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

Melissa M Lemke; Milla R McLean; Christina Y Lee; Ester Lopez; Emily R Bozich; Supachai Rerks-Ngarm; Punnee Pitisuttithum; Sorachai Nitayaphan; Sven Kratochvil; Bruce D Wines; P Mark Hogarth; Stephen J Kent; Amy W Chung; Kelly B Arnold

doi:10.1016/j.xcrm.2021.100386

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

Cell Rep Med. 2021 Sep 1;2(9):100386. doi: 10.1016/j.xcrm.2021.100386. eCollection 2021 Sep 21.

Authors

Melissa M Lemke¹, Milla R McLean², Christina Y Lee¹, Ester Lopez², Emily R Bozich¹, Supachai Rerks-Ngarm³, Punnee Pitisuttithum⁴, Sorachai Nitayaphan⁵, Sven Kratochvil⁶, Bruce D Wines^{7

8

9}, P Mark Hogarth^{7

8

9}, Stephen J Kent^{2

10

11}, Amy W Chung², Kelly B Arnold¹

Affiliations

¹ Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
² Department of Microbiology and Immunology, The University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia.
³ Department of Disease Control, Ministry of Public Health, Bangkok, Thailand.
⁴ Vaccine Trial Centre, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
⁵ Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.
⁶ The Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA.
⁷ Immune Therapies Group, Burnet Institute, Melbourne, VIC, Australia.
⁸ Department of Immunology and Pathology, Monash University, Melbourne, VIC, Australia.
⁹ Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC, Australia.
¹⁰ ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, The University of Melbourne, Melbourne, VIC, Australia.
¹¹ Melbourne Sexual Health Centre, Alfred Hospital, Monash University Central Clinical School, Carlton, VIC, Australia.

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; RV144; precision medicine; sensitivity analysis; systems serology; vaccine.

Publication types

Clinical Trial, Phase III
Research Support, Non-U.S. Gov't

MeSH terms

HIV Antibodies / immunology*
Humans
Immunoglobulin G / metabolism
Models, Biological
Precision Medicine*
Receptors, Fc / metabolism*
Receptors, IgG / metabolism
Reproducibility of Results
Systems Analysis*
Vaccination*
env Gene Products, Human Immunodeficiency Virus / metabolism

Substances

FCGR3A protein, human
HIV Antibodies
Immunoglobulin G
Receptors, Fc
Receptors, IgG
env Gene Products, Human Immunodeficiency Virus

Associated data

figshare/10.6084/m9.figshare.14810397