IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SARS-CoV-2 Spike Protein

"We propose a hypothetical immune tolerance mechanism induced by mRNA vaccines, which could have at least six negative unintended consequences:

(1) By ignoring the spike protein synthesized as a consequence of vaccination, the host immune system may become vulnerable to re-infection with the new Omicron subvariants, allowing for free replication of the virus once a re-infection takes place. In this situation, we suggest that even these less pathogenic Omicron subvariants could cause significant harm and even death in individuals with comorbidities and immuno-compromised conditions.

(2) mRNA and inactivated vaccines temporally impair interferon signaling [142,143], possibly causing immune suppression and leaving the individual in a vulnerable situation against any other pathogen. In addition, this immune suppression could allow the re-activation of latent viral, bacterial, or fungal infections and might also allow the uncontrolled growth of cancer cells [144].

(3) A tolerant immune system might allow SARS-CoV-2 persistence in the host and promote the establishment of a chronic infection, similar to that generated by the hepatitis B virus (HBV), the human immune deficiency virus (HIV), and the hepatitis C virus (HCV) [145].

(4) The combined immune suppression (produced by SARS-CoV-2 infection [15,16,17,18,19,20,21,22] and further enhanced by vaccination [142,143,144]) could explain a plethora of autoimmune conditions, such as cancers, re-infections, and deaths temporally associated with both. It is conceivable that the excess deaths reported in several highly COVID-19-vaccinated countries may be explained, in part, by this combined immunosuppressive effect.

(5) Repeated vaccination could also lead to auto-immunity: in 2009, the results of an important study went largely unnoticed. Researchers discovered that in mice that are otherwise not susceptible to spontaneous autoimmune disorders, repeated administration of the antigen promotes systemic autoimmunity. The development of CD4+ T cells that can induce autoantibodies (autoantibody-inducing CD4+ T cells, or aiCD4+ T cells), which had their T cell receptors (TCR) modified, was triggered by excessive stimulation of CD4+ T cells. The aiCD4+ T cell was generated by new genetic TCR modification rather than a cross-reaction. The excessively stimulated CD8+ T cells induced them to develop into cytotoxic T lymphocytes (CTL) that are specific for an antigen. These CTLs were able to mature further by antigen cross-presentation, so in that situation, they induced autoimmune tissue damage resembling systemic lupus erythematosus (SLE) [146]. According to the self-organized criticality theory, when the immune system of the host is continually overstimulated by antigen exposure at concentrations higher than the immune system’s self-organized criticality can tolerate, systemic autoimmunity inevitably occurs [147].

It has been proposed that the amount and duration of the spike protein produced are presumably affected by the higher mRNA concentrations in the mRNA-1273 vaccine (100 µg) compared to the BNT162b2 vaccine (30 µg) [31]. Thus, it is probable that the spike protein produced in response to mRNA vaccination is too high and lasts too long in the body. That could overwhelm the capacity of the immune system, leading to autoimmunity [146,147]. Indeed, several investigations have found that COVID-19 immunization is associated with the development of autoimmune responses [148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166].

(6) Increased IgG4 levels induced by repeated vaccination could lead to autoimmune myocarditis; it has been suggested that IgG4 antibodies can also cause an autoimmune reaction by impeding the immune system’s ability to be suppressed by regulatory T cells [102]. Patients using immune checkpoint inhibitors alone or in combination have been linked to occurrences of acute myocarditis [103,104,105,106,107], sometimes with lethal consequences [102]. As anti-PD-1 antibodies are class IgG4, and these antibodies are also induced by repeated vaccination, it is plausible to suggest that excessive vaccination could be associated with the occurrence of an increased number of myocarditis cases and sudden cardiac deaths.

Finally, these negative outcomes are not expected to affect all people who have received these mRNA vaccines. Individuals with genetic susceptibility, immune deficiencies, and comorbidities are probably the most likely to be affected. However, this gives rise to a disturbing paradox—if people who are the most affected by the COVID-19 disease (the elderly, diabetics, hypertensive, and immunocompromised people like those with HIV) are also more susceptible to suffering the negative effects of repeated mRNA vaccination, is it then justified to booster them? As Omicron subvariants have been demonstrated to be less pathogenic [133,134,135,136,137], and mRNA vaccines do not protect against re-infection [14,138], clinicians should be aware of the possible detrimental effects on the immune system by administering boosters."