Phase 2 Placebo-Controlled Trial of Two Vaccines to Prevent Ebola in Liberia
The Ebola virus disease (EVD) outbreak, that began in December 2013 in western Africa, created new challenges for the design and implementation of protocols to test experimental vaccines and therapeutic agents. The National Institutes of Health engaged in discussions with the Liberian Ministry of Health regarding possible studies. Preclinical data were available on two candidate Ebola virus vaccines, the chimpanzee adenovirus 3–based vaccine (GlaxoSmithKline ChAd3-EBO-Z) and the recombinant vesicular stomatitis virus–based vaccine (Merck rVSV∆G-ZEBOV-GP), which were in phase 1 testing. In order to evaluate these vaccines rapidly, a randomized, placebo-controlled, phase 3 trial (PREVAIL I) was designed with the aim of preventing EVD; the trial included an embedded phase 2 subtrial to evaluate safety and immunogenicity. At the time that this trial was designed and implemented, there were no completed and published phase 1 studies. The phase 3 trial was not completed because of a declining number of EVD cases and, ultimately, because of the end of the epidemic. The authors reported the results of the phase 2 subtrial.
From February to April 2015, a total of 1500 volunteers (18 years or older) were randomly assigned in a 2:1:2:1 ratio to receive an intramuscular injection of the ChAd3-EBO-Z vaccine (2 ml), 2 ml of placebo, the rVSV∆GZEBOV-GP vaccine (1 ml), or 1 ml of placebo at Redemption Hospital in Monrovia, Liberia. The 1:1:1 ratio for the analyses was obtained by combining the two placebo groups. The groups were well balanced at baseline. The median age was 30 years, and 36.6% of the participants were women.
There was a very little drop out during the follow up. There were no cases of EVD.
Within 1 month after injection, 20 participants had a serious adverse event: 6 participants (1.2%) in the ChAd3-EBO-Z group, 6 (1.2%) in the rVSV∆G-ZEBOV-GP group, and 8 (1.6%) in the placebo group (P=0.68 for the comparison of each vaccine with placebo): 70% of these events were attributed to malaria. Over the 12 months follow-up period, a serious adverse event occurred 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: most of these (71%) were attributed to malaria, fewer in the treated 2 groups compared to placebo group (P=0.03 in the ChAd3-EBO-Z group and P = 0.25 in the rVSV∆GZEBOV-GP group, respectively, compared to placebo group).
By 12 months, one death had occurred among participants in the ChAd3-EBO-Z group, five among those in the rVSV∆G-ZEBOV-GP group, and six among those in the placebo group, but none were attributed to EVD.
During the week after injection, injection-site reactions were reported in 28.5% of the participants in the ChAd3-EBO-Z group and 30.9% of those in the rVSV∆G-ZEBOV-GP group, compared to 6.8% of those in the placebo group (P< 0.001 for both comparisons).
Targeted symptoms were reported more often in each vaccine group than in the placebo group at week 1 (P < 0.001 for both comparisons), but at month 1, they did not significantly differ among the groups. The most commonly reported symptoms were headache, muscle pain, feverishness, and fatigue.
The authors concluded that both the vaccines, as compared to placebo, elicited an immune response by 1 months (70.8% in the ChAd3-EBO-Z group and 83.7% in the rVSV∆GZEBOV-GP group, P < 0.001 for both comparisons), that was largely maintained through 12 months (63.5% and 79.5%, respectively, P < 0.001 for both comparisons).
They, also, highlighted some limitations of the study: the absence of children; the lack of an identified laboratory correlate of protective immunity; the incapability of establishing whether either vaccine was effective in preventing EVD as the number of cases of EVD declined drastically in Liberia.
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