Phase 2 Placebo-Controlled Trial of Two Vaccines to Prevent Ebola in Liberia

Abstract

Background: The safety and efficacy of vaccines to prevent Ebola virus disease (EVD) were unknown when the incidence of EVD was peaking in Liberia.

Methods: We initiated a randomized, placebo-controlled, phase 3 trial of the chimpanzee adenovirus 3 vaccine (ChAd3-EBO-Z) and the recombinant vesicular stomatitis virus vaccine (rVSV∆G-ZEBOV-GP) in Liberia. A phase 2 subtrial was embedded to evaluate safety and immunogenicity. Because the incidence of EVD declined in Liberia, the phase 2 component was expanded and the phase 3 component was eliminated.

Results: A total of 1500 adults underwent randomization and were followed for 12 months. The median age of the participants was 30 years; 36.6% of the participants were women. During the week after the administration of vaccine or placebo, adverse events occurred significantly more often with the active vaccines than with placebo; these events included injection-site reactions (in 28.5% of the patients in the ChAd3-EBO-Z group and 30.9% of those in the rVSV∆G-ZEBOV-GP group, as compared with 6.8% of those in the placebo group), headache (in 25.1% and 31.9%, vs. 16.9%), muscle pain (in 22.3% and 26.9%, vs. 13.3%), feverishness (in 23.9% and 30.5%, vs. 9.0%), and fatigue (in 14.0% and 15.4%, vs. 8.8%) (P<0.001 for all comparisons); these differences were not seen at 1 month. Serious adverse events within 12 months after injection were seen in 40 participants (8.0%) in the ChAd3-EBO-Z group, in 47 (9.4%) in the rVSV∆G-ZEBOV-GP group, and in 59 (11.8%) in the placebo group. By 1 month, an antibody response developed in 70.8% of the participants in the ChAd3-EBO-Z group and in 83.7% of those in the rVSV∆G-ZEBOV-GP group, as compared with 2.8% of those in the placebo group (P<0.001 for both comparisons). At 12 months, antibody responses in participants in the ChAd3-EBO-Z group (63.5%) and in those in the rVSV∆G-ZEBOV-GP group (79.5%) remained significantly greater than in those in the placebo group (6.8%, P<0.001 for both comparisons).

Conclusions: A randomized, placebo-controlled phase 2 trial of two vaccines that was rapidly initiated and completed in Liberia showed the capability of conducting rigorous research during an outbreak. By 1 month after vaccination, the vaccines had elicited immune responses that were largely maintained through 12 months. (Funded by the National Institutes of Allergy and Infectious Diseases and the Liberian Ministry of Health; PREVAIL I ClinicalTrials.gov number, NCT02344407 .).

Figure 1. Targeted Symptoms Reported at Week 1

Shown are the percentages of participants who reported the indicated symptom at the week 1 visit in the placebo group, in the group that received the recombinant vesicular stomatitis virus–based vaccine (rVSVΔG-ZEBOV-GP), and in the group that received the chimpanzee adenovirus 3–based vaccine (ChAd3-EBO-Z). Symptoms are ordered according to the frequency with which they were reported by participants in the placebo group. Symptoms were prespecified in a checklist (i.e., targeted) at the week 1 visit.

Figure 2. Geometric Mean Titers after Randomization

Shown are the geometric mean IgG antibody titers against the Ebola virus surface glycoprotein among participants who did not have an elevated level (>607 enzyme-linked immunosorbent assay units [EU] per milliliter) at baseline. I bars indicate 95% confidence intervals. Titers were measured at week 1, month 1, month 6, and month 12 in serum in the ChAd3-EBO-Z group, the rVSVΔG-ZEBOV-GP group, and the placebo group. Antibody titers had a skewed distribution and were log₁₀-transformed. Geometric means were determined by back-transforming the transformed means and confidence intervals to the original scale. P values for the comparison of each active vaccine group with the placebo group were significant at a level of less than 0.001 at each visit, except at week 1, at which time the P value was 0.004 for the comparison of rVSVΔG-ZEBOV-GP with placebo.