@article{15cfcbe4a33146d79162b417d45f09ea,
title = "A systems approach to elucidate personalized mechanistic complexities of antibody-Fc receptor activation post-vaccination",
abstract = "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.",
keywords = "ADCC, Fc receptor, HIV, IgG, ODE model, precision medicine, RV144, sensitivity analysis, systems serology, vaccine",
author = "Lemke, {Melissa M.} and McLean, {Milla R.} and Lee, {Christina Y.} and Ester Lopez and Bozich, {Emily R.} and Supachai Rerks-Ngarm and Punnee Pitisuttithum and Sorachai Nitayaphan and Sven Kratochvil and Wines, {Bruce D.} and Hogarth, {P. Mark} and Kent, {Stephen J.} and Chung, {Amy W.} and Arnold, {Kelly B.}",
note = "Funding Information: This work was supported by the Australia National Health & Medical Research Center (NHMRC) (APP1125164 to A.W.C.) and the American Foundation for AIDS Research (amfAR) Mathilde Krim Fellowship (109499-61-RKVA to A.W.C), and by start-up funds from the University of Michigan to K.B.A. S.J.K. and A.W.C. were supported by NHMRC fellowships. The data necessary to calculate allotype conversion was generously shared by Robin J. Shattock and Paul F. McKay (Imperial College, London). The authors would like to thank the participants in the RV144 trial, as well as Paul Wolberg and Denise Kirschner (University of Michigan) for assistance in implementing the global-sensitivity analysis, and Katy Norman and Katarina DiLillo (University of Michigan) for manuscript review. M.M.L. designed the study, performed computational analyses, created figures, and wrote the manuscript. M.R.M. and E.L. performed experimental measurements and edited the manuscript. C.Y.L. and E.R.B. performed computational analyses and edited the manuscript. S.K. provided data used to calculate conversion factors for IgG1 allotypes. S.R.-N. P.P. and S.N. conducted the RV144 vaccine trial. B.D.W. and P.M.H. provided rsFc?R dimers and edited the manuscript. S.J.K arranged institutional ethics and edited the manuscript. A.W.C. designed the study, wrote the manuscript, and oversaw the experimental analyses. K.B.A. designed the study, wrote the manuscript, and oversaw computational analysis. The authors declare no competing interests. Funding Information: This work was supported by the Australia National Health & Medical Research Center (NHMRC) ( APP1125164 to A.W.C.) and the American Foundation for AIDS Research (amfAR) Mathilde Krim Fellowship ( 109499-61-RKVA to A.W.C), and by start-up funds from the University of Michigan to K.B.A.. S.J.K., and A.W.C. were supported by NHMRC fellowships. The data necessary to calculate allotype conversion was generously shared by Robin J. Shattock and Paul F. McKay (Imperial College, London). The authors would like to thank the participants in the RV144 trial, as well as Paul Wolberg and Denise Kirschner (University of Michigan) for assistance in implementing the global-sensitivity analysis, and Katy Norman and Katarina DiLillo (University of Michigan) for manuscript review. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = sep,
day = "21",
doi = "10.1016/j.xcrm.2021.100386",
language = "English",
volume = "2",
journal = "Cell Reports Medicine",
issn = "2666-3791",
publisher = "Cell Press",
number = "9",
}