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

Frontiers in Immunology. 2019;10 DOI 10.3389/fimmu.2019.02741

 

Journal Homepage

Journal Title: Frontiers in Immunology

ISSN: 1664-3224 (Online)

Publisher: Frontiers Media S.A.

LCC Subject Category: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy

Country of publisher: Switzerland

Language of fulltext: English

Full-text formats available: PDF, HTML, ePUB, XML

 

AUTHORS

Leigh Fisher (Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States)
Melissa Zinter (Department of Surgery, Duke University Medical Center, Durham, NC, United States)
Sherry Stanfield-Oakley (Department of Surgery, Duke University Medical Center, Durham, NC, United States)
Lindsay N. Carpp (Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States)
R. Whitney Edwards (Department of Surgery, Duke University Medical Center, Durham, NC, United States)
R. Whitney Edwards (Duke University Medical Center, Duke Human Vaccine Institute, Durham, NC, United States)
Thomas Denny (Duke University Medical Center, Duke Human Vaccine Institute, Durham, NC, United States)
Zoe Moodie (Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States)
Fatima Laher (Perinatal HIV Research Unit, Faculty of Health Sciences, University of the Witwatersrand, Soweto, South Africa)
Linda-Gail Bekker (The Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa)
M. Juliana McElrath (Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States)
Peter B. Gilbert (Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States)
Peter B. Gilbert (Department of Biostatistics, University of Washington, Seattle, WA, United States)
Lawrence Corey (Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States)
Georgia Tomaras (Department of Surgery, Duke University Medical Center, Durham, NC, United States)
Georgia Tomaras (Duke University Medical Center, Duke Human Vaccine Institute, Durham, NC, United States)
Georgia Tomaras (Department of Immunology, Duke University Medical Center, Durham, NC, United States)
Georgia Tomaras (Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, United States)
Justin Pollara (Department of Surgery, Duke University Medical Center, Durham, NC, United States)
Justin Pollara (Duke University Medical Center, Duke Human Vaccine Institute, Durham, NC, United States)
Guido Ferrari (Department of Surgery, Duke University Medical Center, Durham, NC, United States)
Guido Ferrari (Duke University Medical Center, Duke Human Vaccine Institute, Durham, NC, United States)
Guido Ferrari (Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, United States)

EDITORIAL INFORMATION

Blind peer review

Editorial Board

Instructions for authors

Time From Submission to Publication: 14 weeks

 

Abstract | Full Text

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 effector cells improved the ability of the vaccine-induced antibodies to recruit effector cells for ADCC. Through immunophenotyping experiments, we showed that this improved killing was likely due to IL-15 mediated activation of NK effector cells and higher intracellular levels of perforin and granzyme B in the IL-15 pretreated NK 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.