Publications & Reports

A Quantitative Approach to Unravel the Role of Host Genetics in IgG-FcgammaR Complex Formation After Vaccination.

Lemke MM, Theisen RM, Bozich ER, McLean MR, Lee CY, Lopez E, Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kratochvil S, Wines BD, Hogarth PM, Kent SJ, Chung AW, Arnold KBKelly B Arnold
Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, United States.

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 FcgammaR polymorphisms influence IgG-FcgammaRIIIa complex formation in vaccine-relevant settings. Using data from the RV144 HIV vaccine trial, we map the landscape of IgG-FcgammaRIIIa complex formation predicted post-vaccination for three different IgG1 allotypes and two different FcgammaRIIIa polymorphisms. Overall, the model illustrates how specific vaccine interventions could be applied to maximize IgG-FcgammaRIIIa 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 FcgammaRIIIa 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.

Link to publisher’s web site

Publication

  • Journal: Frontiers in Immunology
  • Published: 22/02/2022
  • Volume: 13
  • Pagination: 820148

Authors

Download