The Anti-SARS-CoV-2 IgG1 and IgG3 Antibody Isotypes with Limited Neutralizing Capacity against Omicron Elicited in a Latin Population a Switch toward IgG4 after Multiple Doses with the mRNA Pfizer–BioNTech Vaccine
Another new pre-print on IgG4 — this one comparing two mRNA vaccines (Pfizer and Moderna) with a protein-based vaccine (Novavax). IgG4 was dramatically higher in both mRNAs.
But the second from August 2020, pre-vaccine, is more interesting.
“In a cohort of patients with esophageal cancer we found that IgG4-containing B lymphocytes and IgG4 concentration were significantly increased in cancer tissue and IgG4 concentrations increased in serum of patients with cancer. Both were positively related to increased cancer malignancy and poor prognoses, that is, more IgG4 appeared to associate with more aggressive cancer growth. We further found that IgG4, regardless of its antigen specificity, inhibited the classic immune reactions of antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity against cancer cells…”
“An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy”
Another paper on IgG4 class switch. “Suppressed IgG4 class switching in dupilumab- and TNF inhibitor-treated patients after repeated SARS-CoV-2 mRNA vaccination.” Anika M. Valk, et al. https://www.medrxiv.org/content/10.1101/2023.09.29.23296354v1
The Cleveland Clinic updated its famous study, which showed more vaccine doses yielded more infections. Once again, they find employees “up to date” on their boosters are more susceptible to infection than those “not up to date.” https://www.medrxiv.org/content/10.1101/2023.06.09.23290893v1
Yet another new paper, published in Vaccines, looking at the IgG4 class-switch problem, this time focused on the possibility of increased cancer risk. "IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SARS-CoV-2 Spike Protein." https://www.mdpi.com/2076-393X/11/5/991.
"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."
Dr. Paul Offit, a pediatric vaccine expert, has now written in the NEJM about the bivalent Covid-19 vaccine failure, specifically citing immune imprinting as one culprit. "Why did the strategy for significantly increasing BA.4 and BA.5 neutralizing antibodies using a bivalent vaccine fail? The most likely explanation is imprinting. The immune systems of people immunized with the bivalent vaccine, all of whom had previously been vaccinated, were primed to respond to the ancestral strain of SARS-CoV-2." https://www.nejm.org/doi/full/10.1056/NEJMp2215780.
Yet another paper, this one from Chinese researchers published in iScience, shows repeated SARS2 vaccination can induce tolerance, depress the immune system, and potentially make you more susceptible to the virus. "Extended SARS-CoV-2 RBD booster vaccination induces humoral and cellular immune tolerance in mice." https://www.sciencedirect.com/science/article/pii/S2589004222017515
A new paper in Frontiers in Immunology confirms the basic phenomenon of IgG4 elevation, and possible "tolerance," after repeated Covid-19 vaccination, especially for the mRNA vaccines, which we described above. "mRNA vaccines against SARS-CoV-2 induce comparably low long-term IgG Fc galactosylation and sialylation levels but increasing long-term IgG4 responses compared to an adenovirus-based vaccine." https://www.frontiersin.org/articles/10.3389/fimmu.2022.1020844/full
Just adding to the massive IgG4 literature. This new paper emphasizes reduced NK Cell activation, which harms ability to fight viruses and cancers.
Repeated COVID-19 mRNA vaccination results in IgG4 class switching and decreased NK cell activation by S1-specific antibodies in older adults
https://immunityageing.biomedcentral.com/articles/10.1186/s12979-024-00466-9
Another IgG4 paper, this one on children.
Delayed Induction of Noninflammatory SARS-CoV-2 Spike-Specific IgG4 Antibodies Detected 1 Year After BNT162b2 Vaccination in Children. Kobbe, Robin, et al. https://journals.lww.com/pidj/fulltext/9900/delayed_induction_of_noninflammatory_sars_cov_2.959.aspx
Published version of Raj Kalkeri et al. “Altered IgG4 Antibody Response to Repeated mRNA versus Protein COVID Vaccines.”https://www.journalofinfection.com/article/S0163-4453(24)00053-7/fulltext
Another paper on imprinting!
Persistent immune imprinting occurs after vaccination with the COVID-19 XBB.1.5 mRNA booster in humans
https://www.cell.com/immunity/fulltext/S1074-7613(24)00092-X
Yet more on IgG4!
