Editorial

SARS-CoV-2 vaccine-triggered autoimmunity: Molecular mimicry and/or bystander activation of the immune system

A more recent pandemic of COVID-19 caused by the SARS-CoV-2 is one of the most devastating global problems, seriously threatening public health worldwide.^1,2 Despite the incredible effectiveness of the vaccines against COVID-19 in controlling pandemic and significantly reducing mortality, their biological impacts (e.g., long-term safety, adverse effects [AEs], and long-term efficacy) should be carefully clarified, especially among those who have chronic immune system-related disorders. The viral vaccination may be associated with mild to severe levels of AEs which are usually tolerable and harmless. However, individuals with a history of allergic reactions with possible IgE-mediated responses might severely respond to the vaccination and generate severe immunologic reactions.³

It has been shown that viral vaccination may induce autoimmunity, as a rare vaccine-related AEs.⁴ Accordingly, several studies have shown autoimmune reactions after anti-infectious vaccination against tetanus, rubella, hepatitis B, and influenza.⁵ Following the universal vaccination of COVID-19, some concerns about vaccine-triggered autoimmunity or autoinflammatory-like conditions as multifactorial phenomena have been raised. Such AEs may be caused by the overstimulation of the immune system through different immunological mechanisms, including (i) antigen-specific reactions related to the epitope-based vaccines, and (ii) antigen-independent activation of CD8⁺/CD4⁺ T or B-cells, which can be mainly addressed in the vaccines developed using conventional methods.^6,7

Molecular mimicry (MM), an antigen-specific immune response, seems to be a possible mechanism in acquired autoimmunity post-COVID-19 vaccination. Accordingly, it has been suggested that the potential cross-reactivity of the nucleoprotein/spike protein of SARS-CoV-2 with human tissue due to the viral antigenic mimicry may be connected to an increase in autoimmune diseases.⁸ In the occurrence of such autoimmune reactions, the cross-reaction phenomena must take place at “disease-related” epitopes. Perhaps, such phenomena might occur through peptides of self-antigens that are presented by major histocompatibility complex II (MHC class II) on antigen-presenting cells (APCs) to auto-reactive CD4⁺ T-cells.⁹ Regarding the MM hypothesis, there are concerns about using entire SARS-CoV-2 antigens in vaccine development and it seems that considering only specific and unique peptides would be the most effective strategy against such AEs.¹⁰ In addition to the MM mechanism(s), mRNA vaccines before the translation might activate several pro-inflammatory cascades and lead to aberrant responses of innate and acquired immune systems, which are the basis of numerous immune-mediated diseases. Due to the higher immune system activity against viral antigens in people under 55 years, such abnormalities may occur providing great protection against viral antigens and also making them predisposed to a higher burden of immunological AEs.¹¹

In addition to the specific viral antigens, the components classified as non-target antigens of a vaccine product may occasionally induce an undesired immune response in a small part of the population. Most non-target antigens can be derived from (i) the cell culture medium supplements, (ii) proteins shed from the mammalian cells into the culture medium, and (iii) adjuvants/stabilizers used for vaccine development. Bystander activation is a non-specific stimulation of auto-reactive CD8⁺ T cells (even CD4⁺ T cells/B cells), which can be initiated following antigen-specific responses against the viral vaccines. The proliferation of CD8⁺ T cells can be mediated by IL-15 association with its specific receptor-α (IL-15R-α) on the surface of the APC, which can trigger the bystander stimulation of memory-phenotype CD8⁺ T cells. In this pathway, the production of IL-15 can be provoked by increasing the interferons (INFs) α/β, γ, and INF-inducer cytokines such as IL-12 and IL-18. Added to the auto-reactive CD8⁺ T cells, the CD4⁺ T cells may be stimulated through IL-2 cytokine and affected the immune responses, even though the involvement of this pathway in bystander activation is less well-known.¹² It has been also suggested that vaccine adjuvants may contribute to autoimmunity by stimulating bystander activation of irrelevant T cells.¹³ The exact mechanism of such a process is yet to be fully clarified, for which specific studies are further needed to address such outstanding issues.

Intriguingly, it has been also proposed that autoimmunity post-vaccination may be related to specific genetic patterns, such as human leukocyte antigen in the case of multiple sclerosis following the hepatitis B vaccine.^4,14 Thereby, personalized approaches such as genetic risk factors for autoimmunity must also be considered in the development of new vaccines.¹⁵ Recently, different case reports or observational studies have published autoimmune diseases post-vaccination with different types of COVID-19 vaccines (Table 1). Overall, immunological side effects may be connected to several factors such as vaccine type, vaccine dose, age, gender, specific genetic patterns, and history of immune-mediated diseases. However, the clinical trials related to the approved vaccines by the World Health Organization (WHO) did not show serious safety concerns during observation,^16-19 extensive follow-up evaluations are needed to consider long-term safety and autoimmunity issues of new vaccines for public administration.

