Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Autoimmune Inflammatory Reactions Triggered by the COVID-19 Genetic Vaccines in Terminally Differentiated Tissues

Version 1 : Received: 7 March 2023 / Approved: 8 March 2023 / Online: 8 March 2023 (02:57:33 CET)

A peer-reviewed article of this Preprint also exists.

Panagis Polykretis, Alberto Donzelli, Janci C. Lindsay, David Wiseman, Anthony M. Kyriakopoulos, Michael Mörz, Paolo Bellavite, Masanori Fukushima, Stephanie Seneff & Peter A. McCullough (2023) Autoimmune inflammatory reactions triggered by the COVID-19 genetic vaccines in terminally differentiated tissues, Autoimmunity, 56:1, DOI: 10.1080/08916934.2023.2259123 Panagis Polykretis, Alberto Donzelli, Janci C. Lindsay, David Wiseman, Anthony M. Kyriakopoulos, Michael Mörz, Paolo Bellavite, Masanori Fukushima, Stephanie Seneff & Peter A. McCullough (2023) Autoimmune inflammatory reactions triggered by the COVID-19 genetic vaccines in terminally differentiated tissues, Autoimmunity, 56:1, DOI: 10.1080/08916934.2023.2259123

Abstract

As a result of the spread of SARS-CoV-2, a global pandemic was declared. Indiscriminate COVID-19 vaccination has been extended to include age groups and naturally immune people with minimal danger of suffering serious complications due to COVID-19. Solid immuno-histopathological evidence demonstrates that the COVID-19 genetic vaccines can display an off-target distribution in tissues that are terminally differentiated, triggering autoimmune reactions. These include the heart and brain, which may incur in situ production of spike protein eliciting a strong autoimmunological inflammatory response. Due to the fact that every human cell which synthesizes non-self antigens becomes inevitably the target of the immune system, and since the human body is not a strictly compartmentalized system, accurate pharmacokinetic and pharmacodynamic studies are needed in order to determine precisely which tissues can be harmed. Therefore, our article aims to draw the attention of the scientific and regulatory communities on the critical need of bio-distribution studies for the genetic vaccines against COVID-19, as well as of rational harm-benefit assessments by age group.

Keywords

COVID-19; genetic vaccines; adverse reactions; autoimmunity; immunohistochemistry; spike protein

Subject

Biology and Life Sciences, Immunology and Microbiology

Comments (3)

Comment 1
Received: 8 March 2023
Commenter: Vinu Arumugham
The commenter has declared there is no conflict of interests.
Comment: https://twitter.com/SynthIge/status/1633536089741991936
I don't think it is correct to refer to this as autoimmunity. Autoimmunity means antibodies or T-cells directed against self-antigens,not a foreign antigen such as spike.
I pointed this out to immunologist Prof.Byram Bridle and he agreed.

