Due to the unparalleled dedication of many players both within and beyond the HUG in this time of emergency, the trial was planned, prepared, approved and launched with unprecedented alacrity (Figure 4). This swiftness did not, however, imply that the approvals process, both at the level of two ethics committees (Geneva Canton Ethics Commission, CCER, and WHO’s Ethics Review Committee) and the Swiss Agency for Therapeutic Products (Swissmedic), was an easy one. While the trial was indeed fast-tracked given the level of international concern during the epidemic’s peak, members of these entities performed the work with their usual thoroughness and rigor—if not more, as trial documents were unusually complex. As an example, there were eight different iterations of the informed consent document: that for deployable vs. non-deployable volunteers (explained below), run-in group vs.
randomized volunteers, and English vs. French-speaking volunteers.
Study objectives
The primary safety objective was initially to assess the safety and tolerability of the VSV-EBOV vaccine candidate when administered to healthy volunteers at a dose of 107 pfu (initially called the “lower dose”) and a dose of 5 x 107 pfu (“higher dose”). After the safety-driven study hold described below, the
primary safety objective was to assess the safety and tolerability of the vaccine candidate at the “very low dose” of 3 x 105 pfu.
The primary immunogenicity objective was to determine whether seroresponses differed significantly following immunization with these different doses of VSV-EBOV.
Secondary objectives were to assess the cellular and humoral immunogenicity of the Ebola Zaire vaccine BPSC1001 when administered to healthy volunteers at 107 pfu, 5 x 107 pfu and 3 x 105 pfu.
The following parameters have been/are being assessed:
• GMTs of ZEBOV-specific IgG antibodies measured by ELISA at day 0, 7, 14, 28, 84, 168 and 365 after immunization (all subjects, but the deployable were allowed to leave after day 14 and provide a serum sample as soon as possible after day 28 and for days 168 and 365)
• Seroconversion rates for ZEBOV-specific IgG antibodies at day 0, 7, 14, 28, 84, 168 and 365 after immunization (idem)
• Geometric mean titers (GMTs) of ZEBOV-specific neutralizing antibodies at day 0, 7, 14, 28, 84, 168 and 365 after immunization
• Frequency and phenotype of ZEBOV-specific T cell responses at day 0, 14, 28, 168 and 365 after immunization
Trial design
The Geneva trial was designed to be of the highest methodologic quality: a randomized, double-blind (Figure 5), placebo-controlled, dose-finding trial. It was the largest of the four VEBCON trials, with 100 planned vaccinees. But funding for the study, later secured from Wellcome Trust by WHO, was limited;
WHO could approve resources for only around 15 placebo volunteers. In addition, many deemed it unethical to randomize volunteers who might be deploying to Ebola-affected regions (“deployable”) to placebo. Thus two separate randomization schemes were designed: one for the deployable, who would be randomized to either dose of vaccine, and one for the non-deployable (local volunteers with no immediate risk for Ebola exposure), who would be randomized to either dose of vaccine or placebo (Figure 5).
Determination of sample size
A sample size calculation (based on the preliminary immunogenicity of another EBOV-GP construct, ChAd3) indicated that 74-124 subjects per vaccine dose would be needed to demonstrate a ≥ 2-fold difference in ZEBOV-GP antibody titers. Thus the overall goal of the VEBCON Consortium was to collect safety and immunogenicity data on roughly 200 VSV-EBOV-immunized subjects (+ controls). This initially included:
• 30 volunteers enrolled in a dose-escalation (3 x 106,2 x 107, 5 x 107 pfu) study led by the Universitätsklinikum Hamburg-Eppendorf, Germany
• 60 volunteers enrolled in a randomized dose-selection (3 x 105, 3 x 106, 2 x 107 pfu) study in Lambarene, Gabon
• 40 volunteers enrolled in a randomized dose-selection (3 x 106 and 107 pfu) study in Kilifi, Kenya
• 115 volunteers enrolled in a randomized, placebo-controlled, dose-selection (107, 5 x 107 pfu) study in the HUG
These data were then combined with those from two US trials, each enrolling roughly 40 volunteers in a dose-escalation (3 x 106, 2 x 107, 108 pfu), single-administration study conducted by WRAIR and a
two-Figure 5. Geneva trial’s study design before (upper panel) and after (lower panel) the safety-driven study hold.
dose, prime-boost study conducted by NIAID and NIH, in order to determine the optimal dose for phase 3 testing of the vaccine in the field. (For field studies, the dose of 2 x 107pfu was ultimately chosen.)
