“IgG4 Subclass Switching Does Not Reduce Breakthrough Infections.” Great! But Why Not Explore Whether the Exact Opposite Applies?

This publication (https://www.tandfonline.com/doi/epdf/10.1080/21645515.2025.2547517?needAccess=true) once again illustrates how dangerous a tool science becomes when placed in the hands of narrowly trained scientists. The conclusions of this study (as reflected in the title) are those of a mere case report, cannot in any way be generalized from the available data, and are therefore useless for anyone seeking to understand the true impact of Covid-19 (C-19) mass vaccination on the adaptive immune response of C-19-vaccinated populations.

The authors conclude that there is a correlation between the binding IgG antibody (Ab) titers (measured by ELISA) and their neutralizing capacity. However, this says nothing about the functional differences between Abs in the compared groups. Indeed, high titers of binding serum Abs after the booster consistently correlated with strong in vitro virus-neutralizing capacity, even when these Abs contained a greater proportion of IgG4 Abs, which are known to have lower viral affinity and reduced functional effectiveness.

The authors seem to suggest that, because the neutralizing capacity of serum Abs is similar, it is logical that the number of vaccine breakthrough infections (VBTIs) after the booster is also comparable between the 2 groups. This conclusion is rather shallow. Even if -given the small number of individuals tested-the results are not statistically significant, the number of VBTIs was clearly higher among individuals with a significant post-booster increase in IgG4 Abs (8/22 versus 4/16). This suggests that the protective function of IgG antibodies against VBTIs may indeed decrease in those whose IgG4 Ab levels rose markedly after the booster.

From this study, it is in any case evident that C-19 vaccination does not protect against VBTIs. So: bye-bye to the woke myth of hybrid immunity!
Although the authors attempt to argue that increased IgG4 levels do not reduce virus neutralization, or even cross-neutralization, I strongly doubt this. Their conclusions are based on comparing two immunologically differently primed groups of very small size (a third of whom were obese!). This is essentially comparing apples with pears. To detect potential differences in the infection-inhibiting capacity of the sera tested, it would have been very useful to also perform neutralization assays against a variant more divergent from the Wuhan-Hu-1 strain than Omicron BA.1. Such differences might then have become evident, as shown by previous studies of cross-protection in mRNA-vaccinated individuals across several distinct Omicron lineages (https://pmc.ncbi.nlm.nih.gov/articles/PMC8687472/).

To investigate in a correct and scientifically robust manner whether IgG4 Abs confer more or less protection against VBTIs, one should first determine within a single cohort whether there is a correlation between the average post-booster IgG4 Ab concentration and the number of VBTIs over a defined time frame (e.g., up to one year after the booster injection). In addition, one could test whether IgG4 Ab levels are significantly increased in individuals who experienced VBTIs. It is known that also in individuals first infected naturally and subsequently vaccinated, IgG4 Abs can rise sharply because high IgG titers in individuals exposed to a heterologous variant may lead to antibody-dependent enhancement of infection (ADEI), and thereby trigger immune refocusing and drive IgG4 production. In both scenarios (i.e., in immunologically naïve and infection-primed individuals vaccinated and boosted with mRNA vaccines), the increased IgG4 Ab production merely reflects immune refocusing, induced either by the booster injection itself or by ADEI-mediated VBTIs with heterologous SARS-CoV-2 variants (https://voiceforscienceandsolidarity.substack.com/p/vaccine-induced-igg4-increase-another?r=y46t6).

The present study provides no insight into the neutralizing action of IgG4 Abs as such, nor does it clarify whether elevated IgG4 Ab concentrations contribute to better or worse protection against VBTIs with heterologous variants. The authors’ interpretation -claiming that “our study uniquely demonstrates that this response (i.e., IgG4 subclass switching following repeated mRNA vaccination) specifically elevated in infection-naïve individuals post-booster does not compromise in vitro neutralization capacity or increase breakthrough infection rates”-is clearly far-fetched and nearly the opposite of what the title of their publication itself suggests! (“Elicitation of neutralizing antibodies and IgG4 subclass switching following booster vaccination with ancestral COVID-19 mRNA vaccines does not reduce breakthrough infections”).

The authors further postulate that “the booster vaccination likely restimulates memory B cells generated by the initial doses, including those B cell clones that have acquired mutations enabling recognition of variant epitopes.” This would, however, assume specific recognition of mutated epitopes by monoclonal Abs from such epitope-specific memory B cells. Yet, no epitope mapping was performed. There is thus no proof that BA.1 pseudovirion recognition by sera from boosted individuals is due to specific binding of Abs to variable Spike-associated epitopes rather than to T-helper-dependent recognition of more conserved epitopes. With repeated mRNA vaccination or VBTIs, it is reasonable to assume that immune refocusing toward less immunogenic, more conserved epitopes increases, thereby enhancing non-cognate T-helper assistance to the generation of cross-reactive Abs. This promotes higher IgG4 Ab titers with lower antigen-binding affinity and reduced neutralizing capacity. It is precisely for this reason that monitoring IgG4 Ab titers as VBTIs accumulate and testing their neutralization capacity against heterologous variants would be highly relevant. Even the authors themselves admit that “Continued monitoring will be important to determine whether an accumulating IgG4 bias could influence the durability of immunity or responses to subsequent exposures.” Yet, a study with such limited sample size, limited booster numbers, and without post-VBTI sera analysis is completely irrelevant because it cannot truly assess whether increased IgG4 Ab levels correlate with diminished Ab function.

Further adding to the irrelevance of their data, the authors themselves implicitly admit that their study does not clarify the impact of anti-RBD[1] IgG4 induction on immune protection: “One possible explanation is that IgG4 comprised only a subset of the total antibody pool, which remained overwhelmingly dominated by IgG1. The high overall antibody titers achieved after the booster likely outweighed any modest reduction in Fc-effector function due to IgG4.” Hence, their dataset and conclusions must be qualified as a case report, and they cannot legitimately conclude that no correlation exists between the mRNA vaccination-associated increase in IgG4 Abs and immune refocusing or VBTIs.

Immune refocusing toward conserved epitopes may improve cross-neutralization. However, as the increased breadth of virus-neutralization does not prevent viral transmission or infection, it merely accelerates broad, cross-reactive immune selection pressure on viral infectivity, thereby driving large-scale viral immune escape. This exactly explains why this pandemic is increasingly evolving into a state of chronicity while progressively dysregulating and exhausting adaptive immune function.

Overall conclusion: None of the above observations support the authors’ sweeping claim: “This study is the first to longitudinally demonstrate that IgG4 subclass switching following repeated mRNA vaccination in infection-naïve individuals does not impair cross-variant neutralization or increase breakthrough infection.”
Studies like this are essentially useless-a waste of energy, time, and resources.
The publication itself has become the product -insight is irrelevant. Who cares whether they provide critical insights into the pathobiology of this immune escape pandemic, or whether they contribute to solving this societal crisis? Clearly not these scientists, nor their peer reviewers.

---

[1] RBD: Receptor-binding domain