The Anti-SARS-CoV-2 IgG1 and IgG3 Antibody Isotypes with Limited Neutralizing Capacity against Omicron Elicited in a Latin Population a Switch toward IgG4 after Multiple Doses with the mRNA Pfizer–BioNTech Vaccine
https://www.mdpi.com/1999-4915/16/2/187
With a great explainer video by Dr. Mikolaj Raszek https://x.com/thechiefnerd/status/1773699970433962341
Yet another. A major paper from Dan Baruch of Harvard on both imprinting and IgG4 tolerance.
Waning immunity and IgG4 responses following bivalent mRNA boosting
https://www.science.org/doi/10.1126/sciadv.adj9945
Another new pre-print on IgG4 — this one comparing two mRNA vaccines (Pfizer and Moderna) with a protein-based vaccine (Novavax). IgG4 was dramatically higher in both mRNAs.
Raj Kalkeri et al. “Altered IgG4 Antibody Response to Repeated mRNA versus Protein COVID Vaccines.” https://www.medrxiv.org/content/10.1101/2024.01.17.24301374v1.full.pdf
Two more papers on IgG4 immune dysregulation, one new, finding much the same as the others:
“Suppressed IgG4 class switching in dupilumab- and TNF inhibitor-treated patients after repeated SARS-CoV-2 mRNA vaccination.” https://www.medrxiv.org/content/10.1101/2023.09.29.23296354v1.full.pdf
But the second from August 2020, pre-vaccine, is more interesting.
“In a cohort of patients with esophageal cancer we found that IgG4-containing B lymphocytes and IgG4 concentration were significantly increased in cancer tissue and IgG4 concentrations increased in serum of patients with cancer. Both were positively related to increased cancer malignancy and poor prognoses, that is, more IgG4 appeared to associate with more aggressive cancer growth. We further found that IgG4, regardless of its antigen specificity, inhibited the classic immune reactions of antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis and complement-dependent cytotoxicity against cancer cells…”
“An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy”
https://pubmed.ncbi.nlm.nih.gov/32819973/
Another paper on IgG4 class switch. “Suppressed IgG4 class switching in dupilumab- and TNF inhibitor-treated patients after repeated SARS-CoV-2 mRNA vaccination.” Anika M. Valk, et al. https://www.medrxiv.org/content/10.1101/2023.09.29.23296354v1
The Cleveland Clinic updated its famous study, which showed more vaccine doses yielded more infections. Once again, they find employees “up to date” on their boosters are more susceptible to infection than those “not up to date.” https://www.medrxiv.org/content/10.1101/2023.06.09.23290893v1
Yet another new paper, published in Vaccines, looking at the IgG4 class-switch problem, this time focused on the possibility of increased cancer risk. "IgG4 Antibodies Induced by Repeated Vaccination May Generate Immune Tolerance to the SARS-CoV-2 Spike Protein." https://www.mdpi.com/2076-393X/11/5/991.
"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."
See Jessica Rose's analysis here: https://jessicar.substack.com/p/igg4-antibodies-induced-by-repeated.
Dr. Paul Offit, a pediatric vaccine expert, has now written in the NEJM about the bivalent Covid-19 vaccine failure, specifically citing immune imprinting as one culprit. "Why did the strategy for significantly increasing BA.4 and BA.5 neutralizing antibodies using a bivalent vaccine fail? The most likely explanation is imprinting. The immune systems of people immunized with the bivalent vaccine, all of whom had previously been vaccinated, were primed to respond to the ancestral strain of SARS-CoV-2." https://www.nejm.org/doi/full/10.1056/NEJMp2215780.
Here's a new article in Science Immunology examining the IgG4 class-switching "tolerance" phenomenon. "Is it bad, is it good, or is IgG4 just misunderstood?" https://www.science.org/doi/10.1126/sciimmunol.adg7327
Yet another paper, this one from Chinese researchers published in iScience, shows repeated SARS2 vaccination can induce tolerance, depress the immune system, and potentially make you more susceptible to the virus. "Extended SARS-CoV-2 RBD booster vaccination induces humoral and cellular immune tolerance in mice." https://www.sciencedirect.com/science/article/pii/S2589004222017515
A new paper in Frontiers in Immunology confirms the basic phenomenon of IgG4 elevation, and possible "tolerance," after repeated Covid-19 vaccination, especially for the mRNA vaccines, which we described above. "mRNA vaccines against SARS-CoV-2 induce comparably low long-term IgG Fc galactosylation and sialylation levels but increasing long-term IgG4 responses compared to an adenovirus-based vaccine." https://www.frontiersin.org/articles/10.3389/fimmu.2022.1020844/full