 The COVID-19 pandemic led to a unforeseen advancement in medical product technology with the emergency use authorization of the first-ever mRNA gene technology ("COVID vaccines")—BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). These "vaccines" utilized synthetic mRNA molecules that encode the SARS-CoV-2 Spike protein, encapsulated in synthetic lipid nanoparticles (LNPs), allowing for the widespread delivery of mRNA into virtually all human cells. This technology is intended to mimic a natural infection, enabling the host cells to produce the viral spike protein (which happens to induce the well-known cytokine storm, and lasts for months), which then triggers a hyperactive immune response that can lead to severe inflammation and damage to tissues. One of the more concerning observations is that mRNA vaccines may stimulate the production of IgG4 antibodies, otherwise known as immunoglobulin G, subtype 4. More specifically, IgG4 antibodies induced by repeated vaccination appear to generate immune tolerance to the SARS-CoV-2 spike protein. Immune tolerance means the immune system is less likely to mount a strong inflammatory response to the antigen (in this case, the Spike protein of SARS-CoV-2), which can lead to a host of various immune problems, including but not limited to cancer. "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." What are immunoglobulins? Immunoglobulins (antibodies) play a vital role in the human immune system, acting as the primary defense against infections and foreign substances. Among the various immunoglobulin classes (IgA, IgE, IgM, and IgG), IgG is the most abundant and is subdivided into four subclasses: IgG1, IgG2, IgG3, and IgG4. These subclasses differ in their structure, physiological roles, and interaction with immune cells. While IgG1 is the most common, accounting for the majority of serum immunoglobulins (66%), IgG4 represents a smaller fraction (4%) but has gained significant interest due to its unique properties and effects on the immune system. Structure and Unusual Behavior of IgG4  IgG4 differs from other subclasses due to its limited ability to activate the complement system, a key immune mechanism responsible for destroying infected cells. This characteristic has led to IgG4 being classified as an unusual antibody. One of its most intriguing features is Fab arm exchange, a process in which the two halves of an IgG4 antibody can dissociate and recombine with halves from other IgG4 antibodies. This creates bi-specific antibodies with two distinct Fab arms, reducing their ability to form immune complexes and stimulate immune responses. IgG4 antibodies have low affinity for C1q and Fc receptors, which limits their capacity to initiate effector responses. However, this bi-specific structure enables IgG4 to potentially block the inflammatory effects of other antibody classes, such as IgG1 or IgE, by displacing their antigen-binding capabilities. This property contributes to IgG4's role as a "blocking antibody", known for its anti-inflammatory effects. Think of C1q as a "signal booster" in the immune system. When an antibody (like other IgGs) sticks to a virus or bacteria, C1q can attach to the antibody and kickstart a bigger immune response. This response helps destroy the invader by activating a defense system called the complement system, which can puncture the bad cell or attract more immune cells to the area to help fight. However, IgG4 doesn’t do this as effectively as other types of IgG antibodies. It has a much weaker ability to call on C1q, meaning it doesn't start this complement attack as strongly. This makes IgG4 more of a "quiet observer" in some situations, which can be helpful in avoiding too much inflammation. Fc receptors are like "docking stations" found on the surface of immune cells. These docking stations grab onto the "tail" end of antibodies (this part of the antibody is called the Fc region) and help immune cells, like phagocytes (cells that eat invaders), detect and destroy harmful germs or infected cells. IgG4 doesn’t bind well to these Fc receptors, so it doesn’t trigger a strong immune attack like other antibodies (such as IgG1). In Other Words:
IgG4-Related Systemic DiseaseIgG4 is linked to a broad range of clinical conditions, collectively referred to as IgG4-related systemic disease. This condition involves multiple organs, characterized by significant fibrosis, infiltration of IgG4-positive plasma cells, and dispersed immune cell infiltrates. Although the disease can affect different organs, common histological (anatomical tissue) features are observed, such as tissue fibrosis and immune cell infiltration. IgG4: Friend or Foe?The role of IgG4 in human health is complex, with evidence pointing to both protective and pathogenic effects. In allergy immunotherapy, for example, IgG4 is often viewed as a protective antibody due to its ability to reduce inflammation and prevent IgE-mediated allergic reactions. Elevated levels of antigen-specific IgG4 are associated with successful desensitization to allergens, allowing for the development of immune tolerance. During prolonged exposure to allergens, IgG4 competes with IgE