Unraveling variability in Fc receptor engagement after SARS-CoV2 vaccination and boosting

Introduction:: Introduction: Vaccination against the SARS-CoV-2 virus has been a valuable tool for combatting the COVID-19 pandemic worldwide. Similar to other vaccines, protection is primarily driven by the induction of neutralizing antibodies (Abs), typically immunoglobulin G (IgG), capable of binding spike protein on the surface of the SARS-CoV-2 and hindering viral entry into host cells. However, recent studies suggest that Fc mediated immune responses such as antibody dependent cellular phagocytosis (ADCP) and antibody dependent cellular cytotoxicity (ADCC) are also important correlates of vaccine mediated protection against SARs-CoV-2 that may be less affected by viral variant escape from neutralizing antibodies. These responses are activated when the Fc portion of IgGs form complexes with antigen and Fc receptors (FcRs) on the surface of innate immune cells. Understanding mechanisms that underly the formation of these complexes is a focus of current vaccine research, but is hindered by variability in IgG and Fc receptor features evident across individuals. This variability is especially apparent after vaccine boosting, which skews IgG subclass distributions by reducing IgG3 and increasing IgG4 concentrations, and has been correlated with reduced Fc effector functions. To understand mechanisms driving this and how they vary across individuals, we used high-throughput measurements from human vaccine samples and an ordinary differential equation (ODE) model to predict IgG-FcγR engagement in individuals after SARS-CoV-2 vaccination and boosting. The model reveals new mechanisms by which variation in IgG subclass concentrations influences IgG-FcR complex formation, and how these mechanisms differ in individuals after 2^nd vaccination vs. after boosting.


Materials and Methods:: Materials and Methods: We used an ODE model to predict steady-state IgG-FcγR complex formation as a function of IgG subclass concentrations, IgG affinity for SARS-CoV-2 receptor binding domain (RBD), and IgG subclass affinities for individual FcγRs. IgG subclass concentrations were measured from samples in 18 recipients of the primary series of the Pfizer vaccine. IgG affinities for both RBD and individual FcγRs were obtained from published work. The model was validated for FcγRIIIA-158V and FcγRIIA-131H by comparing model-predicted Fc-FcγR complex formation to values experimentally measured in a custom multiplex assay. We then used the model to predict FcγR complex formation following a booster by modifying each vaccinee’s IgG subclass concentrations based on recent published values of subclass changes. In addition, we selectively left each individual’s IgG3 or IgG4 levels equivalent to that following dose two to determine changes in complex formation driven by modifications to IgG3 or IgG4 alone.


Results, Conclusions, and Discussions:: Results and Discussion: The model agreed well with experimental data, able to rank vaccinees in terms of IgG-FcγR complex formation for each FcγR, with spearman rank correlation coefficients of .825 and .624 for FcγRIIA-131H and FcγRIIIA-158V respectively (Figure 1A). Vaccinees with a simulated boost showed a 15.3% decrease in median levels of FcγR complex formation compared to vaccinees following dose two, demonstrating that the expected changes in IgG subclass concentration between dose two and a booster dose did result in lower levels if IgG-FcγR engagement. This aligns well with the observation of decreased Fc mediated effector functions following a booster as compared to following dose two. Selective replacement of the projected booster levels of IgG4 with dose two levels of IgG4 did not restore dose two levels of FcγR complex formation in the simulated booster population (Figure 1B). However, the selective replacement of booster levels of IgG3 with those of dose two did restore dose two levels of complex formation in the simulated booster population (Figure 1B). Taken together, these results indicate that the decrease in IgG3 between dose two and booster doses of the SARS-CoV-2 vaccine is partially responsible for the reduction in FcγR complex between vaccine doses.

Conclusions: Changes in IgG subclass concentration between doses of the COVID-19 vaccine are capable of modifying FcγR complex formation and likely downstream Fc mediated effector functions. The decrease in complex formation between dose two and a booster dose is partially driven by a reduction in IgG3 as opposed to an increase in IgG4.


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