Mechanisms and implications of IgG4 responses to SARS-CoV-2 and other repeatedly administered vaccines

Vaccine-induced immunoglobulin G (IgG) profiles can vary with respect to the predominant subclasses that characterize the response. Among IgG subclasses, IgG4 is reported to have anti-inflammatory properties, but can also exhibit reduced capacity for virus neutralization and activation of Fc-dependent effector functions. Here, we review evidence that IgG4 subclass responses can be disproportionately increased in response to some types of vaccines targeting an array of diseases, including pertussis, HIV, malaria, and COVID-19. The basis for enhanced IgG4 induction by vaccines is poorly understood but may be associated with platform- or dose regimen–specific differences in antigen exposure and/or cytokine stimulation. The clinical implications of vaccine-induced IgG4 responses remain uncertain, though collective evidence suggests that proportional increases in IgG4 might reduce vaccine antigen-specific immunity. Additional work is needed to determine underlying mechanisms and to elucidate what role IgG4 may play in modifications of vaccine-induced immunity to disease.