The IgG4 Puzzle: Why Boosters May Weaken One Defense but Strengthen Another

Post-Vaccination IgG4 and IgG2 Class Switching is linked to Increased Risk of SARS-CoV-2 Infections

A new study published in Infectious Disease Practice has revealed a concerning correlation between the class switching of antibodies after COVID-19 mRNA booster vaccinations and a heightened risk of breakthrough infections. Specifically, the study found that elevated levels of IgG4 and IgG2 antibodies, which increase significantly following the third mRNA dose, are linked to an increased risk of symptomatic SARS-CoV-2 infections. 

The study followed a longitudinal cohort of 83 healthcare workers who received three vaccine doses, with an additional 66 participants analyzed at a specific timepoint (T9, May 2022), four months after the first booster. Conducted in Spain, the research tracked immune responses over nearly three years, revealing that the proportion of non-cytophilic antibodies (IgG4 and IgG2) increased relative to cytophilic subclasses (IgG1 and IgG3) after the booster.

This class switch matters: IgG4 and IgG2 are less effective at activating immune effector mechanisms such as complement activation and antibody-dependent cellular cytotoxicity (ADCC). Consequently, their predominance was associated with reduced viral neutralization capacity—potentially explaining why some fully vaccinated individuals still experience breakthrough infections despite prior immunization.

However, the picture is more nuanced than it may seem. Although high IgG4/IgG2 ratios correlated with reduced protection against infection, these same antibodies might help prevent severe disease by dampening excessive inflammation. Their “tolerant” immunological profile could thus be double-edged - blunting both viral defense and tissue-damaging immune overreactions.

Importantly, new complementary findings add depth to this discussion. A recent study titled “Vaccination-induced T cell responses maintain polyclonality with high antigen receptor avidity” demonstrates that mRNA vaccination continues to elicit robust, diverse, and high-affinity T cell responses even after multiple doses. These polyclonal T cells recognize a broad array of viral epitopes and maintain high receptor avidity, suggesting that cellular immunity remains resilient and adaptable, even as humoral antibody profiles shift.

This means that while repeated mRNA boosters may alter antibody subclass distributions - potentially reducing neutralization efficiency - the T cell arm of the immune system still provides durable protection against severe outcomes. Together, the findings highlight the complex interplay between humoral and cellular immunity following mRNA vaccination.

In summary, the observed IgG4/IgG2 class switching raises important questions about the long-term consequences of repeated mRNA boosting and how vaccine design might evolve. Still, the persistence of broad, high-avidity T cell responses provides reassurance that vaccine-induced immunity remains complex and resilient.

Future vaccination strategies may focus on balancing antibody subclass responses while maintaining strong, durable T cell-mediated protection, refining defense against both infection and severe disease. Ultimately, these findings underscore that immune responses are not uniform across individuals - genetics, prior exposures, and immune history all shape outcomes. Thus, personalized vaccination approaches, rather than one-size-fits-all schedules, may represent the next frontier in optimizing protection for everyone.

REFERENCES

1. Pérez, Carla Martín et al. Post-vaccination IgG4 and IgG2 class switch associates with increased risk of SARS-CoV-2 infections Journal of Infection, Volume 0, Issue 0, 106473

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