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

Fisher, Leigh

Zinter, Melissa

Stanfield-Oakley, Sherry

Carpp, Lindsay N

Edwards, R Whitney

Denny, Thomas

Moodie, Zoe

Laher, Fatima

Bekker, Linda-Gail

McElrath, M Juliana

Gilbert, Peter B

Corey, Lawrence

Tomaras, Georgia

Pollara, Justin

Ferrari, Guido

2021-01-04T22:00:29Z

2021-01-04T22:00:29Z

2019-01

2021-01-04T22:00:26Z

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.

1664-3224

1664-3224

https://hdl.handle.net/10161/21998

eng

Frontiers Media SA

Frontiers in immunology

10.3389/fimmu.2019.02741

Killer Cells, Natural

Humans

HIV-1

HIV Infections

Interleukin-15

AIDS Vaccines

HIV Antibodies

Antibody-Dependent Cell Cytotoxicity

Adult

Female

Male

Granzymes

Young Adult

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

Journal article

Tomaras, Georgia|0000-0001-8076-1931

Ferrari, Guido|0000-0001-7747-3349

2741

School of Medicine

Duke Human Vaccine Institute

Duke Global Health Institute

Medicine, Duke Human Vaccine Institute

Duke

Institutes and Centers

University Institutes and Centers

Institutes and Provost's Academic Units

Medicine

Clinical Science Departments

Molecular Genetics and Microbiology

Surgery, Surgical Sciences

Basic Science Departments

Surgery

Immunology

Duke Innovation & Entrepreneurship

Initiatives

Published

10