Immunoglobulin G4 (IgG4) is an antibody often associated with immune tolerance or long-term exposure to certain substances. It has drawn attention in discussions surrounding COVID-19 vaccines, particularly mRNA-based ones, due to its role in the immune response after vaccination.
The Immune System’s Antibody Arsenal
Antibodies are specialized proteins produced by the immune system to identify and neutralize foreign invaders like bacteria and viruses. These Y-shaped molecules bind specifically to unique markers on pathogens, known as antigens, thereby tagging them for destruction or directly blocking their activity. The human body produces five main classes of antibodies: IgG, IgM, IgA, IgD, and IgE, each with distinct functions and locations in the body.
Among these, Immunoglobulin G (IgG) is the most abundant antibody in the blood and extracellular fluids, playing a significant role in long-term immunity. IgG is further divided into four subclasses: IgG1, IgG2, IgG3, and IgG4, which differ in their structure and their ability to activate various immune responses. For example, IgG1 and IgG3 are known for their strong ability to activate other immune cells and pathways, while IgG2 is primarily involved in responses to certain bacterial components.
A natural process called antibody class switching allows B cells, a type of white blood cell, to change the class of antibody they produce while maintaining the same antigen-binding specificity. This mechanism enables the immune system to tailor its response to different threats or prolonged exposure.
IgG4 and COVID-19 Vaccine Responses
Specific changes in IgG4 levels have been observed following COVID-19 vaccination, particularly with mRNA vaccines. After the initial two doses, the immune response is largely dominated by IgG1 and IgG3 subclasses. However, studies indicate that after a few months following the second dose, and especially after a third mRNA booster dose or subsequent SARS-CoV-2 infections, there is a notable increase in spike-specific IgG4 antibodies.
For example, IgG4 antibodies, almost undetectable after the second vaccine dose, increased significantly to nearly 20% of the total anti-spike IgG antibodies late after a third vaccination. This phenomenon, known as an “IgG4 class switch,” is a known immunological response to repeated or prolonged exposure to an antigen. While not unique to COVID-19 vaccines, its prevalence and implications are actively being investigated. The induction of IgG4 antibodies was primarily observed with mRNA COVID-19 vaccines and not with adenoviral vector-based vaccines.
Understanding the Role of IgG4
IgG4 is often associated with immune tolerance, meaning it can help reduce inflammation or allergic reactions rather than directly neutralizing pathogens. This contrasts with IgG1 and IgG3, which are more effective at activating immune cells and pathways to clear infections.
A unique characteristic of IgG4 is its “Fab-arm exchange,” where it can swap half-molecules with other IgG4 antibodies, leading to “bispecific” antibodies that can bind to two different antigens. This makes IgG4 functionally monovalent for a single antigen, meaning it is less effective at cross-linking antigens and forming large immune complexes, which are typically cleared by other immune mechanisms.
IgG4 also has a low affinity for activating certain immune receptors and does not efficiently activate the complement system, a part of the immune response that helps clear pathogens. While IgG4 can still neutralize viruses and toxins, its reduced ability to trigger other immune effector functions compared to subclasses like IgG1 raises questions about its protective capabilities against viral infection. An increase in IgG4 might be a mechanism to prevent an excessive inflammatory response during repeated antigen encounters. However, elevated IgG4 levels have been associated with increased risk of SARS-CoV-2 breakthrough infections in some studies.
What This Means for Future Immunity
While the observed increase in IgG4 levels after multiple mRNA vaccine doses is a clear immunological phenomenon, its full clinical significance for protection against severe disease, infection, and transmission is still being actively studied.
This evolving understanding could influence future vaccine development and booster strategies. For instance, researchers are exploring whether different vaccine designs or dosing schedules might modulate the IgG subclass response to optimize protective immunity. The goal is to ensure that vaccine-induced immunity remains robust against new variants and provides lasting protection.
The immune system is complex and constantly adapting; while specific antibody responses are investigated, other arms of immunity, such as T-cell responses and memory B cells, also contribute significantly to protection.