Controversial IgG4 Study On Covid Vaccine Efficacy: What It Means Clinically


Back in July 2022, a preprint, finding a rise in IgG4 antibodies after repeated mRNA vaccination, was used by the anti-vaccine community as proof that mRNA vaccines impair immunity against Covid-19. 

Now that the preprint is formally published in Science Immunology, a similar anti-vaccine movement has resurfaced, additionally claiming that mRNA vaccines cause IgG4-related diseases. 

But the pro-vaccine community says otherwise — that increased IgG4 regulates inflammation and may improve immunity against Covid. 

So, I evaluated both sides of the argument and conclude that the pro-vaccine side is more reasonable, but ultimately, we don’t really know much about what the IgG4 study means clinically. 

What the study did and found (feel free to skip)

Irrgang et al. from the University of Erlangen-Nuremberg, Germany, conducted the study, titled “Class switch towards non-inflammatory, spike-specific IgG4 antibodies after repeated SARS-CoV-2 mRNA vaccination.”

The study recruited 29 (median age of 44, 55% female) healthcare workers who got three doses of mRNA vaccine (Pfizer). They got their 1st and 2nd doses at 3–4 weeks apart, and the 3rd dose 7 months later. They collected their blood samples and measured the anti-spike IgG* responses 10 days after each vaccination, as well as 210 days after the 2nd and 180 days after the 3rd dose (total of 5 timepoints).

*IgG means immunoglobulin, synonymous with antibodies. Anti-spike IgG, thus, means IgG targeting the spike protein. IgG has four subclasses: IgG1, IgG2, IgG3, and IgG4, with IgG4 being the least abundant. 

Here are the results.

1. IgG4 class switch occurred 7 months after the 2nd mRNA vaccine dose:

  • At 10 days after the 1st and 2nd doses, anti-spike IgG1 and IgG3 were detected, as expected. Anti-spike IgG2 was also detected but at much lower levels, whereas anti-spike IgG4 was undetected. 
  • At 210 days after the 2nd dose, overall anti-spike IgG dropped, as expected of antibody waning, but anti-spike IgG4 was surprisingly detectable in about half of the vaccinees.

2. IgG4 class switch only occurred after repeated mRNA vaccination, not with DNA or mixed mRNA and DNA vaccinations:

  • They also tested if IgG class switching would occur in another cohort of vaccinees who received a mix of Pfizer mRNA and AstraZeneca DNA vaccines. At 5–6 months after the 2nd dose, anti-spike IgG4 was again detectable in half of the vaccinees who got two mRNA vaccine doses (n = 30), but only in 1 out of 51 vaccinees who got mixed mRNA and DNA vaccine doses (n = 30) or two DNA vaccine doses (n = 21).

3. IgG4 class switch persists and even increases after the 3rd mRNA vaccine dose. Subsequent breakthrough infection enhances IgG4 class switch.

  • Anti-spike IgG rose again 10 days after the 3rd mRNA vaccine dose. IgG1 and IgG2 levels were similar to the time point after the 2nd dose, but IgG3 levels were lower and IgG4 levels were markedly higher in nearly all the vaccines (Figure 1). Until this time, no vaccinees had Covid.
  • At 180 days after the 3rd dose, samples were again collected from 27 participants. IgG4 levels were still elevated and even increased up to 19.3% of total IgG (Figure 1). By this time, some participants had breakthrough infections, and their IgG4 levels were even higher, forming 40–80% of their IgG antibodies.
Figure 1. The proportion of the different IgG subclasses of the total anti-spike IgG for the four last time points. FU: follow-upPhoto byIrrgang et al. (2022).

4. IgG4 class switch is specific to anti-spike memory B-cells and specific to mRNA vaccines:

  • Among participants with persistent IgG4 class switch up to 180 days after the 3rd mRNA vaccine dose (n = 11), further analyses revealed that anti-spike IgG4-expressing memory cells (cells responsible for long-term immunity) constitute up to 37% of all IgG subclasses. This number is only 1–8% for IgG4-expressing memory cells that are not anti-spike. 
  • IgG4 class switch was absent in individuals with repeated tetanus toxoid vaccination (n = 23) or infected with respiratory syncytial virus (RSV) known to cause regular re-infections (n = 10). 

