Significance of the SARS-CoV-2 Spike
Protein ‘Superantigen’ Sequence in themRNA Vaccines
Steven J. Hatfill, M.D.

By March 2020 the heart was recognized to be a frequent
target organ in SARS-CoV-2 infection, as evidenced by theincreased cardiac troponin levels observed in many late-stage
COVID-19 patients.1 The mechanisms for this cardiac damage
appear multifactorial, involving both a myocarditis initiated by
the direct viral binding to the normal angiotensin converting
enzyme 2 (ACE-2) receptors on the cardiac pericytes, as well
as extra-cardiac processes involving myocardial ischemia.2
Pericarditis/myocarditis post COVID-19 mRNA vaccination is
also an increasing concern.
Vaccine-Induced Cardiac Injury
New data concerning COVID-19 mRNA vaccine injury
comes from a recent report on the autopsy of two adolescentdeaths shortly after the administration of a second Pfizer
BioNTech COVID-19 mRNA injection.3
One autopsy revealed global myocardial injury withareas of coagulative myocytolysis and contraction bands,
with a perivascular pattern of inflammation consistingof predominantly neutrophils with histiocytes, scant
lymphocytes, and occasional eosinophils. The second autopsy
showed predominant subepicardial myocyte injury, while inother sections it was patchy and transmural.
Polymerase chain reaction (PCR) tissue testing performedby the Centers for Disease Control and Prevention (CDC)
on heart and lung found no molecular evidence of SARSCoV-2 infection. Molecular testing on postmortem blood
detected two heterozygous DOLK gene variants of uncertain
significance and a heterozygous MAP2K2 gene (Intronic).
There were no acute or organizing thrombi.
The overall pattern of injury was consistent with anorepinephrine-mediated stress (toxic) cardiomyopathy
involving a direct injury to the myocardium.4 This has somecommonalities with patients diagnosed with Takotsubo
cardiomyopathy.5

and the COVID-19 mRNA vaccines.1 This commonality appears
to be located in a short amino acid sequence in the S1 spike
protein of the virus.
Toxic “Superantigen” Motif in the mRNA Vaccines
Extensive writings about the furin cleavage site (FCS) of
the spike protein of the SARS-CoV-2 virus largely ignore apreceding curious stretch of 20 amino acids (segment T678
to Q690) embedded in the S1 monomer of the trimeric spike
protein. This segment harbors a unique sequence motif thatis not present in other known SARS-related β-coronaviruses.
In September 2020, a computational molecular modelingstudy revealed that this amino acid region is similar both infunction and three-dimensional structure to the functional
motif of staphylococcal enterotoxin B (SEB) (amino acidsequence T150NKKKATVQELD161), a potent bacterial“superantigen” (SAg) toxin produced by Gram-positive
Staphylococcus aureus bacteria (Figure ).7,8 It is of note that the
SEB toxin itself is potent enough to be classified as a category
B select agent and that it was manufactured on a large scale
as a biological weapon during the 1960s (William C. Patrick III,
personal communication, Jul 11, 1998).

Positive Norepinephrine-Cytokine Feedback Loop
Both septic shock and the hyperinflammatory side effects
associated with several new cancer therapies have revealed
the existence of a self-amplifying positive feedback loop
between an excess cytokine release by macrophages and theprogressive abnormal elevation of circulating norepinephrine
levels in patients. In some instances, this expanding positive
feedback loop may progress into an uncontrolled severe lethal
inflammatory response called a “cytokine storm” or cytokine
release syndrome.6
The fact that cytokine storms may appear in some latestage COVID-19 patients prompted a search for a causative
component common to both a natural SARS-CoV-2 infection

Figure 1. Sequence Alignment of SARS-CoV-2 and Related
Strains Near the S1/S2 Cleavage Site. Viruses belonging to
the same lineage are shown by the same color shade. The
only other strain with a furin-like cleavage site is the distantly
related MERS coronavirus highlighted in bold font. So far, thepolybasic insert PRRA and the upstream SAg-like motif of
SARS-CoV-2 has not been found in any closely related SARSlike coronavirus. (Illustration courtesy of Brian Scaglione at the
P-Value Group)