As a perspective, some vaccinologists have recently focused on the next generation of epitope-based vaccines, which are designed based on the immunodominant/safe regions of one or more protective antigen(s).^34-36 To avoid any possible undesired autoimmune reactions, amino acid residues that may show homology with vaccine recipients’ proteome are predicted. In this line, sequence- and structure-based computational methods (e.g., local alignment algorithms and molecular docking/dynamics simulations, respectively) are used and the possible flaws are excluded from the vaccine construct.^37,38 Such an approach seems to be a time and cost-effective strategy to improve the vaccine safety in terms of potential tissue cross-reactive epitope(s).

In conclusion, autoinflammatory and autoimmune conditions may be associated with the cross-reactivity between SARS-CoV-2 viral peptides and self-antigens; thus, avoiding the stimulation of autoreactive T-cells should be considered one of the most crucial safety issues in constructing new vaccines. So far, the autoimmunity phenomenon following COVID-19 vaccination has not been approved due to the low incidence of the identified individuals and lack of sufficient evidence. Therefore, deep insight into the subject's incidental and idiopathic conditions is needed to develop this hypothesis. Moreover, further studies are warranted to monitor possible predisposed individuals and clarify immunological mechanisms induced by viral vaccines and adjuvants. Collectively, it should be emphasized that the vaccination modality is the best medical practice in controlling most infectious diseases even though autoimmunity might occur with low and mild clinical symptoms compared to those associated with the incidence of severe COVID-19 infection. Nonetheless, such symptoms could become much more severe in the cases of autoimmune diseases, in which precise care might be very helpful. Collectively, similar to other types of vaccines, SARS-CoV-2 vaccine-induced autoimmunity is a complex and dynamic area of research, characterized by molecular mimicry and immune system activation. Doubtlessly, COVID-19 vaccines have been crucial in mitigating the global impact of the pandemic. However, it is important to recognize that rare cases of autoimmune reactions might occur. These reactions may arise due to interactions between vaccine components, immune system activation, and underlying genetic predispositions. By implementing rigorous monitoring, timely reporting, and further research, we can enhance vaccine safety through quality-by-design approaches to ensure that the benefits of vaccination continue to outweigh potential risks in the battle against any emerging/re-emerging infections and future pandemics.

Competing interests

None to be stated.

Ethical statement

None to be stated.

Funding sources

None to be stated.