5. IgG4 class switch impairs antibody-dependent phagocytosis and complement activation:

  • Despite elevated IgG4 antibodies after the 3rd mRNA vaccine dose, the antibodies’ overall ability to bind to and neutralize the spike protein remains functional. 
  • Because IgG2 and IgG4 are known to be less effective in mediating antibody-dependent responses like phagocytosis (ingesting foreign particles like virus-infected cells) and complement activation (part of the immune system that enhances other immune functions), they tested these functions. And found that serum samples taken after the 3rd mRNA vaccination exhibited lower phagocytosis and complement activation than samples taken after two doses (Figure 2).
Figure 2. ADCP: antibody-dependent cellular phagocytosis; ADCD: antibody-dependent complement deposition.Photo byIrrgang et al. (2022).

What the IgG4 class switch means clinically

Overall, Irrgang et al. discovered evidence of persistent IgG4 class switch after repeated vaccination with the Pfizer mRNA vaccine, an effect not seen with other vaccines or infections. The IgG4 class switch seems specific to mRNA vaccine and mRNA vaccine-breakthrough infection.

SARS-CoV-2 infection alone barely triggered any IgG4 antibodies, as past studies have confirmed. If anything, studies found IgG4 to be associated with fatal Covid-19, as Irrgang et al. noted but also emphasized the unclear direction of causality, for it could be that severe Covid-19 causes IgG4 responses, not vice-versa. 

While Irrgang et al. admit it’s unclear how the IgG4 class switch occurs, they hypothesized it may be due to the persistence of mRNA vaccines in lymph nodes, as a previous study has shown (which I covered here). In essence, mRNA vaccine persistence in the lymph nodes may have somehow altered B-cells and induced class switching to IgG4. 

The study authors also admit that IgG4 class switch could pose functional consequences in how the immune system operates. 

On one hand, IgG4 class switch may result in less effective antibody-dependent responses compared to IgG1 and IgG3, as prior literature has indicated. For instance, repeated vaccination against human immunodeficiency virus (HIV) in clinical trials also led to increased IgG4 antibodies, which also inhibited antibody-dependent phagocytosis and complement activation activites. 

On the other hand, IgG4 class switch may promote anti-inflammatory activities. For example, beekeepers have increased IgG4 antibodies against bee venom, thus preventing chronic inflammation from repeated antigen (i.e., bee venom) exposure from bee stings (Figure 3). 

Immunotherapy for allergies also induces IgG4 class switch, so that symptoms don’t flare when exposed to the antigen (i.e., allergen). As Prof. Rob Aalberse, an expert on allergy immune responses, noted in a 2009 paper: “In general, the presence of allergen-specific IgG4 indicates that anti-inflammatory, tolerance-inducing mechanisms have been activated. The existence of the IgG4 subclass … may help the immune system to dampen inappropriate inflammatory reactions.”
Figure 4. Individuals undergoing venom immunotherapy (VIT) and beekeepers have statistically significant (** and ***) increases in IgG4.Photo byBoonpiyathad et al. (2017).

In the end, increased IgG4 could either mean decreased vaccine efficacy or enhanced anti-inflammatory responses, depending on how you argue about it. The anti-vaccine side will argue it’s the former, while the pro-vaccine side will argue it’s the latter. 

Irrgang et al. also acknowledged the duality interpretations of their study, “…an increase in IgG4 subclasses might result in longer viral persistence in case of infection…[It might also] reduce immunopathology while virus is still being neutralized [by antibodies].”

Although clinical trials support the safety and efficacy of mRNA vaccine boosters against Covid, these trials have a short follow-up time of a few weeks or months. That said, we also have longer-term observational data — though they are prone to biases such as the healthy vaccinee effect — which show that mRNA vaccine boosters still protect against Covid, particularly severe Covid, even if it’s from Omicron. 

So, even if the IgG4 class switch results in less effective antibody-dependent responses, it doesn’t seem to translate to ineffective or negative vaccine effectiveness in real-life. After all, Irrgang et al.’s study did show that the antibodies still neutralized the spike proteins despite the IgG4 class switch. 

Or it could even mean that the IgG class switch has no substantial impacts in real life, despite the weakening of antibody-dependent phagocytic and complement activation activities in laboratory settings. This is a widespread problem in translational research — translating and applying laboratory preclinical research to real-life clinical settings. 

At least in the field of therapeutics, only 5–10% of the most promising preclinical studies — those published in high-quality journals — are successfully translated into useful clinical applications.

The immune system is arguably the most complex biological system outside of the brain. It’s therefore unlikely for a single component (IgG4 class switch) to alter the immune function drastically. It might have a small effect, but whether it is clinically meaningful is debatable. 

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MSc Biology | 8x first-author academic papers | 280+ articles on coronavirus | Independent science writer


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