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The spike protein of SARS-CoV-2 is a trimeric trans­
membrane protein responsible for host cell recognition,
attachment, and entry of the virus. It features two extremely
large monomers termed S1 and S2, each containing roughly
1,300 amino acid residues. These are fixed to a protein
backbone to form the complete trimeric three-dimensional
spike protein structure.9
Furin Cleavage Site Enclosed within the SAg-like Motif of
the S1 Protein Subunit
Upon the cleavage of the viral PRRA polybasic insert
by the furin enzyme located on the host cell surface, theS1 protein is released into the extracellular space and the
20-amino acid SAg-like sequence similar to SEB, is available
to undergo a high-affinity general binding to T-cell receptors(TCRs) largely irrespective of their antigenic clonality. This
polyclonal TCR binding ability is common to both SARSCoV-2 and the spike protein-based mRNA vaccines when the
S1 protein is cleaved.
After intracellular viral replication, the new daughter
viruses are transported back to the surface of the cell where
they are released to infect more normal cells. As part of thisprocess, the virus’s S1 monomer in the new daughter viruses
is cleaved at the FCS, and it changes its three-dimensional
conformation from a closed into an open configuration(Figure 2). This now-open conformation exposes the aminoacid sequences forming the SEB SAg-like motif of thecleaved S1 subunit to the outside where they are accessible
for binding to TCRs found on circulating cytotoxic T-cell
lymphocytes to cause large-scale polyclonal T-cell activationand proliferation. This leads to a massive production of
circulating proinflammatory cytokines (cytokine storm)that includes IFNγ, TNFα, and IL-2 from T cells, as well as IL-1
and TNFα from macrophages.8 This can cause a progressive
positive feedback loop between elevated cytokine levels
and circulating norepinephrine levels, leading to severe
cardiac damage.9

Clinical Effects of Superantigen Exposure
SEB is one of the most potent bacterial superantigens
known to science, and it can generate severe clinicalsymptoms in humans at concentrations as low as 0.0004 μg/
kg with death from multi-organ failure and toxic shock at 0.02
μg/kg of body weight.10
Severe pulmonary exposure to the purified SEB
superantigen causes fever, chills, headache, and muscle pain,with reactive interstitial and later pulmonary edema. This issimilar to late-phase COVID-19 infection in adults who may
progress into an adult respiratory distress syndrome (ARDS)
and septic shock.1
The inflammatory cytokine release from T-cells andmacrophages induced by the bacterial SEB SAg toxin has a
profile similar to the cytokine profile in COVID-19 patientswith a prognosis of severe infection and death.12 This includes
elevated levels of IL-6, TNFα, IL-8, and IL-1β, which lead tomultiorgan tissue damage.12
Such an abnormal cytokine profile is also observedin infected children that develop COVID-19-associatedmultisystem inflammatory syndrome (MIS-C),13,14 and in
COVID-19 “long hauler syndrome.”15 A cohort analysis ofadult COVID-19 patients reveals that cases with severe
hyperinflammatory disease also exhibit a marked skewingof the TCR repertoire that is consistent with superantigen
activity.7
Another study indicates that the rare SARS-CoV-2 spike
protein mutation (D839Y/N/E) detected in a European strain of
the COVID virus may potentially further enhance TCR bindingin late-phase COVID-19 patients.7
It is therefore reasonable to assume that thehyperinflammatory syndrome of COVID-19 originates fromthe superantigen sequence embedded in the S1 monomer ofthe spike protein in both SARS-CoV-2 and the mRNA vaccines.
It is also reasonable to propose that in some cases thesuperantigen motif in the spike protein of SARS-CoV-2 cantrigger an uncontrolled positive feedback loop between
excessive cytokine release and excessive norepinephrine
release, causing both cytotoxic and ischemic myocardialdamage. This is expected to occur in natural COVID-19
infections and in some mRNA vaccine recipients, as well as inrare cases of the multisystem inflammatory syndrome (MIS-C)
observed in COVID-19-infected European and American
children.3, 14
More Studies of Myocardial Injury Urgently Needed

Figure 2. Conformation Changes in the Free-floating Fragmentof the S1 Protein after Furin Cleavage of the SARS-CoV-2 Spike
Protein
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More data on norepinephrine-induced myocardial injury
in mRNA vaccine recipients are urgently needed. Studies
must focus on new immunizations involving the original
mRNA vaccines, and they should not include Omicron andits subvariant clinical cases or recipients of the new OmicronmRNA vaccine, because of the extensive mutational changes
that have occurred in the spike protein of these new variants.16
Omicron exhibits mutations in the P681RRAR685 putative
SAg-like segment of the S1 subunit with possible changes inspike protein cleavage and exposure of the C-terminal end,53

