The rise is delayed but persistent: low after 2 doses, it rises slowly (6 months after the 2nd dose) and explodes after the 3rd or 4th booster. 2025 studies confirm high persistence for several months/years after repeated boosters, linked to prolonged antigenic exposure (possible persistence of mRNA or Spike).
Published on 3 January 2026 by pgibertie
There are no robust longitudinal data on Spike-specific IgG4 levels beyond 2 years after the last dose of mRNA vaccine,
In children (Pediatric Infectious Disease Journal study, December 2024), the increase was significant 1 year after the 2nd dose.
Increased risk of breakthrough infections: A key study from March 2025 (Journal of Infection) shows that high levels of IgG4 (and a high ratio of non-cytophilic to cytophilic IgG) after mRNA boosters are significantly associated with a higher risk of symptomatic infections (HR 1.8 for a 10-fold increase in IgG4). Reduced effector functions: IgG4, which is anti-inflammatory, partially inhibits the pro-inflammatory responses (ADCC, ADCP, NK activation) of IgG1/IgG3, even though total neutralising antibodies remain high. Immune tolerance: This “class switch” towards IgG4 mimics a response to chronic exposure, favouring tolerance which could make viral replication easier when re-exposed.
And IgG4 is at the heart of autoimmune mechanisms
IgG4 antibodies are anti-inflammatory (or ‘blocking’) antibodies that inhibit the pro-inflammatory effector functions of the other subclasses (IgG1 and IgG3), such as complement activation, antibody-dependent phagocytosis (ADCP) or antibody-dependent cellular cytotoxicity (ADCC).
Systemic fibro-inflammatory disease (formerly known as sclerosing disease), characterised by lymphoplasmacytic infiltration rich in IgG4+ plasma cells, storiform fibrosis and tumour-like swellings, often affecting the pancreas (type 1 autoimmune pancreatitis), biliary tract, salivary glands/lacrimony, orbits, kidneys, retroperitoneum and aorta. Mechanism: probably autoimmune, with role of T/B cells and pro-fibrotic cytokines (IL-1β, TGF-β); exact role of IgG4 remains debated (marker or player?) Increased risk of malignancies (lymphomas, solid cancers).
In some natural tumor settings or in IgG4-related disease (IgG4-RD, a rare fibro-inflammatory disease), high levels of IgG4 may promote immune evasion of cancer cells by blocking these pro-inflammatory responses, theoretically contributing to tumor progression (studies such as Wang et al., 2020; Karagiannis et al., 2013). Vaccine IgG4 hypotheses (2023-2025): Several articles and reviews (e.g. Uversky et al., 2023; Rubio-Casillas et al., 2024) hypothesise that the increase in Spike-specific IgG4 induced by repeated doses of mRNA vaccines could: Reduce anti-viral effector functions (tolerance to SARS-CoV-2).
Theoretically, extend an anti-inflammatory effect favoring tumor escape, by blocking anti-tumor IgG1 or inhibiting Fcγ receptors on innate immune cells.
This article, published in January 2026 in Frontiers in Immunology (DOI: 10.3389/fimmu.2025.1727049), confirms a significant increase in SARS-CoV-2-specific IgG4 levels after an mRNA-based booster dose, irrespective of the primary vaccination regimen (BNT162b2, mRNA-1273 or heterologous with ChAdOx1-S followed by mRNA).
The mRNA boosters induced a marked increase in IgG4, particularly in those who had received two primary doses of mRNA-1273 (Moderna). This was accompanied by a shift in the distribution of IgG subclasses: an increase in the proportion of IgG4 (and IgG1), with a reduction in IgG3. The authors note that IgG4 has an immunoregulatory role and may inhibit the pro-inflammatory effects of the other subclasses (IgG1 and IgG3). They mention that this elevation of IgG4, linked to repeated or prolonged antigenic exposure, could potentially induce immune tolerance, but stress that this requires further investigation into its actual functional impact.
