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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02741

Vaccine-induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells

 Leigh Fisher1*, Melissa Zinter2,  Sherry Stanfield-Oakley2,  Lindsay N. Carpp1, Regina W. Edwards2, 3,  Thomas N. Denny3, Zoe Moodie1, Fatima Laher4, Linda-Gail Bekker5, M J. McElrath1, Peter B. Gilbert1, 6,  Lawrence Corey1, Georgia Tomaras2, 3, 7, 8, Justin Pollara2, 3 and Guido Ferrari2, 3, 8*
  • 1Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, United States
  • 2Department of Surgery, School of Medicine, Duke University, United States
  • 3Duke Human Vaccine Institute, School of Medicine, Duke University, United States
  • 4Perinatal HIV Research Unit, South Africa
  • 5Desmond Tutu HIV Foundation, Faculty of Health Sciences, University of Cape Town, South Africa
  • 6Department of Biostatistics, School of Public Health, University of Washington, United States
  • 7Department of Immunology, School of Medicine, Duke University, United States
  • 8Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, United States

The secondary analyses for correlates of risk of infection in the RV144 HIV-1 vaccine trial implicated vaccine-induced antibody-dependent cellular cytotoxicity (ADCC) responses in the observed protection, highlighting the importance of assessing such responses in ongoing and future HIV-1 vaccine trials. However, in vitro assays that detect ADCC activity in plasma from HIV-1 infected seropositive individuals are not always effective at detecting ADCC activity in plasma from HIV-1 vaccine recipients. In vivo, ADCC-mediating antibodies must operate at the site of infection, where effector cells are recruited and activated by a local milieu of chemokines and cytokines. Based on previous findings that interleukin 15 (IL-15) secretion increases during acute HIV-1 infection and enhances NK cell-mediated cytotoxicity, we hypothesized that IL-15 pretreatment of NK effector cells could be used to improve killing of infected cells by vaccine-induced antibodies capable of mediating ADCC. Using the HIV-1 infectious molecular clone (IMC)-infected target cell assay along with plasma samples from HIV-1 vaccine recipients, we found that IL-15 treatment of NK cells improved the ability of the vaccine-induced antibodies to recruit NK cells for ADCC. Through immunophenotyping experiments, we showed that this improved killing was likely due to IL-15 mediated activation of the NK cells and higher intracellular levels of perforin and granzyme B in the IL-15 pretreated cells. We also found that using a 4-fold dilution series of plasma and subtraction of pre-vaccination responses resulted in lowest response rates among placebo recipients and significant separation between treatment groups. This represents the first attempt to utilize IL-15-treated effector cells and optimized analytical approaches to improve the detection of HIV-1 vaccine-induced ADCC responses and will inform analyses of future HIV vaccine clinical trials.

Keywords: Antibody-Dependent Cell Cytotoxicity (ADCC), HIV vaccine trial, Interleukin-15 (IL-15), Natural killer (Nk) cell, HIV-1 infectious molecular clone-infected target cell assay

Received: 19 Jun 2019; Accepted: 08 Nov 2019.

Copyright: © 2019 Fisher, Zinter, Stanfield-Oakley, Carpp, Edwards, Denny, Moodie, Laher, Bekker, McElrath, Gilbert, Corey, Tomaras, Pollara and Ferrari. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Leigh Fisher, Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, Washington, United States, lfisher@fredhutch.org
Dr. Guido Ferrari, Department of Surgery, School of Medicine, Duke University, Durham, 27707, North Carolina, United States, gflmp@duke.edu