for antigen binding, effectively neutralizing allergic responses without activating immune effector cells. However, IgG4 can also be involved in pathogenic processes. In some autoimmune diseases, such as pemphigus vulgaris (autoimmune disease that causes blistering of the skin and mucous membranes, such as the mouth, throat, and genitals), IgG4 plays a role in the disease’s progression by contributing to tissue damage. Additionally, IgG4 has been linked to the suppression of immune responses in certain types of cancer, where its blocking ability may inhibit the immune system's capacity to fight tumor cells. Protective Role in Allergy ImmunotherapyIn the context of allergy immunotherapy, IgG4’s lack of effector function and its capacity for half-antibody exchange raise questions about its role in modulating immune responses. Several studies have demonstrated that high levels of antigen-specific IgG4 are associated with successful outcomes in allergen-specific immunotherapy. This is because IgG4 can inhibit the effects of IgE, the antibody responsible for allergic reactions. Through allergen-specific memory T- and B-cell responses, the immune system adapts to tolerate allergens, reducing chronic inflammation and allergic responses. This process is crucial for building a more robust and balanced immune system. IgG4-Related Disease and Its PathogenesisIgG4-related disease (IgG4-RD) is a condition that causes inflammation and tissue damage in various parts of the body. It is marked by high levels of a specific type of immune cell called IgG4 plasma cells, which are found in the affected tissues, and higher-than-normal levels of IgG4 antibodies in the blood. IgG4-RD includes a wide variety of diseases:
It also plays a significant role in the pathogenesis of at least 13 autoimmune disorders, including rheumatoid arthritis, and myasthenia gravis. The clinical manifestations of IgG4-RD are usually tumor-like masses or organ enlargement, which result from dense tissue infiltration by immune cells and expansion of the extra-cellular matrix. One or more organs are affected; the 11 organs considered typical of IgG4-RD including the:
In certain autoimmune diseases, IgG4 levels correlate with disease severity, and in experimental models, IgG4 has been shown to cause disease manifestations when injected into animals. This indicates the pathogenic role of IgG4 in these disorders. IgG4’s Role in CancerRecent studies suggest that IgG4 antibodies may play a role in immune evasion by cancer cells, contributing to cancer progression. Immune checkpoint inhibitors (ICBs) are commonly used in cancer immunotherapy to block proteins like PD-1 (programmed cell death protein 1) and allow the immune system to attack cancer cells. However, IgG4 antibodies, including PD-1 antibodies, have been linked to cases of rapid disease progression, known as hyper-progressive disease (HPD).  IgG4 antibodies were found to interfere with anti-tumor immune responses, blocking the ability of other antibodies (such as IgG1) to target and destroy cancer cells. This was demonstrated in studies of cancers like malignant melanoma, where locally produced IgG4 antibodies hindered the immune system's response, allowing tumors to grow unchecked. Studies using animal models confirmed that IgG4 promotes tumor growth by blocking local immune responses. For example, in a breast cancer model, the local administration of IgG4 significantly accelerated tumor growth compared to controls. These findings suggest that IgG4 antibodies assist cancer cells in escaping immune detection, facilitating tumor progression. Although immune checkpoint inhibitors targeting PD-1 are effective in some cancers, their IgG4 subclass raises concerns about potential side effects, including autoimmune reactions and rapid tumor progression. IgG4's role in blocking immune responses may explain the occurrence of hyper-progressive disease in some patients undergoing cancer immunotherapy. Studies have shown that certain cancers, including malignant melanoma, extrahepatic cholangiocarcinoma, and pancreatic cancer, often have an abundance of IgG4-positive plasma cells in and around the tumor. A groundbreaking study by Karagiannis et al. revealed that cancer-specific IgG4 antibodies, unlike their IgG1 counterparts, do not activate the immune processes required to destroy cancer cells. Instead, IgG4 appears to interfere with IgG1's ability to promote tumor cell death, allowing the cancer to evade immune attack. This mechanism of immune escape enables the tumor to grow unchecked, making IgG4 a key player in cancer progression. IgG4's Impact on Tumor Immune Evasion Karagiannis and colleagues demonstrated that tumors producing IgG4 can actively inhibit the immune system’s ability to kill cancer cells. In their study, they found that IL-4 and IL-10, cytokines associated with immune regulation, were elevated in cancerous tissues, leading to increased IgG4 production. The research showed that IgG4 not only failed to fight tumors but also blocked other immune antibodies, like IgG1, from effectively doing so. This was further supported by experiments using immunocompetent mice models, where the