Researcher contextualizes a study on IgG4 anti-Spike levels after repeated SARS-CoV-2 mRNA vaccination

NewsGuard 100/100 Score

In a recent focus piece published in Science Immunology, a researcher emphasized the need to reconsider messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccination strategies in the future.

Study: Is it bad, is it good, or is IgG4 just misunderstood? Image Credit:
Study: Is it bad, is it good, or is IgG4 just misunderstood? Image Credit:


Researchers showed that while repeated mRNA vaccination induced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S)-specific antibodies of the immunoglobulin G4 (IgG4) subtype, an adenoviral vector COVID-19 vaccine did not. Since long evolutionary and functional aspects of IgG4, constituting three to six percent of all human IgG, remained poorly understood. Rob Aalberse et al. uncovered many unknown facts about IgG4 in the past few decades.

For instance, they showed that structural variations in the constant heavy chain 2 (CH2) domain loop of IgG4 impede its binding to complement component 1q (C1q) and to fragment crystallizable (Fc) receptors (FcR). Thus, scientists postulated that IgG4 might be evolving to diminish inflammation.

In addition, these researchers showed that an arginine (R) at 409 amino acid position in the CH3 domain of IgG4 impeded CH3:CH3 pairing, facilitating its dissociation into two half molecules comprising one heavy and an associated light chain. These two half-molecules pair to form bispecific IgG4 antibodies by a process called “Fab arm exchange.” In vivo, this occurs in endosomes during FcRn-mediated recycling.

It is worth noting that IgG4 isotype in complex with IgG1 neutralizes well. However, in a pure form, it is less effective in facilitating opsonization by phagocytes, complement activation, and antibody-dependent cellular cytotoxicity (ADCC), i.e., elimination of pathogen-infected cells by natural killer (NK) cells. It makes the IgG4 isotype unsuitable for therapeutic monoclonal antibodies.

IgG4 and mRNA COVID-19 vaccines

Before discussing IgG4 in the context of mRNA COVID-19 vaccines, it is first necessary to discern the phenomenon termed IgG4 class switching. The humoral arm of the innate immune system switches towards the IgG4 isotype after prolonged exposure to a protein antigen, a phenomenon termed IgG4 class switching. A recent study among beekeepers showed that initial exposure to an antigen in bee venom (called phospholipase A2) elicited precipitating IgG1 antibodies. However, in about six months, these were replaced by IgG4 antibodies that eventually dominated the serological response.

Similarly, prolonged activation of recently described CD4+ helper T cells aids the differentiation of the interleukin 10 (IL-10)-expressing extrafollicular helper T cells, which then drives IgG4 class switching. Interestingly, this cell type also collaborated with reactivated B cells that had switched to other IgG subtypes.

Coming to mRNA vaccines, studies have shown that these also facilitate  IgG4 switching over time. Though mRNA lacks immunogenic alterations, the lipid nanoparticles in an mRNA vaccine confer an adjuvant effect that facilitates IgG4 switching.

From an evolutionary perspective, likely IgG subtype evolved in humans accidentally. There is no evidence that its functional monovalency or bispecificity is advantageous to the host. Yet, it has some advantageous functions; for instance, IgG4 neutralizes effectively, transfers across the placenta, and contributes to dampening immunity. In addition, it competes with IgE isotype and prevents anaphylaxis. In the anti-muscle specific kinase (MUSK) form of myasthenia gravis, an autoimmune disorder, IgG4 antibodies antagonize the enzyme to disturb neuromuscular synapses.


To conclude, it was not feasible to precisely decipher the negative consequences of increased IgG4 levels, if any, post-repeated vaccination with mRNA COVID-19 vaccines. Yet, in light of these findings, there is an urgent need to reconsider the relevance of COVID-19 vaccination for public health.

The proportion of total anti-SARS-CoV-2 S IgG after vaccination was relatively small initially, though of higher affinity since they surface late. Moreover, they formed immune complexes with IgG1.

Overall, the IgG4 isotype did not compromise immunity in vaccinated COVID-19 patients or SARS-CoV-2 neutralization owing to its functional monovalency.

Nevertheless, based on the evidence presented in this study and theoretical knowledge, future studies should evaluate the effect of spreading out mRNA vaccine boosts over a year.

Alternatively, studies could investigate whether using lesser amounts of mRNA for booster doses and using these vaccines for only priming are feasible options. Most importantly, breakthrough infections post-vaccination also induce anti-SARS-CoV-2 S IgG4. Thus, studies should continuously evaluate ways to tweak mRNA vaccination strategies for the future.

Journal reference:
Neha Mathur

Written by

Neha Mathur

Neha is a digital marketing professional based in Gurugram, India. She has a Master’s degree from the University of Rajasthan with a specialization in Biotechnology in 2008. She has experience in pre-clinical research as part of her research project in The Department of Toxicology at the prestigious Central Drug Research Institute (CDRI), Lucknow, India. She also holds a certification in C++ programming.


Please use one of the following formats to cite this article in your essay, paper or report:

  • APA

    Mathur, Neha. (2023, February 09). Researcher contextualizes a study on IgG4 anti-Spike levels after repeated SARS-CoV-2 mRNA vaccination. News-Medical. Retrieved on April 22, 2024 from

  • MLA

    Mathur, Neha. "Researcher contextualizes a study on IgG4 anti-Spike levels after repeated SARS-CoV-2 mRNA vaccination". News-Medical. 22 April 2024. <>.

  • Chicago

    Mathur, Neha. "Researcher contextualizes a study on IgG4 anti-Spike levels after repeated SARS-CoV-2 mRNA vaccination". News-Medical. (accessed April 22, 2024).

  • Harvard

    Mathur, Neha. 2023. Researcher contextualizes a study on IgG4 anti-Spike levels after repeated SARS-CoV-2 mRNA vaccination. News-Medical, viewed 22 April 2024,


  1. Andre Burnens Andre Burnens Switzerland says:

    Excellent summary of what is known about IgG4 (little). And IgG4 switching after repeated mRNA vaccination should indeed be loiked at more closely indeed.

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
Post a new comment

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
Study reveals how SARS-CoV-2 hijacks lung cells to drive COVID-19 severity