The effect of dose on the safety and immunogenicity of the VSV Ebola candidate vaccine: a randomised double-blind, placebo-controlled phase 1/2 trial

• Published in: The Lancet infectious diseases Vol. 15; no. 10; pp. 1156 - 1166
• Main Authors: Huttner, Angela, MD, Dayer, Julie-Anne, MD, Yerly, Sabine, MSc, Combescure, Christophe, PhD, Auderset, Floriane, PhD, Desmeules, Jules, Prof, Eickmann, Markus, PhD, Finckh, Axel, Prof, Goncalves, Ana Rita, PhD, Hooper, Jay W, PhD, Kaya, Gürkan, MD, Krähling, Verena, PhD, Kwilas, Steve, PhD, Lemaître, Barbara, MSc, Matthey, Alain, MD, Silvera, Peter, PhD, Becker, Stephan, Prof, Fast, Patricia E, MD, Moorthy, Vasee, MD, Kieny, Marie Paule, PhD, Kaiser, Laurent, Prof, Siegrist, Claire-Anne, Prof
• Format: Journal Article
• Language: English
• Published: United States Elsevier Ltd 01.10.2015; Elsevier Limited
• Subjects: Adenoviruses; Adolescent; Adult; Aged; Ankle; Antibodies, Viral - blood; Antigens, Viral - genetics; Arthritis; Arthritis - chemically induced; Arthritis - epidemiology; Arthritis - pathology; Consortia; Dermatitis; Dermatitis - epidemiology; Dermatitis - pathology; Disease; Double-Blind Method; Drug Carriers; Drug-Related Side Effects and Adverse Reactions - epidemiology; Drug-Related Side Effects and Adverse Reactions - pathology; Ebola Vaccines - administration & dosage; Ebola Vaccines - adverse effects; Ebola Vaccines - immunology; Ebola virus; Ebolavirus - genetics; Epidemics; Female; Fingers & toes; Hemorrhagic Fever, Ebola - prevention & control; Humans; Immunogenicity; Infectious Disease; Infectious diseases; Injection; Male; Middle Aged; Pain; Placebos - administration & dosage; Public health; Safety; Skin; Switzerland; Vaccination - adverse effects; Vaccination - methods; Vaccines; Vaccines, Synthetic - administration & dosage; Vaccines, Synthetic - adverse effects; Vaccines, Synthetic - immunology; Vasculitis - chemically induced; Vasculitis - epidemiology; Vasculitis - pathology; Vesiculovirus - genetics; Wrist; Young Adult; Switzerland; Gabon; Germany
• ISSN: 1473-3099; 1474-4457
• DOI: 10.1016/S1473-3099(15)00154-1

Summary Background Safe and effective vaccines against Ebola could prevent or control outbreaks. The safe use of replication-competent vaccines requires a careful dose-selection process. We report the first safety and immunogenicity results in volunteers receiving 3 × 105 plaque-forming units (pfu) of the recombinant vesicular stomatitis virus-based candidate vaccine expressing the Zaire Ebola virus glycoprotein (rVSV-ZEBOV; low-dose vaccinees) compared with 59 volunteers who had received 1 ×107 pfu (n=35) or 5 × 107 pfu (n=16) of rVSV-ZEBOV (high-dose vaccinees) or placebo (n=8) before a safety-driven study hold. Methods The Geneva rVSV-ZEBOV study, an investigator-initiated phase 1/2, dose-finding, placebo-controlled, double-blind trial conducted at the University Hospitals of Geneva, Switzerland, enrolled non-pregnant, immunocompetent, and otherwise healthy adults aged 18–65 years. Participants from the low-dose group with no plans to deploy to Ebola-aff5cted regions (non-deployable) were randomised 9:1 in a double-blind fashion using randomly permuted blocks of varying sizes to a single injection of 3 × 105 pfu or placebo, whereas deployable participants received single-injection 3 × 105 pfu open-label. Primary safety and immunogenicity outcomes were the incidence of adverse events within 14 days of vaccination and day-28 antibody titres, respectively, analysed by intention to treat. After viral oligoarthritis was observed in 11 of the first 51 vaccinees (22%) receiving 107 or 5 × 107 pfu, 56 participants were given a lower dose (3 × 105 pfu, n=51) or placebo (n=5) to assess the effect of dose reduction on safety and immunogenicity. This trial is ongoing with a follow-up period of 12 months; all reported results are from interim databases. This study is registered with ClinicalTrials.gov , number NCT02287480. Findings Between Jan 5 and Jan 26, 2015, 43 non-deployable participants received low-dose rVSV-ZEBOV (3 × 105 pfu) or placebo in a double-blind fashion, whereas 13 deployable participants received 3 × 105 pfu open-label. Altogether, in the low-dose group, 51 participants received rVSV-ZEBOV and five received placebo. No serious adverse events occurred. At 3 × 105 pfu, early-onset reactogenicity remained frequent (45 [88%] of 51 compared with 50 [98%] of 51 high dose and two [15%] of 13 placebo recipients), but mild. Objective fever was present in one (2%) of 51 low-dose versus 13 (25%) of 51 high-dose vaccinees receiving at least 1 ×107 pfu (p<0·0001). Subjective fever (p<0·0001), myalgia (p=0·036), and chills (p=0·026) were significantly reduced and their time of onset delayed, reflecting significantly lower viraemia (p<0·0001) and blood monocyte-activation patterns (p=0·0233). Although seropositivity rates remained similarly high (48 [94%] of 51), day-28 EBOV-glycoprotein-binding and neutralising antibody titres were lower in low-dose versus high-dose vaccinees (geometric mean titres 344·5 [95% CI 229·7–516·4] vs 1064·2 [757·6–1495·1]; p<0·0001; and 35·1 [24·7–50·7] vs 127·0 [86·0–187·6] ; p<0·0001, respectively). Furthermore, oligoarthritis again occurred on day 10 (median; IQR 9–14) in 13 (25%) of 51 low-dose vaccinees, with maculopapular, vesicular dermatitis, or both in seven (54%) of 13; arthritis was associated with increasing age in low-dose but not high-dose vaccinees. Two vaccinees presented with purpura of the lower legs; histological findings indicated cutaneous vasculitis. The presence of rVSV in synovial fluid and skin lesions confirmed causality. Interpretation Reducing the dose of rVSV-ZEBOV improved its early tolerability but lowered antibody responses and did not prevent vaccine-induced arthritis, dermatitis, or vasculitis. Like its efficacy, the safety of rVSV-ZEBOV requires further definition in the target populations of Africa. Funding Wellcome Trust through WHO.