References

1. Micronutrient therapy and effective immune response: a promising approach for management of COVID-19. Infection 2021; 49:1133-47. doi: 10.1007/s15010-021-01644-3 [Crossref]
2. Baricitinib combination therapy: a narrative review of repurposed Janus kinase inhibitor against severe SARS-CoV-2 infection. Infection 2022; 50:295-308. doi: 10.1007/s15010-021-01730-6 [Crossref]
3. Adverse reactions to vaccination: from anaphylaxis to autoimmunity. Vet Clin North Am Small Anim 2018; 48:279. doi: 10.1016/j.cvsm.2017.10.005 [Crossref]
4. Acquired autoimmunity after viral vaccination is caused by molecular mimicry and antigen complimentarity in the presence of an immunologic adjuvant and specific HLA patterns. Med Hypotheses 2008; 70:346-8. doi: 10.1016/j.mehy.2007.04.043 [Crossref]
5. Could autoimmunity be induced by vaccination?. Int Rev Immunol 2010; 29:247-69. doi: 10.3109/08830181003746304 [Crossref]
6. Vaccinations and Autoimmune Diseases. Vaccines 2021; 9:815. doi: 10.3390/vaccines9080815 [Crossref]
7. Bystander activation and autoimmunity. J Autoimmun 2019; 103:102301. doi: 10.1016/j.jaut.2019.06.012 [Crossref]
8. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clin Immunol 2020; 217:108480. doi: 10.1016/j.clim.2020.108480 [Crossref]
9. Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev 2006; 19:80-94. doi: 10.1128/CMR.19.1.80-94.2006 [Crossref]
10. On the molecular determinants of the SARS-CoV-2 attack. Clin Immunol 2020; 215:108426. doi: 10.1016/j.clim.2020.108426 [Crossref]
11. Do COVID-19 RNA-based vaccines put at risk of immune-mediated diseases? In reply to "potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases". Clin Immunol 2021; 224:108665. doi: 10.1016/j.clim.2021.108665 [Crossref]
12. Bystander activation of irrelevant CD4+ T cells following antigen-specific vaccination occurs in the presence and absence of adjuvant. PloS One 2017; 12:e0177365. doi: 10.1371/journal.pone.0177365 [Crossref]
13. Systemic immunotoxicity reactions induced by adjuvanted vaccines. Int Immunopharmacol 2014; 20:170-80.
14. Vaccination and autoimmunity—‘vaccinosis’: a dangerous liaison?. J Autoimmun 2000; 14:1-10. doi: 10.1006/jaut.1999.0346 [Crossref]
15. Autoinflammatory and autoimmune conditions at the crossroad of COVID-19. J Autoimmun 2020; 114:102506. doi: 10.1016/j.jaut.2020.102506 [Crossref]
16. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 2020; 383:2603-15. doi: 10.1056/NEJMoa2034577 [Crossref]
17. SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia treated with immunoglobulin and argatroban. Lancet 2021; 397:e19. doi: 10.1016/S0140-6736(21)01238-1 [Crossref]
18. Efficacy and Safety of COVID-19 Vaccines: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Vaccines 2021; 9:467. doi: 10.3390/vaccines9050467 [Crossref]
19. A randomized, double-blind, placebo-controlled phase III clinical trial to evaluate the efficacy and safety of SARS-CoV-2 vaccine (inactivated, Vero cell): a structured summary of a study protocol for a randomised controlled trial. Trials 2021; 22:276. doi: 10.1186/s13063-021-05180-1 [Crossref]
20. Flare of rheumatoid arthritis after COVID-19 vaccination. Lancet Rheumatol 2021; 3:e469-e470. doi: 10.1016/S2665-9913(21)00108-9 [Crossref]
21. Autoimmune hepatitis triggered by SARS-CoV-2 vaccination. J Autoimmun 2021; 123:102710. doi: 10.1016/j.jaut.2021.102710 [Crossref]
22. Autoimmune hepatitis developing after coronavirus disease 2019 (COVID-19) vaccine: Causality or casualty?. J Hepatol 2021; 75:222-4. doi: 10.1016/j.jhep.2021.04.003 [Crossref]
23. Autoimmune hepatitis developing after the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccine. J Hepatol 2021; 75:1249-50. doi: 10.1016/j.jhep.2021.06.014 [Crossref]
24. Autoimmune phenomena following SARS-CoV-2 vaccination. Int Immunopharmacol 2021; 99:107970. doi: 10.1016/j.intimp.2021.107970 [Crossref]
25. Neurological Complications of COVID-19: Guillain-Barre Syndrome Following Pfizer COVID-19 Vaccine. Cureus 2021; 13:e13426. doi: 10.7759/cureus.13426 [Crossref]
26. Guillain-Barré syndrome after COVID-19 vaccination. BMJ Case Rep 2021; 14:e244125. doi: 10.1136/bcr-2021-244125 [Crossref]
27. Recurrence of Graves' Disease (a Th1-type Cytokine Disease) Following SARS-CoV-2 mRNA Vaccine Administration: A Simple Coincidence?. Eur J Case Rep Intern Med 2021; 8:002807. doi: 10.12890/2021_002807 [Crossref]
28. Granulomatous vasculitis after the AstraZeneca anti-SARS-CoV-2 vaccine. Kidney Int 2021; 100:706-7. doi: 10.1016/j.kint.2021.06.033 [Crossref]
29. ANCA-Associated Vasculitis Following Pfizer-BioNTech COVID-19 Vaccine. Am J Kidney Dis 2021; 78:611-3. doi: 10.1053/j.ajkd.2021.06.016 [Crossref]
30. A case of ANCA-associated vasculitis after AZD1222 (Oxford-AstraZeneca) SARS-CoV-2 vaccination: casualty or causality?. Kidney Int 2021; 100:937-8. doi: 10.1016/j.kint.2021.07.026 [Crossref]
31. Systemic lupus erythematosus after COVID-19 vaccination: A case report. J Cosmet Dermatol 2021; 20:3103-4. doi: 10.1111/jocd.14386 [Crossref]
32. De novo vasculitis after mRNA-1273 (Moderna) vaccination. Kidney Int 2021; 100:474-6. doi: 10.1016/j.kint.2021.05.016 [Crossref]
33. Autoimmune inflammatory rheumatic diseases post-COVID‐19 vaccination. Int Immunopharmacol 2022; 110:109061. doi: 10.1016/j.intimp.2022.109061 [Crossref]
34. A domain-based vaccine construct against SARS-CoV-2, the causative agent of COVID-19 pandemic: development of self-amplifying mRNA and peptide vaccines. Bioimpacts 2021; 11:65-84. doi: 10.34172/bi.2021.11 [Crossref]
35. Epitope-based vaccine design: a comprehensive overview of bioinformatics approaches. Drug Discov Today 2020; 25:1034-42. doi: 10.1016/j.drudis.2020.03.006 [Crossref]
36. Vaccination with rEGVac elicits immunoprotection against different stages of Echinococcus granulosus life cycle: A pilot study. Acta Trop 2021; 218:105883. doi: 10.1016/j.actatropica.2021.105883 [Crossref]
37. Large-Scale Structure-Based Screening of Potential T Cell Cross-Reactivities Involving Peptide-Targets From BCG Vaccine and SARS-CoV-2. Front Immunol 2021; 12:812176. doi: 10.3389/fimmu.2021.812176 [Crossref]
38. Next-generation vaccines and the impacts of state-of-the-art in-silico technologies. Biologicals 2021; 69:83-5. doi: 10.1016/j.biologicals.2020.10.002 [Crossref]