzed in this study. Data on clinical
trials can be found at clinicaltrials.gov.
Acknowledgments:
The authors acknowledge the contributions of Francesca Havens, Dana F. Flavin,
and A.J. In addition, the authors acknowledge the seminal contributions of the FLCCC Alliance and
the publication of protocols for the management of the vaccine injured (https://COVIDCOVID1
9criticalcare.com/treatment-protocols/i-prevent-vaccine-injury/, accessed on 15 April 2023).
Conflicts of Interest:
M.T.J.H., C.P., and T.A.L. are on the Health and Science Committee of the World
Council for Health, a people-centered initiative of the not-for-profit Community Interest Company
(CIC) EbMCsquared, for advancing holistic health.
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