Yes, the article (published in December 2024 in The Pediatric Infectious Disease Journal) confirms a delayed increase in IgG4 specific to the SARS-CoV-2 Spike protein in children (aged 5-11 years) one year after two doses of BNT162b2 (Pfizer, 10 µg). Key points of this study (on a small cohort of 14 children): Initially (5 weeks after the 2nd dose), the response is dominated by IgG1 and IgG3 (pro-inflammatory).
At one year, there was a significant increase in IgG4 (and IgG2), similar to what has been described in adults (reference to Irrgang et al., 2023, among others).
The authors describe IgG4 as an “anti-inflammatory” or “blocking” antibody, incapable of effectively activating effector functions (such as phagocytosis or complement activation).
They underline the importance of better understanding this mechanism, especially with the development of new mRNA vaccines.
There is no mention or suggestion of a link with an increased risk of cancer. The article remains cautious and calls for larger studies to assess the long-term implications for immunity.
This phenomenon of increased IgG4 after repeated doses of mRNA has been well documented since 2023 (Irrgang et al., Buhre et al., etc.), and is more pronounced with mRNA vaccines than with adenoviral vectors. It is linked to repeated antigenic exposure, favoring a “class switch” towards anti-inflammatory subclasses.
We knew that mRNA led to an imbalance in the antibodies of those ‘vaccinated’, with a proliferation of IGG4. A new study confirms this one year after the injection.
The problem is not limited to covid but to ALL mRNA VACCINES
In summary, we report an increase in Spike-specific IgG4 levels in children one year after BNT162b2 vaccination, similar to the effect observed in adults. Although our study cannot predict population-level effects due to the small cohort size, it provides insight into the longitudinal dynamics of Spike-specific IgG subclass composition in children. IgG4 responses should receive greater attention in health and disease, particularly in the context of mRNA vaccination. Understanding the unusual mechanism triggering IgG4 production is crucial, as more mRNA vaccines are currently under development and may soon reach the global market.
French Irrgang et al were the first to report an increased proportion of SARS-CoV-2 Spike-specific IgG4 in adults, starting after the second dose and increasing further after the third dose of mRNA vaccine, resulting in up to 19.27% of total Spike-specific IgG levels. In addition, they observed a reduced ability of Spike-specific antibodies to mediate antibody-dependent cell phagocytosis and complement deposition, as well as substantial frequencies of IgG4-switched B cells. In adults, this mRNA-specific effect appears to be more pronounced in individuals naïve to infection.
The more doses the more IgG4 multiplies in the body. IgG4 is a unique antibody that has the lowest concentration among IgG subtypes in healthy individuals, and its function has not … Read more →
The distribution, abundance, actions, properties and possible mechanisms of IgG4 have been studied in human cancer samples and animal tumor models using a wide range of in vitro and in vivo techniques.
In a cohort of oesophageal cancer patients, we found that IgG4-containing B lymphocytes and IgG4 concentration were significantly increased in cancer tissues and that IgG4 concentrations were increased in the serum of cancer patients. Both were positively associated with increased cancer malignancy and poor prognosis, i.e. higher IgG4 levels appeared to be associated with more aggressive cancer growth.
We found that topical application of IgG4 significantly accelerated the growth of inoculated breast and colorectal cancers and carcinogen-induced skin papillomas. We also tested the cancer immunotherapy antibody nivolumab, which was IgG4 in nature with a stabilising S228P mutation, and found that it significantly promoted cancer growth in mice. This could provide an explanation for the recent appearance of hyperprogressive disease sometimes associated with cancer immunotherapy.
In this study, we found that IgG4 reacted with IgG1 not only on Western blots but also on cancer tissue sections. We demonstrated that non-cancer-specific IgG4 reacted with cancer-specific IgG1 bound to cancer cells. This would allow IgG4 to block the subsequent immune effector response that would otherwise detect and destroy the cancer cells. Our study was the first to demonstrate in cancer tissue that non-cancer-specific IgG4 was able to bind to cancer-bound IgG1, thus blocking the cancer-targeting immunity induced by cancer-specific antibodies.
Our results suggest that these IgG4 antibodies could have undesirable side-effects by inhibiting local immune responses and indirectly promoting cancer growth.
image top of page: Tokyo University of Science
