Safety and Immunogenicity of an Accelerated Ebola Vaccination Schedule in People with and without Human Immunodeficiency Virus: A Randomized Clinical Trial

Abstract

The safety and immunogenicity of the two-dose Ebola vaccine regimen MVA-BN-Filo, Ad26.ZEBOV, 14 days apart, was evaluated in people without HIV (PWOH) and living with HIV (PLWH). In this observer-blind, placebo-controlled, phase 2 trial, healthy adults were randomized (4:1) to receive MVA-BN-Filo (dose 1) and Ad26.ZEBOV (dose 2), or two doses of saline/placebo, administered intramuscularly 14 days apart. The primary endpoints were safety (adverse events (AEs)) and immunogenicity (Ebola virus (EBOV) glycoprotein-specific binding antibody responses). Among 75 participants (n = 50 PWOH; n = 25 PLWH), 37% were female, the mean age was 44 years, and 56% were Black/African American. AEs were generally mild/moderate, with no vaccine-related serious AEs. At 21 days post-dose 2, EBOV glycoprotein-specific binding antibody responder rates were 100% among PWOH and 95% among PLWH; geometric mean antibody concentrations were 6286 EU/mL (n = 36) and 2005 EU/mL (n = 19), respectively. A total of 45 neutralizing and other functional antibody responses were frequently observed. Ebola-specific CD4+ and CD8+ T-cell responses were polyfunctional and durable to at least 12 months post-dose 2. The regimen was well tolerated and generated robust, durable immune responses in PWOH and PLWH. Findings support continued evaluation of accelerated vaccine schedules for rapid deployment in populations at immediate risk. Trial registration: NCT02598388 (submitted 14 November 2015).

Keywords: Ebola virus; immunogenicity; vaccine safety.

Figure 1

CONSORT diagram. Inf.U, infectious units; N, number of participants; PLWH, people living with HIV; PWOH, people without HIV; vp, viral particles. ^a Participants who discontinued vaccination could still complete the study.

Figure 2

Solicited adverse events. (A) Solicited local adverse events; (B) Solicited systemic adverse events. Percentages reflect n/N, where n is the number of participants with one or more adverse events and N is the number of participants with available reactogenicity data after the given dose. Ad26, Ad26.ZEBOV; MVA, MVA-BN-Filo; PLWH, people living with HIV; PWOH, people without HIV.

Figure 3

FANG anti-EBOV GP IgG ELISA measurements of EBOV GP-specific binding antibody responses. (A) In PWOH; (B) In PLWH; (C) All PWOH and PLWH active vaccine regimen and placebo recipients. The points (symbols) represent individual GMCs, and error bars denote 95% CIs. Ad26, Ad26.ZEBOV; CI, confidence interval; EBOV, Ebola virus; ELISA, enzyme-linked immunosorbent assay; FANG, Filovirus Animal Non-Clinical Group; GMC, geometric centration; GP glycoprotein; IgG, immunoglobulin G; LLOQ, lower limit of quantification; MVA, MVA-BN-Filo; N, number of participants; NA, not applicable; PLWH, people living with HIV; PWOH, people without HIV.

Figure 4

EBOV GP-specific functional antibody responses. (A) Neutralizing antibody responses to EBOV GP Zaire 95 Kikwit (psVNA); (B) Antibody-dependent cellular phagocytosis (ADCP); (C) Antibody-dependent natural killer cell activation (ADNKA); (D) Antibody-dependent complement deposition (ADCD). Specimens from PWOH or PLWH who were vaccinated with MVA, Ad26, or placebo were evaluated by (A) psVNA to measure the cross-neutralizing antibody response against EBOV Zaire 95 Kikwit strain. Blood was collected on Days 0, 15, 36, 57, 195, and 360 and ran in the assays. (B) Antibody-dependent cellular phagocytosis, (C) NK cell activation as measured by ICS, and (D) complement deposition were evaluated on Days 0, 36, and 360. For (A), data are plotted as geometric mean IC₅₀ titers ± 95% CI, and the lower assay limit was 20 (dotted line). For (B–D), data are plotted as geometric mean ± 95% CI, and the threshold for positivity was determined using plasma from controls (dotted line). Ad26, Ad26.ZEBOV; CI, confidence interval; EBOV, Ebola virus; GP glycoprotein; IC50, 50% inhibitory concentration; ICS, intracellular cytokine staining; IFN-γ, interferon γ; MVA, MVA-BN-Filo; NK, natural killer; PLWH, people living with HIV; psVNA, pseudovirion neutralization assay; PWOH, people without HIV; TNF, tumor necrosis factor.

Figure 4

EBOV GP-specific functional antibody responses. (A) Neutralizing antibody responses to EBOV GP Zaire 95 Kikwit (psVNA); (B) Antibody-dependent cellular phagocytosis (ADCP); (C) Antibody-dependent natural killer cell activation (ADNKA); (D) Antibody-dependent complement deposition (ADCD). Specimens from PWOH or PLWH who were vaccinated with MVA, Ad26, or placebo were evaluated by (A) psVNA to measure the cross-neutralizing antibody response against EBOV Zaire 95 Kikwit strain. Blood was collected on Days 0, 15, 36, 57, 195, and 360 and ran in the assays. (B) Antibody-dependent cellular phagocytosis, (C) NK cell activation as measured by ICS, and (D) complement deposition were evaluated on Days 0, 36, and 360. For (A), data are plotted as geometric mean IC₅₀ titers ± 95% CI, and the lower assay limit was 20 (dotted line). For (B–D), data are plotted as geometric mean ± 95% CI, and the threshold for positivity was determined using plasma from controls (dotted line). Ad26, Ad26.ZEBOV; CI, confidence interval; EBOV, Ebola virus; GP glycoprotein; IC50, 50% inhibitory concentration; ICS, intracellular cytokine staining; IFN-γ, interferon γ; MVA, MVA-BN-Filo; NK, natural killer; PLWH, people living with HIV; psVNA, pseudovirion neutralization assay; PWOH, people without HIV; TNF, tumor necrosis factor.

Figure 5

T-cell–mediated analysis of EBOV-specific vaccine response. (A) CD4+ T-cell responses in PWOH; (B) CD4+ T-cell responses in PLWH; (C) CD8+ T-cell responses in PWOH; (D) CD8+ T-cell responses in PLWH. EBOV GP-specific T-cell responses were measured by intracellular cytokine staining. Total cytokine response, identified by qualified cytokines, was assessed on Days 1, 15, 36, 57, 195, and 380. Participants (N), responders (%), and median responses are listed in rows above each corresponding graph. Data are plotted as individual points with bars indicating median and interquartile range. Ad26, Ad26.ZEBOV; EBOV, Ebola virus; GP, glycoprotein; IFN-γ, interferon γ; IL-2, interleukin-2; MVA, MVA-BN-Filo; NA, not applicable; PLWH, people living with HIV; PWOH, people without HIV.