https://viralimmunologist.substack.com/p/modernas-cmo-believes-spikes-from/comment/9146395
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Comment 2
Received: 13 March 2023
The commenter has declared there is no conflict of interests.
Comment: I think this article is inaccurate in that cells do not express the spike protein fully on the membrane triggering an autoimmune response. Under normal circumstances HLA class I, present on all nucleated cells display peptides derived from the proteins being created inside the cell, as described correctly in the paper. Also dendritic cells and others display peptides from any foreign entity on the HLA class II receptors. HLA Class I bind to the variable parts of the amino acids, are enclosed and only accept peptides that are 5-9 amino acids long. and vary significantly in individuals. HLA Class II bind to the amino part of the peptide and are open ended.
Autoimmunity arises because of B and T cells that have occurred in the peripheral tissue that have not gone through the self/non self selection process in the bone marrow and hence cannot distinguish between self and non self peptides presented on cells and the proceed to target cells that are not infected. Another mechanism that can cause problems is molecular mimicry where peptides are similar to proteins found on native cells and antibodies that are created attacke those native cells, as in Guillain Barre Syndrome.
Thus the sentence at the end of paragraph 3 on page 2 is, I believe, incorrect.
The purpose of antibodies against a viral infection is to bind to the part of the virus that facilitates entry into the host cell, in the case of SARS-CoV-2 this is the spike protein.
The spike protein in breast milk (paragraph 4) lasts for 48 hours and is insignificant in its quantity. Also this was obtained by expressing the milk, which is a different mechanism to suckling infants.
Paragraph 6: How do you know that the patient wasnt infected with SARS-CoV-2? With SARS-CoV-2 derived myocarditis it is the spike protein that is found. The patient described by Morz had multiple co-morbidities, and again how can you say beyond reasonable doubt that the spike protein found in the brain was from the vaccine and not from SARS-CoV-2 virus, again the spike protein from the virus is found in preference to any other part of the virus. See https://www.youtube.com/watch?v=i9JLZuhqRuU particularly the pinned first comment from Dr Seheult about the spike protein in preference to the nucleocapsid being found in those infected with SARS-CoV-2 before the vaccines were even introduced.
Autoimmunity has also been reported in SARS-CoV-2 infected patients (Halpert 2020 "SARS-CoV-2, the autoimmune virus"; Shah et al 2020 "Autoimmune and rheumatic musculoskeletal diseases as a consequence of SARS-CoV-2 infection and its treatment", Sacchi, M.C., Tamiazzo, S., Stobbione, P., Agatea, L., De Gaspari, P., Stecca, A., Lauritano, E.C., Roveta, A., Tozzoli, R., Guaschino, R. and Bonometti, R. (2021), SARS-CoV-2 infection as a trigger of autoimmune response. Clin Transl Sci, 14: 898-907.; Vojdani A, Kharrazian D. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clin Immunol. 2020 Aug;217:108480. doi: 10.1016/j.clim.2020.108480. Epub 2020 May 24.; Algassim, A.A., Elghazaly, A.A., Alnahdi, A.S. et al. Prognostic significance of hemoglobin level and autoimmune hemolytic anemia in SARS-CoV-2 infection. Ann Hematol 100, 37–43)
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Response 1 to Comment 2
Received: 14 March 2023
Commenter:
The commenter has declared there is no conflict of interests.
Comment: The comment is inaccurate for at least three reasons. 1) the full-lenght Spike protein is actually expressed on the surface of mRNA-transfected muscle cells or immune cells (https://www.science.org/content/blog-post/spike-protein-behavior), our paper shows that these proteins are expressed by OTHER differentiated cells besides muscle cells; 2) assuming that only pieces of Spike protein are expressed by target cells, these non-self peptides should be enough to trigger autoimmune and/or autoinflammatory reactions capable of damaging the indicated organs; 3) the proof that Spike protein derived by vaccine and not by virus is quite straightforward: in immunohystochemistry only S protein and not N protein was detected.
Response 2 to Comment 2
Received: 17 March 2023
Commenter:
The commenter has declared there is no conflict of interests.
Comment: We thank the commentator for giving us the opportunity to deepen the contents of our paper. Please, find below a point-by-point answer:

• “I think this article is inaccurate in that cells do not express the spike protein fully on the membrane triggering an autoimmune response. Under normal circumstances HLA class I, present on all nucleated cells display peptides derived from the proteins being created inside the cell, as described correctly in the paper. Also dendritic cells and others display peptides from any foreign entity on the HLA class II receptors. HLA Class I bind to the variable parts of the amino acids, are enclosed and only accept peptides that are 5-9 amino acids long. and vary significantly in individuals. HLA Class II bind to the amino part of the peptide and are open ended.
Autoimmunity arises because of B and T cells that have occurred in the peripheral tissue that have not gone through the self/non self selection process in the bone marrow and hence cannot distinguish between self and non self peptides presented on cells and the proceed to target cells that are not infected. Another mechanism that can cause problems is molecular mimicry where peptides are similar to proteins found on native cells and antibodies that are created attacke those native cells, as in Guillain Barre Syndrome.
Thus the sentence at the end of paragraph 3 on page 2 is, I believe, incorrect.


