A systems approach to elucidate personalized mechanistic complexities of antibody-Fc receptor activation post-vaccination

Immunoglobulin G (IgG) antibodies that activate Fc-mediated immune functions have been correlated with vaccine efficacy, but it is difficult to unravel the relative roles of multiple IgG and Fc receptor (FcR) features that have the capacity to influence IgG-FcR complex formation but vary on a personalized basis. Here, we develop an ordinary differential-equation model to determine how personalized variability in IgG subclass concentrations and binding affinities influence IgG-FcγRIIIa complex formation and validate it with samples from the HIV RV144 vaccine trial. The model identifies individuals who are sensitive, insensitive, or negatively affected by increases in HIV-specific IgG1, which is validated with the addition of HIV-specific IgG1 monoclonal antibodies to vaccine samples. IgG1 affinity to FcγRIIIa is also prioritized as the most influential parameter for dictating activation broadly across a population. Overall, this work presents a quantitative tool for evaluating personalized differences underlying FcR activation, which is relevant to ongoing efforts to improve vaccine efficacy. [Display omitted] Fc-mediated immune functions have been correlated with protection in HIV vaccine trialsA model reveals personalized mechanisms that drive variation in FcγR activationThe model predicts individuals who are sensitive to changes in IgG1 concentrationIgG1 affinity to FcγR best dictates activation across a heterogeneous population Fc-mediated immune functions have been identified as a correlate of protection in vaccine trials for HIV and other pathogens. Lemke et al. present a quantitative tool to understand how personalized differences in antibody and Fc receptor features contribute to variation in FcR activation after vaccination.