introduction of IgG4 antibodies sped up tumor growth. These findings suggest that IgG4 plays a direct role in helping cancers evade the immune system. IgG4 and Cancer Immunotherapy IgG4’s interference with the immune system extends to cancer immunotherapy. Specifically, nivolumab, a PD-1 blocking antibody used in cancer treatment, belongs to the IgG4 class. While effective in some cases, its IgG4 nature may also contribute to the rapid progression of cancer in others. In mouse studies, treatment with nivolumab led to faster tumor growth when compared to controls, suggesting that IgG4’s role in cancer therapy may have unintended negative effects. The connection between IgG4 and cancer highlights the challenges of using ICIs. On the one hand, PD-1 inhibitors can stimulate the immune system to fight cancer, but on the other hand, they may inadvertently promote immune evasion and tumor growth when IgG4 is involved. Cancers Appearing in Ways Never Before Seen After COVID Vaccinations: Dr. Harvey RischDr. Harvey Risch, professor emeritus of epidemiology at the Yale School of Public Health and Yale School of Medicine, has voiced concerns about a potential rise in cancer cases following COVID-19 vaccinations. Dr. Risch, whose research focuses on cancer causes and prevention, recently shared his observations in an interview with EpochTV’s American Thought Leaders. According to him, oncology clinics are facing significant delays in appointment availability, especially in New York, where patients are now waiting months instead of weeks for cancer-related consultations. One of the key points Dr. Risch highlights is the appearance of unusual cancer cases, particularly in younger individuals. For instance, he cites cases of 25-year-olds developing colon cancer despite having no family history, a rare occurrence under normal circumstances. He believes that something must be triggering these early-onset cancers, which don't align with traditional understandings of cancer development, which can take years or even decades to manifest. Dr. Risch explained that a healthy immune system plays a crucial role in detecting and neutralizing cancerous cells before they can multiply. However, if the immune system is weakened or compromised, it may fail to perform this function effectively, allowing cancerous cells to grow unchecked. He believes that in some people, the COVID-19 vaccines have impaired their immune systems to varying degrees, potentially leading to an increased risk of developing cancer, recurring infections, or other serious health conditions. Dr. Risch used the term “turbo cancers” to describe aggressive forms of cancer that seem to develop and progress at an unusually fast rate. He mentioned cases where cancers, such as breast cancer, are reappearing in vaccinated women much sooner than expected. Typically, breast cancer that returns after surgery takes around two decades to reappear, but in some of these cases, it has resurfaced in much shorter timeframes. He also reported instances where tumors grew dramatically in the short period between initial diagnosis and follow-up appointments, surprising oncologists who are accustomed to slower cancer progression.  In light of these findings, Dr. Risch encourages individuals to be particularly attentive to any new or unusual symptoms in their bodies. Being proactive and aware of potential warning signs could help detect issues earlier. Dr. Risch also discussed the way medical agencies track adverse events following vaccination. Officially, a person is not considered "vaccinated" until two weeks after their shot, meaning any negative reactions occurring before then are often counted as happening to unvaccinated individuals. However, Dr. Risch emphasized that a significant portion of adverse reactions, including serious health issues, can occur within the first few days of vaccination, yet they are being incorrectly attributed. Dr. Risch criticized how public health policies were handled during the pandemic, saying key principles of public health were abandoned early on. He cited the denial of early treatments for COVID-19 and what he believes were unnecessary vaccinations, calling the approach a “colossal failure.” In his view, a lot of the current fear surrounding new COVID variants is being fueled by propaganda designed to promote more vaccinations, rather than genuine concern for public health. While Dr. Risch acknowledges that the individual risk of a severe adverse reaction to the vaccine is relatively low, when millions of people are vaccinated, even small risks can translate to large numbers of individuals experiencing serious health consequences. According to him, these reactions can sometimes be worse than the virus itself, leaving hundreds of thousands of people with injuries or long-term health problems. Given the mild nature of current COVID-19 variants, Dr. Risch strongly advises against receiving more mRNA vaccines. He believes that most people already have some immunity from previous infections and that the new variants are not life-threatening. For Dr. Risch, the focus should be on managing these illnesses as we do with other common infections, like