Answer: The fact that the spike protein can be displayed on the cellular membrane even as an entire protein (upon transfection with the mRNA vaccines, or upon infection with the adenoviral vaccines) is not a notion that has been introduced in our paper, but rather it is something that has been discussed by several authors since the introduction of the genetic vaccines against COVID-19. In this regard, please see the reviews by Mascellino et al. (1), and Cagigi and Loré (2). However, there is not a consolidated opinion yet, and in fact, in the paper we quote the words of Pfizer’s Senior Vice President for Vaccine Clinical R&D Dr. William Gruber: “we don't have a complete understanding of the nature of the way that the vaccine works in terms of producing immune response” (3). Having said that, what really matters for the purposes of our paper, is that every antigen presenting cell is going to be perceived as a threat by the immune system and killed regardless of how the vaccine-derived spike protein is presented: as an entire protein, or as a fragment derived from the proteasomal degradation and mounted on the MHC I (in case of the nucleated cells) or on the MHC II (in case of the APCs). In short, even if the entire protein is not displayed on the cell membrane, its peptide fragments are presented on the MHC, because this is how the antigen presentation process works.
The Merriam-Webster medical dictionary defines autoimmunity as: "a condition in which the body produces an immune response against its own tissue constituents" (6). Autoimmunity is a broad definition that can have different origins, depending on the triggering factor. Among them, autoimmunity can have a viral triggering factor. Quote from Hussein and Rahal: "Viral infection has been associated with multiple autoimmune diseases. These infections typically trigger several immune processes some of which could overwhelm the immune regulatory mechanisms. This may result in immune reactions directed to viral as well as host antigens potentially resulting in tissue damage. Several mechanisms, including molecular mimicry, bystander activation of T-cells and epitope spreading have been the primary ways of explaining how a viral infection might induce a series of reactions resulting in an autoimmune disease"(7).
Molecular-mimicry triggers reactions against self antigens that share structural similarities with viral epitopes, for which the immune system has created reacting antibodies; but, as abovementioned, immune reactions resulting in tissue damage can be directed even against viral antigens. The genetic vaccines induce human cells to synthesize a viral antigen, the spike protein, triggering this mechanism.

• “The purpose of antibodies against a viral infection is to bind to the part of the virus that facilitates entry into the host cell, in the case of SARS-CoV-2 this is the spike protein.

Answer: The purpose of the antibodies, or the epitope of the SARS-CoV-2 spike protein against which they have specificity, is irrelevant to our article. The key message of our paper is to underline the notion that every human cell which synthesizes non-self antigens becomes inevitably the target of the immune system, and consequently, accurate bio-distribution studies are needed, in order to determine precisely which tissues can be harmed.

• “The spike protein in breast milk (paragraph 4) lasts for 48 hours and is insignificant in its quantity. Also this was obtained by expressing the milk, which is a different mechanism to suckling infants.

Answer: We mention that the vaccinal mRNA has been detected in breast milk (8), as a proof of the fact that the genetic material can spread beyond the injection site, reaching distal cells and body secretions. However, concerning the statement “insignificant in its quantity”, we are unaware of studies provided by Pfizer or Moderna to determine whether or not levels of mRNA found in breast milk are significant.

• “Paragraph 6: How do you know that the patient wasnt infected with SARS-CoV-2? With SARS-CoV-2 derived myocarditis it is the spike protein that is found. The patient described by Morz had multiple co-morbidities, and again how can you say beyond reasonable doubt that the spike protein found in the brain was from the vaccine and not from SARS-CoV-2 virus, again the spike protein from the virus is found in preference to any other part of the virus. See https://www.youtube.com/watch?v=i9JLZuhqRuU particularly the pinned first comment from Dr Seheult about the spike protein in preference to the nucleocapsid being found in those infected with SARS-CoV-2 before the vaccines were even introduced.
Autoimmunity has also been reported in SARS-CoV-2 infected patients (Halpert 2020 "SARS-CoV-2, the autoimmune virus"; Shah et al 2020 "Autoimmune and rheumatic musculoskeletal diseases as a consequence of SARS-CoV-2 infection and its treatment", Sacchi, M.C., Tamiazzo, S., Stobbione, P., Agatea, L., De Gaspari, P., Stecca, A., Lauritano, E.C., Roveta, A., Tozzoli, R., Guaschino, R. and Bonometti, R. (2021), SARS-CoV-2 infection as a trigger of autoimmune response. Clin Transl Sci, 14: 898-907.; Vojdani A, Kharrazian D. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clin Immunol. 2020 Aug;217:108480. doi: 10.1016/j.clim.2020.108480. Epub 2020 May 24.; Algassim, A.A., Elghazaly, A.A., Alnahdi, A.S. et al. Prognostic significance of hemoglobin level and autoimmune hemolytic anemia in SARS-CoV-2 infection. Ann Hematol 100, 37–43).


Answer:
i) Schwab et al., did not use an anti-spike antibody (Ab) (9). However, in support of the fact that the spike protein was vaccine-derived, they report:

Quote: "According to the available information provided at the time of autopsies, none of the deceased persons had SARS-CoV-2 infection prior to vaccination and nasopharyngeal swabs were negative in all cases."

