Immunogenicity and Safety of Ebola Virus Vaccines in Healthy Adults’ Volunteers: A Systematic Review and Network Meta-Analysis

Abstract

Background: Clinical development of Ebola virus vaccines was accelerated by the West African Ebola virus epidemic which remain the deadliest in history ever witnessed. We aimed to compare and rank Ebola virus vaccines according to their immunogenicity and safety. Methods: We conducted a network meta-analysis using random-effect model within a frequentist setting to obtain direct and indirect comparison of trials. We searched Medline, Embase, and the Cochrane library (CENTRAL) until March 31, 2019, for published phase I or II randomized controlled trials (RCTs) vaccine against Ebola virus in healthy adult’s volunteers. We used the Cochrane Risk of Bias Tools to evaluate RCTs methods, and we extracted the proportion or number of participants who seroconverted and reported adverse events. The primary outcome was immunogenicity assessed by the seroconversion rates, defined as number of participants in each group who showed at least a four-fold increase in antibody titer for enzyme-linked immunosorbent assay (ELISA) 28 days after vaccination. Findings: A total of 18 RCTs, which assessed 18 different treatments involving 58 comparisons and 3,633 participants were included in the analysis. The mean age of participants was between 18 and 65 years, and 59% of them were male. The overall quality of evidence was rated as moderate to low. For immunogenicity, 2,198 (61%) participants had seroconversion at 28-days post-vaccination, and the recombinant vesicular virus-based vaccine expressing a Zaire Ebolavirus glycoprotein (rVSVΔ-ZEBOV-GP) at dose of 2 × 107 was significantly the better vaccine (P-score 0·78). Among the 4,746 reported adverse event (AEs), 97 were severe. For the injection-site pain, a total of 1,222 AEs was reported, and Placebo was associated with few events (P-score 0·93). For fatigue (805 reported AEs) and for headache (1,103 reported AEs), the DNA-EBOV vaccine at dose of ≤ 4 mg was the best one with a P-score of 0·96 and 0·85 respectively. For myalgia, 759 AEs were reported, and the ChAd3 vaccine at dose of 1010 was associated with a lower risk (P-score 0·95). Among the 760 AEs reported for fever, the rVSV-ZEBOV vaccine at dose of ≤ 5 × 105 was ranked as the best one (P-score 0·78). Except for the fatigue AEs, no significant global heterogeneity was found. Interpretation: To prevent the next outbreak of Ebola virus disease, the rVSVΔ-ZEBOV-GP vaccine at dose of 2 × 107 appears as the best available option for sufficiently high immunogenicity. Ad5.ZEBOV (1·6 × 1011) might be a possible alternative for immunogenicity. For AEs, no evidence of the best one vaccine is emerged· Larger RCTs are need to clarify the best candidate vaccine in terms of immunogenicity and safety. Funding Statement: None. Declaration of Interests: The authors declare no competing interests in relation with this work. Ethics Approval Statement: The study protocol number registered in the International Register of Systematic Reviews (PROSPERO) was: CRD42018109473.