Entry criteria
The study included healthy, adult volunteers aged 18 – 65 years. Pregnant women, immunosuppressed persons, and those with regular contact with livestock were not eligible.
Run-in phase
Because at the time of study launch, the vaccine had not yet been systematically tested in humans at a dose higher than 3 x 106 pfu, the Geneva trial opened with a protocol-stipulated run-in group, in which the dose of 107 pfu was given open-label to the first four participants, with an observation period of one week and a planned safety report on immediate adverse events before the randomization phase could commence. Although this run-in safety analysis reported no serious or other significant or unexpected adverse events, Swissmedic then recommended extending the run-in group to the next 15 volunteers scheduled for injection. Thus the first planned interim safety analysis covered 19 subjects receiving 107 pfu open-label.
Selection of doses
At the time of study launch, preclinical observations indicated that VSV-EBOV was ready to undergo trial in humans, but the optimal human dose was still unknown:
o Robust protection was seen with macaques only at doses ≥ 107 pfu, and up to 1 x 108 pfu was given with no safety concerns
o The few humans immunized post-exposure received ≤ 5 x 107 pfu with no reported grade 3 or serious adverse events
o Using a lower dose (107 pfu) would reduce the costs and double the number of potential vaccinees during a period of limited vaccine production
Because among all Consortium studies, the Geneva trial was likely to have the most deployable volunteers (with a relatively increased risk of Ebola exposure), it was decided that Geneva should test
the Consortium’s “highest” doses. Thus WHO thus asked for 107 pfu and 5 x 107 pfu to be tested. The decision to lower the vaccine dose substantially after the trial hold is discussed in more detail below.
Selection and timing of dose Preclinical observations
suggested that a single injection of VSV-EBOV at the doses described above would be sufficient to induce an immune response. All Consortium trials tested a single dose of vaccine only.
Blinding
The Geneva trial was double-blind. Certain study investigators and other personnel were blinded, others were necessarily not blind to treatment allocation, and still others were “facultatively blinded” (Figure 6).
Breaking the blind for a single subject was to be considered when knowledge of the treatment assignment was deemed essential by the subject's physician for the subject's care.
Ultimately, because of vaccine-related side effects (see below), the blind was broken both
unintentionally (e.g., when VSV-EBOV was discovered in peripheral tissues) and intentionally for all volunteers presenting with vaccine-related arthritides and/or skin lesions.
5 Trial findings
Screening began on 3 November 2014; the first volunteer was vaccinated one week later. As there were no safety signals during the initial run-in period, the randomization phase began on 24 November as planned. In early December, however, four volunteers presented with peripheral mono- or oligoarthritis.
Investigators called a safety-driven study hold on 9 December 2014 to allow for in-depth investigations Figure 6. Blinding status of study personnel and subjects.
and the observation of the clinical courses of those affected. These data are described in detail below.
Ultimately, investigators elected to resume the study on 5 January (Figure 5) to test only one much-reduced dose of vaccine (3 x 105 pfu), given that no arthritis had been observed in Lambaréné, Gabon, where lower doses were being tested. Unfortunately, however, 13/51 (29%) volunteers in this “very low dose” group also presented with arthritis.
The safety and immunogenicity results are summarized briefly here; they are described in detail in the two publications that follow: “Phase I Trials of rVSV Ebola Vaccine in Africa and Europe”50 and “The effect of dose on the safety and immunogenicity of the VSV Ebola candidate vaccine: a randomised double-blind, placebo-controlled phase 1/2 trial.”51