with changes in viral fitness, infectivity, and apparently alower virulence.17
Repeated flow-cytometry assessments and measure­ments of circulating catecholamine levels, particularly
norepinephrine, should be performed on new recipients of
the original Moderna and Pfizer vaccines. Existing autopsy
material could also be re-examined and partially characterized
via immunohistochemical studies.
Early clinical use of β2-receptor antagonists to diminish any
developing positive feedback loop between catecholaminedriven signaling and hyperinflammation in active COVID-19
infection, long-hauler syndrome, and non-Omicron postvaccine injuries should also be studied.18
Potential therapeutic agents, already long approvedby the Food and Drug Administration (FDA), include antiinflammatory drugs such as the antibiotic minocycline19 andthe inexpensive drug indomethacin (which has shown value
in SARS1 infection).20 These should be tested in combinationin animal models of SEB-induced toxic shock syndrome. Other
agents to test include CTLA4-Ig, which can inhibit CD28 costimulation of cytotoxic T-cells,21 and the mTOR inhibitor
rapamycin.22
Origin of the Superantigen Sequence
The SAg sequence embedded in the SARS-CoV-2 virus lacks
any defined viral evolutionary lineage. No other SARS-related
β-coronaviruses outside of SARS-CoV-2 is known to have thisSEB-analog sequence. As noted above, the SEB toxin has been
manufactured on a large-scale as a biological weapon.23
Lacking a defined natural evolutionary lineage for the
SEB-like motif in the S1 monomer, we must consider alaboratory origin for SARS-CoV-2. The presence of the SAglike motif was not detected by normal protein or nucleotide
Basic Local Alignment Search Tool (BLAST Search) efforts. It
was only discovered after a structure and dynamics analysis.
With respect to an artificial origin of SARS-CoV-2, the Wuhan
Institute of Virology is often mentioned. However, the creationof the mRNA for this S1 SEB SAg-like sequence would haverequired full structure and dynamics analyses necessitating
the cooperation of a well-resourced advanced researchlaboratory with a computational protein modeling capability.
This would include an experienced proteomics facility withspecialized equipment and expertise not generally available
in a dedicated virology laboratory.
During the 1990s, the former Soviet Biopreparat offensive
biological weapons program was experimenting with thegenetic insertion of peptide toxins and immunogenetic
peptides (myelin basic protein) into known biological warfare
pathogens (Kanatjan Alibekov, personal communication,1998).24 Also note that beginning in 2003 a number of senior
Chinese officials started to advocate that China continue thistype of gain-of-function Soviet offensive biological warfare
research.25,26
Although the majority of SARS-CoV-2 infections todate have been accompanied by a very low mortality rate,
if the SEB SAg-like motif present in the virus proves to be
an intentional genetic insert, this technology represents a
dramatic advancement in offensive biological warfare using
54

incapacitating agents. As has now been witnessed, thisconstitutes a direct, severe strategic threat to the U.S. and its
allies.
Unconscionable Delay
Although the discovery of the SEB-like functional
superantigen motif in the spike protein of SARS-CoV-2 waspublished as an open-access report in the Proceedings of the
National Academy of Sciences on Sept 28, 2020,7 the clinicalsignificance of the SAg-like motif in the spike protein of thevirus is only now receiving attention and debate. Yet millionsof Americans and Europeans have already been injected withthis mRNA sequence as part of the global mRNA vaccination
program. The mRNA produced by these injections can remainin the body for months.
When published in 2020, the in-silico computationalmodeling report should have triggered an immediate vaccine
review by Dr. Anthony Fauci and the COVID-19 Task Force, Dr.
Francis Collins at the National Institutes of Health, Professor
Arnold Monto at the University of Michigan (chairman of theoutside panelists at the FDA Center for Biologics Evaluation),
FDA Commissioner Dr. Stephen Hahn, Dr. Janet Woodcock,and Dr. Peter Marks. It also should have included Moncef
Slaoui, Ph.D., who was tasked to manage the Operation Warp
Speed project, as well as representatives from the vaccine
manufacturers.
As far as I can determine, no such meeting concerning the
COVID-19 superantigen motif ever occurred, yet questions
over mRNA vaccine safety had appeared as early as February
2021. By March 2021, more than 20 European countries had
temporarily stopped using AstraZeneca's COVID-19 vaccine
pending a safety review. In April 2021, an 11-day hold
was placed on the Johnson & Johnson mRNA vaccine. The
extensive serious adverse events associated with the Modernaand Pfizer vaccines are currently the subject of continuing
discussion, with many countries now moving away from theirineffective mRNA vaccination mandates.
Vaccine Adverse Events
Throughout 2021 and into 2022, the number of recorded
serious adverse post-injection clinical events has dramaticallyincreased, even as hesitant Americans have been underintensifying duress to receive these still highly experimental,
non-FDA-approved mRNA vaccines. Additionally, clinicallyunnecessary childhood vaccinations using these preparations
are being intensely promoted.
In contrast to the reported annual 39 deaths attributed
to the influenza vaccine, with roughly 43 percent of the U.S.
population vaccinated,27 thousands of COVID-19 vaccinationsassociated deaths have been reported to the Vaccine Adverse
Event Reporting System (VAERS),28 with roughly 66 percent of
the total population vaccinated.
Conclusion
The mechanism of severe adverse reactions, especially
myocarditis, in both COVID-19 patients and in COVID mRNA
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vaccine recipients may be related to the superantigen motif
in the spike protein of the virus, for which the vaccine mRNA
codes. Yet, the reported presence of this SAg has not been
openly discussed, and its origin is not clear. Urgent study isneeded of this or any other potential mechanism of cardiac
injury in COVID-19 and COVID-19 vaccinated patients. Officials
responsible for failure to act on information pertaining topotentially disastrous vaccine-induced damage should beheld accountable.
Steven J. Hatfill, M.D., served as a daily outside senior medical advisor to the
Executive Office of the President throughout 2020.

Acknowledgement: Special thanks are due to Brian Scaglione at the P-Value
Group for his analysis and graphic illustrations.

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