Browsing by Author "Moodie, Zoe"

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    Safety and immunogenicity of a replication-defective adenovirus type 5 HIV vaccine in Ad5-seronegative persons: a randomized clinical trial (HVTN 054).
    (PLoS One, 2010-10-27) Peiperl, Laurence; Morgan, Cecilia; Moodie, Zoe; Li, Hongli; Russell, Nina; Graham, Barney S; Tomaras, Georgia D; De Rosa, Stephen C; McElrath, M Juliana; NIAID HIV Vaccine Trials Network
    BACKGROUND: Individuals without prior immunity to a vaccine vector may be more sensitive to reactions following injection, but may also show optimal immune responses to vaccine antigens. To assess safety and maximal tolerated dose of an adenoviral vaccine vector in volunteers without prior immunity, we evaluated a recombinant replication-defective adenovirus type 5 (rAd5) vaccine expressing HIV-1 Gag, Pol, and multiclade Env proteins, VRC-HIVADV014-00-VP, in a randomized, double-blind, dose-escalation, multicenter trial (HVTN study 054) in HIV-1-seronegative participants without detectable neutralizing antibodies (nAb) to the vector. As secondary outcomes, we also assessed T-cell and antibody responses. METHODOLOGY/PRINCIPAL FINDINGS: Volunteers received one dose of vaccine at either 10(10) or 10(11) adenovector particle units, or placebo. T-cell responses were measured against pools of global potential T-cell epitope peptides. HIV-1 binding and neutralizing antibodies were assessed. Systemic reactogenicity was greater at the higher dose, but the vaccine was well tolerated at both doses. Although no HIV infections occurred, commercial diagnostic assays were positive in 87% of vaccinees one year after vaccination. More than 85% of vaccinees developed HIV-1-specific T-cell responses detected by IFN-γ ELISpot and ICS assays at day 28. T-cell responses were: CD8-biased; evenly distributed across the three HIV-1 antigens; not substantially increased at the higher dose; and detected at similar frequencies one year following injection. The vaccine induced binding antibodies against at least one HIV-1 Env antigen in all recipients. CONCLUSIONS/SIGNIFICANCE: This vaccine appeared safe and was highly immunogenic following a single dose in human volunteers without prior nAb against the vector. TRIAL REGISTRATION: ClinicalTrials.gov NCT00119873.
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    Vaccine-Induced Antibodies Mediate Higher Antibody-Dependent Cellular Cytotoxicity After Interleukin-15 Pretreatment of Natural Killer Effector Cells.
    (Frontiers in immunology, 2019-01) 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
    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.