the flu, without resorting to unnecessary vaccinations. In summary, Dr. Risch’s concerns reflect growing skepticism over the long-term effects of COVID-19 vaccines, particularly their potential link to an increase in cancer cases. His call for awareness, both from individuals and the medical community, underscores the need for further research into the vaccines’ impact on the immune system and overall health. Hyper-Progressive Disease and Immune EscapeThe phenomenon of HPD—where patients experience accelerated cancer progression during treatment—may be partly explained by IgG4’s involvement. As tumors produce more IgG4 antibodies, they hinder immune responses and facilitate tumor survival and growth. This could explain why a subset of patients receiving PD-1 inhibitors experience HPD rather than remission. IgG4 and AutoimmunityInterestingly, while IgG4 can contribute to immune suppression in cancer, it may also lead to autoimmune reactions. In some cases, the use of PD-1 inhibitors has been associated with the development of acute myocarditis, a severe inflammation of the heart muscle. This potentially life-threatening condition highlights the delicate balance ICIs strike between immune stimulation and suppression. antibody class switchingAntibody class switching is like your immune system changing the type of weapon it uses to fight an infection. When you get vaccinated, your immune system makes antibodies—proteins that help protect you by recognizing and neutralizing harmful invaders like viruses. At first, your body might make certain types of antibodies, like IgG1 and IgG3, which are really good at attacking and destroying a virus. But after repeated exposure to the same vaccine or virus (like with the repeated doses of the COVID-19 mRNA vaccines), your body may shift gears and start producing a different type of antibody, called IgG4. IgG4 antibodies act more like peacekeepers than attackers. Instead of creating a strong inflammatory response to destroy invaders, IgG4 helps calm the immune system down. This happens after the immune system has been repeatedly exposed to the same thing over time, which is why it can occur after multiple mRNA vaccine doses. While this shift to IgG4 antibodies can help prevent excessive inflammation, it also means the immune response might be less aggressive, particularly in detecting and neutralizing immune threats. In the case of the COVID-19 mRNA vaccines, scientists have noticed that repeated doses can lead to higher levels of IgG4, and it appears to leading to higher rates of cancer and other IgG4-related diseases. The body might be learning to tolerate the spike protein (the part of the virus the vaccine targets), but the effects of this shift on long-term immunity are arguably worse than the disease itself. The Impact of Antigen Dose and Repeated Vaccination on IgG4 Antibody ProductionVaccines have long been claimed to be a cornerstone in disease prevention, but recent research has shown that certain vaccines can induce the production of IgG4 antibodies. While the mRNA COVID-19 "vaccines" have brought this response into focus, it's not unique to them—vaccines for diseases like HIV, malaria, pertussis, tetanus toxoid (TT) vaccine and the respiratory syncytial virus (RSV) have also been associated with IgG4 production. This antibody class switch is influenced by three key factors: antigen concentration, repeated vaccination, and the type of vaccine used.
In contrast, adenovirus-based vaccines like AstraZeneca's did not elicit such a long-lasting IgG4 response (despite them being suspended in 18 countries for adverse events). The link between higher antigen doses and immune tolerance is well-documented: too much antigen can lead to T-cell exhaustion and immune tolerance, weakening the immune system’s ability to fight infections. While the traditional view has supported the idea that “more is better” when it comes to antigen doses for vaccines, especially in cases like HIV or tuberculosis where there are no clear immune predictors of protection, this approach is not without drawbacks. The following key concerns arise from excessive antigen dosing:
Studies have also shown that in some cases, lower vaccine doses can result in better T-cell responses. This has led experts to reconsider vaccine dosing strategies, suggesting that smaller doses may sometimes be more effective, especially in boosting immunity. 2. Repeated Vaccination Repeated exposure to vaccines, especially mRNA-based vaccines, can significantly influence the type of antibodies produced. After the initial two doses of COVID-19 mRNA vaccines, most individuals develop IgG1 and IgG3 antibodies, which are typically pro-inflammatory and play a key role in fighting infections. However, as more doses are administered, a shift occurs, with IgG4 levels increasing significantly, particularly after a third dose or subsequent infection with a SARS-CoV-2 variant.  