Quote: "In general, a causal link between myocarditis and anti-SARS-CoV-2 vaccination is supported by several considerations: (A) a close temporal relation to vaccination; all cases were found dead within one week after vaccination, (B) absence of any other significant pre-existing heart disease, especially ischaemic heart disease or cardiomyopathy, (C) negative testing for potential myocarditis-causing infectious agents, (D) presence of a peculiar CD4 predominant T-cell infiltrate, suggesting an immune mediated mechanism."

Quote: "Fig. 3  A The jab site in the deltoid muscle reveals focal inflammation. The composition is similar to the phenotype of the myocardial infiltrates showing predominantly, B CD3 and C CD4-coexpressing lymphocytes and D interspersed CD68-positive macrophages."

Consequently, they give several explanations of the fact that the inflammation within the myocardium has been likely triggered by the translation of the vaccine encoded spike protein.

ii) Baumeier et al. (10), did use anti-spike Ab, but not anti-nucleocapsid protein. However, in support of the fact that the spike protein was vaccine-derived, they report:

Quote: "All EMBs were negatively tested for SARS-CoV-2 using E-gene-specific sequences."

iii) Mörz did use anti-spike and anti-nucleocapsid Abs (11). Consequently, this excludes the viral origin of the spike protein detected in the analysed specimen.:

Quote: “Immunohistochemical staining for the presence of SARS-CoV-2 antigens (spike protein and nucleocapsid) was studied in the brain and heart.

We do not exclude that autoimmune phenomena can be caused even by SARS-CoV-2; however, the histopathological studies that we cite in paragraph 6 are evidences of vaccine induced inflammatory reactions beyond the injection cite, also in terminally differentiated tissues. A damage deriving from an anthropogenic action (like vaccination) has a far higher ethical severity with respect of a natural cause like a viral infection (assuming that SARS-CoV-2 is natural, which is a debated topic that does not pertain to our study).


References
1. Mascellino MT, Di Timoteo F, De Angelis M, Oliva A. Overview of the Main Anti-SARS-CoV-2 Vaccines: Mechanism of Action, Efficacy and Safety. Infect Drug Resist. 2021 Aug 31;14:3459–76.
2. Cagigi A, Loré K. Immune Responses Induced by mRNA Vaccination in Mice, Monkeys and Humans. Vaccines (Basel). 2021 Jan 18;9(1):61.
3. FOOD AND DRUG ADMINISTRATION (FDA) Center for Biologics Evaluation and Research (CBER) 174th Vaccines and Related Biological Products Advisory Committee (VRBPAC) Meeting [Internet]. 2022. Available from: https://www.fda.gov/media/161064/download
4. Rock KL, Reits E, Neefjes J. Present Yourself! By MHC Class I and MHC Class II Molecules. Trends in Immunology. 2016 Nov 1;37(11):724–37.
5. Kotsias F, Cebrian I, Alloatti A. Antigen processing and presentation. Int Rev Cell Mol Biol. 2019;348:69–121.
6. Medical Definition of AUTOIMMUNITY [Internet]. 2022 [cited 2022 Nov 4]. Available from: https://www.merriam-webster.com/medical/autoimmunity
7. Hussein HM, Rahal EA. The role of viral infections in the development of autoimmune diseases. Critical Reviews in Microbiology. 2019 Jul 4;45(4):394–412.
8. Hanna N, Heffes-Doon A, Lin X, Manzano De Mejia C, Botros B, Gurzenda E, et al. Detection of Messenger RNA COVID-19 Vaccines in Human Breast Milk. JAMA Pediatrics [Internet]. 2022 Sep 26 [cited 2022 Nov 20]; Available from: https://doi.org/10.1001/jamapediatrics.2022.3581
9. Schwab C, Domke LM, Hartmann L, Stenzinger A, Longerich T, Schirmacher P. Autopsy-based histopathological characterization of myocarditis after anti-SARS-CoV-2-vaccination. Clin Res Cardiol [Internet]. 2022 Nov 27 [cited 2022 Dec 4]; Available from: https://doi.org/10.1007/s00392-022-02129-5
10. Baumeier C, Aleshcheva G, Harms D, Gross U, Hamm C, Assmus B, et al. Intramyocardial Inflammation after COVID-19 Vaccination: An Endomyocardial Biopsy-Proven Case Series. International Journal of Molecular Sciences. 2022 Jan;23(13):6940.
11. Mörz M. A Case Report: Multifocal Necrotizing Encephalitis and Myocarditis after BNT162b2 mRNA Vaccination against COVID-19. Vaccines. 2022 Oct;10(10):1651.

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