Safety and immunogenicity of an adjuvanted herpes zoster subunit candidate vaccine in HIV-infected adults: a phase 1/2a randomized, placebo-controlled study

Abstract

Background: Human immunodeficiency virus (HIV)-infected individuals are at increased risk of herpes zoster (HZ), even in the antiretroviral therapy (ART) era. Because concerns exist about the use of live-attenuated vaccines in immunocompromised individuals, a subunit vaccine may be an appropriate alternative.

Methods: This phase 1/2, randomized, placebo-controlled study evaluated the immunogenicity and safety of an investigational HZ subunit vaccine (HZ/su). Three cohorts of HIV-infected adults aged ≥18 years were enrolled: 94 ART recipients with a CD4(+) T-cell count of ≥200 cells/mm(3), 14 ART recipients with a CD4(+) T-cell count of 50-199 cells/mm(3), and 15 ART-naive adults with a CD4(+) T-cell count of ≥500 cells/mm(3). Subjects received 3 doses of HZ/su (50 µg varicella-zoster virus glycoprotein E [gE] combined with AS01B adjuvant) or 3 doses of saline at months 0, 2, and 6.

Results: One month after dose 3, serum anti-gE antibody concentrations and frequencies of gE-specific CD4(+) T cells were higher following HZ/su vaccination than after receipt of saline (P < .0001). Median cell-mediated immune responses peaked after dose 2. Humoral and cell-mediated immune responses persisted until the end of the study (month 18). No vaccination-related serious adverse events were reported. No sustained impact on HIV load or CD4(+) T-cell count was noted following vaccinations.

Conclusions: HZ/su was immunogenic and had a clinically acceptable safety profile in HIV-infected adults.

Clinical trials registration: NCT01165203.

Keywords: HIV infection; glycoprotein E; herpes zoster; immunodeficiency; varicella-zoster virus; zoster vaccine.

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.

Figures

Figure 1.

Subject disposition. Herpes zoster (HZ) subunit vaccine (HZ/su) was first administered to human immunodeficiency virus (HIV)–infected subjects receiving antiretroviral therapy (ART) with a CD4+ T-cell count of ≥200 cells/mm3. A, Once the safety of 2 doses of HZ/su had been evaluated in the first 25 subjects (24 subjects with 2 doses and 1 subject with 1 dose) in this cohort by a safety committee composed of GlaxoSmithKline physicians and statistician and 1 non–GlaxoSmithKline-affiliated HIV expert, enrollment was initiated for subjects receiving ART with a lower CD4+ T-cell count (50–199 cells/mm3) and ART-naive subjects (CD4+ T-cell count, ≥500 cells/mm3). B, A similar process was followed after administration of the third dose in the ART/high CD4+ T-cell count cohort (in 70 subjects: 38 with 3 doses, 7 with 2 doses, and 25 with 1 dose) and after the second dose in the ART/low CD4+ T-cell count and ART-naive cohorts (in 24 subjects: 10 with 2 doses and 14 with 1 dose). Once safety had been evaluated, vaccination with the third dose was started in these 2 cohorts. Abbreviations: ATP, according-to-protocol cohort; TVC, total vaccinated cohort.

Figure 2.

Glycoprotein E (gE)– and varicella-zoster virus (VZV)–specific cell-mediated immune responses. A, The median frequencies of CD4+ T cells expressing at least 2 activation markers (CD4[2+]) among CD40 ligand, interleukin 2, tumor necrosis factor α, and interferon γ per 106 CD4+ T cells were determined after stimulation with a pool of gE or VZV peptides by intracellular cytokine staining followed by flow cytometry. Error bars indicate interquartile ranges. Arrows indicate vaccinations. B, Cell-mediated immune (CMI) vaccine response rate. Data are percentages with 95% confidence intervals (CIs). A CMI vaccine response was defined as a ≥2-fold increase in the frequency of CD4(2+) T cells after induction with gE or VZV, compared with prevaccination levels. Bars indicate means and errors bars indicate 95% CIs. Abbreviation: HZ/su, herpes zoster subunit candidate vaccine.

Figure 3.

Anti-glycoprotein E (gE) humoral immune response. A, Anti-gE antibody concentrations were determined by enzyme-linked immunosorbent assay. Data are geometric mean concentrations (GMCs [mIU/mL]), and error bars indicate 95% confidence intervals (CIs). Arrows indicate vaccinations. B, Anti-gE humoral vaccine response rate. Data are percentages with 95% CIs. An anti-gE humoral vaccine response was defined as an anti-gE antibody concentration of ≥4-fold the assay cutoff in initially seronegative subjects and an antibody concentration ≥4-fold the prevaccination antibody concentration in initially seropositive subjects. Abbreviation: HZ/su, herpes zoster subunit candidate vaccine.