A group of 29 people got three doses of the Pfizer mRNA vaccine, Comirnaty. Blood samples were taken from them at different points: after each dose, and later during two follow-up visits, one about 7 months after the second shot and the other about 6 months after the third. During this time, 10 people got infected despite being vaccinated. Researchers measured specific immune responses (different types of antibodies) in their blood using special tests. Results below a certain threshold were marked as very low. The graphs show individual results and averages for the group. Only certain comparisons between the time points are shown in the data. This IgG4 response was not observed in those who received adenovirus-based vaccines. In one study, only recipients of the Pfizer mRNA vaccine exhibited this significant increase in IgG4 levels, particularly 5–6 months after the second vaccination. In contrast, other vaccine schedules, such as mixing Pfizer with AstraZeneca, did not show a similar IgG4 rise, emphasizing the unique nature of the mRNA vaccines in inducing this response. 3. The Consequences of Over-Vaccination Recent studies have raised concerns about the potential negative effects of over-vaccination with mRNA boosters (as of September 2024, the CDC has recommended the American public to administer nine doses of COVID "vaccines" since the onset of the pandemic). In mouse models, extended booster vaccination schedules diminished the effectiveness of the immune system against new infections, particularly for Delta and Omicron variants. The findings showed that excessive boosting resulted in:
This suggests that repeated vaccination may diminish the immune system's ability to respond to new infections or reinfections, potentially leading to more severe disease outcomes for those who become infected again after multiple booster doses. Interestingly, the increase in IgG4 antibodies after mRNA COVID-19 vaccinations does not appear to be caused by genetic predisposition. Around 50% of individuals showed a significant increase in IgG4 after their second mRNA vaccination, and this was consistent across different populations, indicating that repeated exposure to the antigen was the primary cause. This finding contradicts the traditional paradigm of vaccinology, where low antigen doses are generally recommended for booster shots. Both Pfizer and Moderna vaccines used the same antigen doses for primary and booster shots, leading to elevated IgG4 levels. The production of IgG4 antibodies following vaccination is influenced by several factors, including antigen dose, repeated exposure, and the type of vaccine. The unique ability of the mRNA vaccines to induce IgG4 antibody production—especially after multiple doses—raises important questions about long-term immunity and potential immune tolerance. As research continues, striking a balance between sufficient immune response and avoiding immune exhaustion will be crucial in optimizing vaccination strategies for future diseases. REferencesUversky, Vladimir N, et al. “IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SARS-CoV-2 Spike Protein.” Vaccines, vol. 11, no. 5, 17 May 2023, pp. 991–991, www.ncbi.nlm.nih.gov/pmc/articles/PMC10222767/, https://doi.org/10.3390/vaccines11050991.
Koneczny, Inga. “Update on IgG4-Mediated Autoimmune Diseases: New Insights and New Family Members.” Autoimmunity Reviews, vol. 19, no. 10, Oct. 2020, p. 102646, https://doi.org/10.1016/j.autrev.2020.102646. Boretti, Alberto. “MRNA Vaccine Boosters and Impaired Immune System Response in Immune Compromised Individuals: A Narrative Review.” Clinical and Experimental Medicine, vol. 24, no. 1, 27 Jan. 2024, www.ncbi.nlm.nih.gov/pmc/articles/PMC10821957/#:~:text=Immunocompromised%20individuals%20may%20not%20mount, https://doi.org/10.1007/s10238-023-01264-1. Perugino, Cory. “IgG4-Related Disease - Musculoskeletal and Connective Tissue Disorders.” Merck Manuals Professional Edition, Aug. 2023, www.merckmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/igg4-related-disease/igg4-related-disease. Rispens, Theo, and Maartje G Huijbers. “The Unique Properties of IgG4 and Its Roles in Health and Disease.” Nature Reviews Immunology, 24 Apr. 2023, https://doi.org/10.1038/s41577-023-00871-z. Brogna, Carlo, et al. “Detection of Recombinant Spike Protein in the Blood of Individuals Vaccinated against SARS‐CoV‐2: Possible Molecular Mechanisms.” PROTEOMICS - Clinical Applications, 31 Aug. 2023, https://doi.org/10.1002/prca.202300048. Irrgang, Pascal, et al. “Class Switch toward Noninflammatory, Spike-Specific IgG4 Antibodies after Repeated SARS-CoV-2 MRNA Vaccination.” Science Immunology, vol. 8, no. 79, 27 Jan. 2023, https://doi.org/10.1126/sciimmunol.ade2798. Efthymis Oraiopoulos, and Jan Jekielek. “Cancers Appearing in Ways Never before Seen after COVID Vaccinations: Dr. Harvey Risch.” The Epoch Times, 20 Sept. 2023, web.archive.org/web/20230923113807/www.theepochtimes.com/health/cancers-appearing-in-ways-never-before-seen-after-covid-vaccinations-dr-harvey-risch-5495364. Accessed 4 Oct. 2024. Goldman, Serge, et al. “Rapid Progression of Angioimmunoblastic T Cell Lymphoma Following BNT162b2 MRNA Vaccine Booster Shot: A Case Report.” Frontiers in Medicine, vol. 8, 25 Nov. 2021, www.ncbi.nlm.nih.gov/pmc/articles/PMC8656165/, https://doi.org/10.3389/fmed.2021.798095. Accessed 15 May 2024.
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