Safety and immunogenicity of rVSVΔG-ZEBOV-GP Ebola vaccine in adults and children in Lambaréné, Gabon: A phase I randomised trial.

BACKGROUND: The rVSVΔG-ZEBOV-GP vaccine prevented Ebola virus disease when used at 2 × 107 plaque-forming units (PFU) in a trial in Guinea. This study provides further safety and immunogenicity data. METHODS AND FINDINGS: A randomised, open-label phase I trial in Lambaréné, Gabon, studied 5 single intramuscular vaccine doses of 3 × 103, 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU in 115 adults and a dose of 2 × 107 PFU in 20 adolescents and 20 children. The primary objective was safety and tolerability 28 days post-injection. Immunogenicity, viraemia, and shedding post-vaccination were evaluated as secondary objectives. In adults, mild-to-moderate adverse events were frequent, but there were no serious or severe adverse events related to vaccination. Before vaccination, Zaire Ebola virus (ZEBOV)-glycoprotein (GP)-specific and ZEBOV antibodies were detected in 11% and 27% of adults, respectively. In adults, 74%-100% of individuals who received a dose 3 × 104, 3 × 105, 3 × 106, or 2 × 107 PFU had a ≥4.0-fold increase in geometric mean titres (GMTs) of ZEBOV-GP-specific antibodies at day 28, reaching GMTs of 489 (95% CI: 264-908), 556 (95% CI: 280-1,101), 1,245 (95% CI: 899-1,724), and 1,503 (95% CI: 931-2,426), respectively. Twenty-two percent of adults had a ≥4-fold increase of ZEBOV antibodies, with GMTs at day 28 of 1,015 (647-1,591), 1,887 (1,154-3,085), 1,445 (1,013-2,062), and 3,958 (2,249-6,967) for the same doses, respectively. These antibodies persisted up to day 180 for doses ≥3 × 105 PFU. Adults with antibodies before vaccination had higher GMTs throughout. Neutralising antibodies were detected in more than 50% of participants at doses ≥3 × 105 PFU. As in adults, no serious or severe adverse events related to vaccine occurred in adolescents or children. At day 2, vaccine RNA titres were higher for adolescents and children than adults. At day 7, 78% of adolescents and 35% of children had recombinant vesicular stomatitis virus RNA detectable in saliva. The vaccine induced high GMTs of ZEBOV-GP-specific antibodies at day 28 in adolescents, 1,428 (95% CI: 1,025-1,989), and children, 1,620 (95% CI: 806-3,259), and in both groups antibody titres increased up to day 180. The absence of a control group, lack of stratification for baseline antibody status, and imbalances in male/female ratio are the main limitations of this study. CONCLUSIONS: Our data confirm the acceptable safety and immunogenicity profile of the 2 × 107 PFU dose in adults and support consideration of lower doses for paediatric populations and those who request boosting. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201411000919191

Tuberculosis Treatment Outcome and Drug Resistance in Lambaréné, Gabon: A Prospective Cohort Study

Despite overall global progress in tuberculosis (TB) control, TB remains one of the deadliest communicable diseases. This study prospectively assessed TB epidemiology in Lambaréné, Gabon, a Central African country ranking 10th in terms of TB incidence rate in the 2014 World Health Organization TB report. In Lambaréné, between 2012 and 2014, 201 adult and pediatric TB patients were enrolled and followed up; 66% had bacteriologically confirmed TB and 95% had pulmonary TB. The human immunodeficiency virus (HIV) coinfection rate was 42% in adults and 16% in children. Mycobacterium tuberculosis and Mycobacterium africanum were identified in 82% and 16% of 108 culture-confirmed TB cases, respectively. Isoniazid (INH) and streptomycin yielded the highest resistance rates (13% and 12%, respectively). The multidrug resistant TB (MDR-TB) rate was 4/91 (4%) and 4/13 (31%) in new and retreatment TB cases, respectively. Treatment success was achieved in 53% of patients. In TB/HIV coinfected patients, mortality rate was 25%. In this setting, TB epidemiology is characterized by a high rate of TB/HIV coinfection and low treatment success rates. MDR-TB is a major public health concern; the need to step-up in-country diagnostic capacity for culture and drug susceptibility testing as well as access to second-line TB drugs urgently requires actio

Participant flow diagram.

<p>Randomisation and flow of participants over a period of 6 months for adults (cohorts 1 to 5), adolescents (cohort 6; 13–17 years), and children (cohort 7; 6–12 years). Similar dose groups are matched with shading (light grey, 3 × 10⁶ PFU; dark grey, 2 × 10⁷ PFU). GP, glycoprotein; ELISA, enzyme-linked immunosorbent assay; PFU, plaque-forming units; rVSV, recombinant vesicular stomatitis virus.</p

Geometric mean titres, seropositivity rates, and proportions of seroresponders to rVSVΔG-ZEBOV-GP measured by ZEBOV PsVNA50 in adults.

<p>Geometric mean titres, seropositivity rates, and proportions of seroresponders to rVSVΔG-ZEBOV-GP measured by ZEBOV PsVNA50 in adults.</p

Description of viraemia by dose and age.

<p>Description of viraemia by dose and age.</p

Glycoprotein antibody distribution by age group: Comparison of distribution of ZEBOV-GP IgG antibodies (AEU/ml) measured by USAMRIID ZEBOV-GP ELISA for dose 2 × 10⁷ PFU administered to children, adolescents, and adults from day 0, 28, 56, 84, and 180.

<p>Data were not available for children and adolescents at D84. P < 0.05 indicates a statistical difference in ZEBOV-GP IgG between children, adolescents, and adults. AEU, arbitrary enzyme-linked immunosorbent assay units; ELISA, enzyme-linked immunosorbent assay; GP, glycoprotein; PFU, plaque-forming units; USAMRIID, US Army Medical Research Institute of Infectious Diseases; ZEBOV, Zaire Ebola virus.</p

Endpoint geometric mean titres measured by USAMRIID ZEBOV-GP ELISA in adults with and without baseline specific antibodies.

<p>Endpoint geometric mean titres measured by USAMRIID ZEBOV-GP ELISA in adults with and without baseline specific antibodies.</p

Viral load in saliva for children and adolescents.

<p>rVSV<b>Δ</b>G-ZEBOV-GP (rVSV) RNA copy numbers in saliva presented as log10 rVSV RNA copies/ml from day 2 and 7 (d2 and d7) post-injection in adolescents and children vaccinated with 2 × 10⁷ PFU. The broken line denotes the limit of quantitation, and the dotted line denotes the limit of detection. About 67% (12/18) and 30% (6/20) adolescents and children, respectively, had samples above the limit of quantification at day 7. *P < 0.05; **P < 0.01.PFU, plaque-forming units.</p

Baseline characteristics of study participants.

<p>Baseline characteristics of study participants.</p