Assessing the safety and immunogenicity of recombinant vesicular stomatitis virus Ebola vaccine in healthy adults: a randomized clinical trial

Abstract

Background: The 2013-2016 Ebola virus outbreak in West Africa was the most widespread in history. In response, alive attenuated recombinant vesicular stomatitis virus (rVSV) vaccine expressing Zaire Ebolavirus glycoprotein (rVSVΔG-ZEBOV-GP) was evaluated in humans.

Methods: In a phase 1, randomized, dose-ranging, observer-blind, placebo-controlled trial, healthy adults aged 18-65 years were randomized into 4 groups of 10 to receive one of 3 vaccine doses or placebo. Follow-up visits spanned 180 days postvaccination for safety monitoring, immunogenicity testing and any rVSV virus shedding.

Results: Forty participants were injected with rVSVΔG-ZEBOV-GP vaccine (n = 30) or saline placebo (n = 10). No serious adverse events related to the vaccine or participant withdrawals were reported. Solicited adverse events during the 14-day follow-up period were mild to moderate and self-limited, with the exception of injection-site pain and headache. Viremia following vaccination was transient and no longer detectable after study day 3, with no virus shedding in saliva or urine. All vaccinated participants developed serum immunoglobulin G (IgG), as measured by Ebola virus envelope glycoprotein-based enzyme-linked immunosorbent assay (ELISA). Immunogenicity was comparable across all dose groups, and sustained IgG titers were detectable through to the last visit, at study day 180.

Interpretation: In this phase 1 study, there were no safety concerns after a single dose of rVSVΔG-ZEBOV-GP vaccine. IgG ELISA showed persistent high titers at 180 days postimmunization. There was a period of reactogenicity, but in general, the vaccine was well tolerated. This study provides evidence of the safety and immunogenicity of rVSVΔG-ZEBOV-GP vaccine and importance of its further investigation. Trial registration: Clinical-Trials.gov no., NCT02374385.

Conflict of interest statement

Competing interests: May ElSherif reports grants from the Canadian Institutes of Health Research/Public Health Agency of Canada, during the conduct of the study. Donna MacKinnon-Cameron reports an operating grant from the Canadian Institutes of Health Research/Public Health Agency of Canada, during the conduct of the study. Li Li reports an operating grant from the Canadian Institutes of Health Research/Public Health Agency of Canada, during the conduct of the study. Judie Alimonti reports personal fees from NewLink Genetics, outside the submitted work; and Her Majesty the Queen in right of Canada holds a patent related to the rVSVΔG-ZEBOV-GP vaccine (patents: EU 1 527 087; US 8 012 489; CA 2,493,142). W. Jay Ramsey was an employee of NewLink Genetics during the conduct of the study, and reports personal fees as a salaried employee of NewLink Genetics, outside the submitted work. Donald Gray Heppner reports grants from the Department of Health and Human Services, during the conduct of the study and employment by NewLink Genetics Inc. (which is developing the vaccine described in this article), outside the submitted work. Tracy Kemp was an employee of NewLink Genetics during the conduct of the study; she also reports personal fees as a salaried employee of NewLink Genetics, outside the submitted work. Thomas Monath reports a grant from BARDA and the US Department of Health and Human Services, and financial support for study, personal salary and benefits from New-Link Genetics. Shelly McNeil reports an operating grant from the Canadian Institutes of Health Research/Public Health Agency of Canada, during the conduct of the study; and grants and personal fees from vaccine manufacturers (such as Merck, GlaxoSmithKline Biologicals, Sanofi Pasteur and Pfizer) outside the submitted work. Joanne Langley reports an operating grant from the Canadian Institutes of Health Research/Public Health Agency of Canada, during the conduct of the study, as well as grants and personal fees from vaccine manufacturers (such as Merck, Glaxo-SmithKline Biologicals, Sanofi Pasteur, Pfizer, and Novartis) to conduct vaccine clinical trials, outside the submitted work. Scott Halperin reports an operating grant from the Canadian Institutes of Health Research/Public Health Agency of Canada, during the conduct of the study, and grants and personal fees from vaccine manufacturers (such as Merck, GlaxoSmithKline Biologicals, Sanofi Pasteur, Pfizer and Novartis) outside the submitted work. No other competing interests were declared.

© 2017 Canadian Medical Association or its licensors.

Figures

Figure 1:

Trial diagram showing subjects randomized to vaccine cohorts or placebo. Note: NA = not applicable, pfu = plaque-forming units.

Figure 2:

Frequency of local and systemic adverse events (AEs) among vaccine cohorts or placebo. Note: Solicited AEs and their severity reported in the 14 days postinjection for vaccine doses of 1 × 105 plaque-forming units (pfu) (cohort 1), 5 × 105 pfu (cohort 2), 3 × 106 pfu (cohort 3) and placebo shown with 95% confidence intervals for any grade of AEs within each group.

Figure 3:

Neutralization antibody responses to Ebola glycoprotein. Note: There were no significant differences between groups using the pseudovirion neutralization assay (PsVNA) at day 28. The PsVNA50 of the 3 × 106 plaque-forming units (pfu) dose compared with the 1 × 105 pfu and 5 × 105 pfu doses was p = 0.788 and p = 0.575, respectively.