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

Abstract

Less than a year after the global emergence of the coronavirus SARS-CoV-2, a novel vaccine platform based on mRNA technology was introduced to the market. Globally, around 13.38 billion COVID-19 vaccine doses of diverse platforms have been administered. To date, 72.3% of the total population has been injected at least once with a COVID-19 vaccine. As the immunity provided by these vaccines rapidly wanes, their ability to prevent hospitalization and severe disease in individuals with comorbidities has recently been questioned, and increasing evidence has shown that, as with many other vaccines, they do not produce sterilizing immunity, allowing people to suffer frequent re-infections. Additionally, recent investigations have found abnormally high levels of IgG4 in people who were administered two or more injections of the mRNA vaccines. HIV, Malaria, and Pertussis vaccines have also been reported to induce higher-than-normal IgG4 synthesis. Overall, there are three critical factors determining the class switch to IgG4 antibodies: excessive antigen concentration, repeated vaccination, and the type of vaccine used. It has been suggested that an increase in IgG4 levels could have a protecting role by preventing immune over-activation, similar to that occurring during successful allergen-specific immunotherapy by inhibiting IgE-induced effects. However, emerging evidence suggests that the reported increase in IgG4 levels detected after repeated vaccination with the mRNA vaccines may not be a protective mechanism; rather, it constitutes an immune tolerance mechanism to the spike protein that could promote unopposed SARS-CoV2 infection and replication by suppressing natural antiviral responses. Increased IgG4 synthesis due to repeated mRNA vaccination with high antigen concentrations may also cause autoimmune diseases, and promote cancer growth and autoimmune myocarditis in susceptible individuals.

Keywords: COVID-19; IgG4 antibodies; SARS-CoV-2; auto-immunity; immuno-tolerance; mRNA vaccines.

Figure 1

IgG4 antibody has a distinctive structure. (A). Two heavy chains and two light chains make up the IgG4 antibody. (B). The Fc fragment of one IgG4 molecule can react with the Fc fragment of another. (C). When half-molecules are exchanged (called a Fab-arm interchange), IgG4 combines two distinct specificities into a unique molecule (bispecific antibody). Reproduced from [41]. This is an open-access article distributed under the terms of the Creative Commons CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Figure 2

In (A), a pollen grain is recognized through the fragment antigen-binding region (Fab) of an IgE antibody. After that, the IgE attaches to its receptor, called Fc epsilon RI (FcεRI), located on eosinophil leukocytes, and induces histamine release from cytoplasmic granules. Histamine is a vasoactive peptide that causes symptoms such as itching, sneezing, runny nose, itchy throat, eyes, and ears, and trouble breathing during a pollen-induced allergic reaction. In (B), the fragment cristalizable (Fc) region of an IgG4 antibody binds to the Fc region of an IgE antibody, inhibiting its binding to the FcεRI receptor and thus blocking IgE-mediated effects. Created with Biorender.

Figure 3

The suggested pathway for immune evasion evolved by cancer cells through IgG4 produced from B lymphocytes is depicted diagrammatically. Prolonged exposure to cancer antigens causes B cells to change their class and generate IgG4. With its Fc-Fc binding characteristic, such enhanced IgG4 can interact with cancer-bound IgG as well as Fc receptors on immune effector cells. Increased IgG4 in the cancer microenvironment promotes an efficient immune evasion mechanism for cancer due to its special structural and biological properties. The acronyms ADCC, ADCP, CDC, and NK stand for antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell phagocytosis, complement-dependent cytotoxicity, and natural killer cells, respectively. Reproduced from [101]. This is an open-access article distributed under the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial.

Figure 4

An effective humoral response induced by vaccination consists of the synthesis of high IgG3 concentrations. (A). IgG3 antibodies attach to viral antigens exposed on infected cells’ membranes through its variable region. This antibody has a constant region (Fc) that is recognized by the corresponding receptor found on cytotoxic T cells and other immune cells. The cytotoxic T cell becomes activated and releases chemical agents that destroy the infected cell. (B). Repeated vaccination induces high IgG4 levels (depicted in red). This antibody inhibits the attachment of the Fc region from the IgG3 antibody to its receptor located on cytotoxic T cells, thus blocking its activation, and consequently, the infected cell is not destroyed. In this sense, repeated boosting causes a switch to the production of high IgG4 levels, which impair immune responses. Created with Biorender.