Abstract
Fc-mediated immune functions have been correlated with protection in the RV144 HIV vaccine trial and are important for immunity to a range of pathogens. IgG antibodies (Abs) that form complexes with Fc receptors (FcRs) on innate immune cells can activate Fc-mediated immune functions. Genetic variation in both IgGs and FcRs have the capacity to alter IgG-FcR complex formation via changes in binding affinity and concentration. A growing challenge lies in unraveling the importance of multiple variations, especially in the context of vaccine trials that are conducted in homogenous genetic populations. Here we use an ordinary differential equation model to quantitatively assess how IgG1 allotypes and FcγR polymorphisms influence IgG-FcγRIIIa complex formation in vaccine-relevant settings. Using data from the RV144 HIV vaccine trial, we map the landscape of IgG-FcγRIIIa complex formation predicted post-vaccination for three different IgG1 allotypes and two different FcγRIIIa polymorphisms. Overall, the model illustrates how specific vaccine interventions could be applied to maximize IgG-FcγRIIIa complex formation in different genetic backgrounds. Individuals with the G1m1,17 and G1m1,3 allotypes were predicted to be more responsive to vaccine adjuvant strategies that increase antibody FcγRIIIa affinity (e.g. glycosylation modifications), compared to the G1m-1,3 allotype which was predicted to be more responsive to vaccine boosting regimens that increase IgG1 antibody titers (concentration). Finally, simulations in mixed-allotype populations suggest that the benefit of boosting IgG1 concentration versus IgG1 affinity may be dependent upon the presence of the G1m-1,3 allotype. Overall this work provides a quantitative tool for rationally improving Fc-mediated functions after vaccination that may be important for assessing vaccine trial results in the context of under-represented genetic populations.
Highlights
Fc functional capacity is directly correlated to the number of immune complexes formed that activate Fc receptors [8], which is regulated by numerous factors including Immunoglobulin G (IgG) subclass concentrations, availability of FcRs and their respective binding properties [9]
These properties vary in individuals and several studies have demonstrated that they are influenced by genetic factors including IgG1 allotypes and FcR polymorphisms [10–12]
We identify specific mechanisms by which heterogeneity in FcgR activation after vaccination may be linked to IgG1 allotypes and FcgR polymorphisms
Summary
Antibodies (Abs) are a vital component of the protective immune response elicited by vaccination. Fc functional capacity is directly correlated to the number of immune complexes formed that activate Fc receptors [8], which is regulated by numerous factors including IgG subclass concentrations, availability of FcRs and their respective binding properties [9]. These properties vary in individuals and several studies have demonstrated that they are influenced by genetic factors including IgG1 allotypes and FcR polymorphisms [10–12]. Recent research suggests that IgG1 allotypic variation is linked with all four IgG subclass concentrations, potentially due to allotype-linked variation in expression and degradation [12] These allotype-linked differences in IgG subclass concentrations are observed in an antigen-specific manner upon vaccination. For example a recent phase I HIV vaccine trial [17] observed that G1m1 vaccinees (G1m1 & G1m1,3) reported to have higher HIV-specific IgG1:IgG2 ratios compared to the G1m-1,3 allotype, mainly driven by elevated HIVspecific IgG1 titers in G1m1 individuals [10]
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