A Recombinant Vesicular Stomatitis Virus Ebola Vaccine

Abstract

Background: The worst Ebola virus disease (EVD) outbreak in history has resulted in more than 28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials of an attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate designed to prevent EVD.

Methods: We conducted two phase 1, placebo-controlled, double-blind, dose-escalation trials of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all) were consecutively enrolled into groups of 13. At each site, volunteers received one of three doses of the rVSV-ZEBOV vaccine (3 million plaque-forming units [PFU], 20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites received a second dose at day 28. Safety and immunogenicity were assessed.

Results: The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months.

Conclusions: This Ebola vaccine candidate elicited anti-Ebola antibody responses. After vaccination, rVSV viremia occurred frequently but was transient. These results support further evaluation of the vaccine dose of 20 million PFU for preexposure prophylaxis and suggest that a second dose may boost antibody responses. (Funded by the National Institutes of Health and others; rVSV∆G-ZEBOV-GP ClinicalTrials.gov numbers, NCT02269423 and NCT02280408 .).

Figure 1. Frequency of Solicited Adverse Events According to Cohort and Grade

Cohort 1 received a dose of 3 million plaque-forming units (PFU) of the vaccine, Cohort 2 a dose of 20 million PFU, and Cohort 3 a dose of 100 million PFU. All adverse events were assessed for relatedness to the vaccine; events that were judged by the investigating physicians not to be related to the vaccine are not shown. Adverse events were graded for severity on the basis of Food and Drug Administration toxicity grading. Unsolicited adverse events and laboratory adverse events are shown in the Supplementary Appendix.

Figure 2. Antibody Responses to Ebola Glycoprotein

Individual antibody titers as assessed at 14 and 28 days after vaccination are shown according to vaccine dose group, as measured by an enzyme-linked immunosorbent assay (ELISA) against the Zaire–Kikwit strain glycoprotein (Panel A) and a pseudovirion neutralization assay (Panel B). Geometric mean titers (horizontal lines) are shown for each group and time point. Geometric mean titers from 28 days after initial vaccination through 180 days after initial vaccination are shown for the glycoprotein ELISA (Panel C) and the pseudovirion neutralization assay (Panel D). Solid lines indicate groups that received a second dose at day 28, and dashed lines indicate groups that did not receive a second dose at day 28. In all panels, I bars indicate 95% confidence intervals.