Summary Background The 2014 Zaire Ebola virus outbreak highlighted the need for a safe, effective vaccine with a rapid onset of protection. We report the safety and immunogenicity of the recombinant ...vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSV∆G-ZEBOV-GP) across a 6 log10 dose range in two sequential cohorts. Methods In this phase 1b double-blind, placebo-controlled, dose-response study we enrolled and randomly assigned healthy adults (aged 18–61 years) at eight study sites in the USA to receive a single injection of vaccine or placebo, administered by intramuscular injection. In cohort 1, participants were assigned to receive 3 × 103 , 3 × 104 , 3 × 105 , or 3 × 106 PFU doses of rVSV∆G-ZEBOV-GP or placebo. In cohort 2, participants were assigned to receive 3 × 106 , 9 × 106 , 2 × 107 , or 1 × 108 PFU doses of rVSV∆G-ZEBOV-GP or placebo. Participants were centrally allocated by the study statistician to vaccine groups or placebo through computer-generated randomisation lists. The primary safety outcome was incidence of adverse events within 14 days in the modified intention-to-treat population (all randomly assigned participants who received vaccine or placebo), and the primary outcome for immunogenicity was IgG ELISA antibody titres at day 28 in the per-protocol population. Surveillance was enhanced for arthritis and dermatitis through to day 56. This study is registered with ClinicalTrials.gov , number NCT02314923. Findings Between Dec 26, 2014, and June 8, 2015, 513 participants were enrolled and randomly assigned; one was not immunised because of unsuccessful phlebotomy. In cohort 1, 256 participants received vaccine (3 × 103 n=64, 3 × 104 n=64, 3 × 105 n=64, or 3 × 106 PFU n=64) and 74 received placebo. In cohort 2, 162 participants received vaccine (3 × 106 n=20, 9 × 106 n=47, 2 × 107 n=47, or 1 × 108 PFU n=48) and 20 received placebo. Most adverse events occurred in the first day after vaccination, and were mild to moderate in intensity, of a short duration, and more frequent at high vaccine doses (9 × 106 PFU and greater). At the 2 × 107 PFU dose (used in phase 3 trials), the most common local adverse events versus placebo within the first 14 days were arm pain (57·4% 27 of 47 vs 7·4% seven of 94) and local tenderness (59·6% 28 of 47 vs 8·5% eight of 94). The most common systemic adverse events at the 2 × 107 PFU dose versus placebo, occurring in the first 14 days, were headache (46·8% 22 of 47 vs 27·7% 26 of 94), fatigue (38·3% 18 of 47 vs 19·1% 18 of 94), myalgia (34·0% 16 of 47 vs 10·6% 10 of 94), subjective fever (29·8% 14 of 47 vs 2·1% two of 94), shivering or chills (27·7% 13 of 47 vs 7·4% seven of 94), sweats (23·4% 11 of 47 vs 3·2% three of 94), joint aches and pain (19·1% nine of 47 vs 7·4% seven of 94), objective fever (14·9% seven of 47 vs 1·1% one of 94), and joint tenderness or swelling (14·9% seven of 47 vs 2·1% two of 94). Self-limited, post-vaccination arthritis occurred in 4·5% (19 of 418) of vaccinees (median onset 12·0 days IQR 10–14; median duration 8·0 days 6–15) versus 3·2% (three of 94) of controls (median onset 15·0 days 6–20; median duration 47·0 days 37–339), with no apparent dose relationship. Post-vaccination dermatitis occurred in 5·7% (24 of 418) of vaccinees (median onset 9·0 days IQR 2–12; median duration 7·0 days 4–9) versus 3·2% (three of 94) of controls (median onset 5·0 days 3–53; median duration 33·0 days 5–370). A low-level, transient, dose-dependent viraemia occurred in concert with early reactogenicity. Antibody responses were observed in most participants by day 14. IgG and neutralising antibody titres were dose-related (p=0·0003 for IgG ELISA and p<0·0001 for the 60% plaque-reduction neutralisation test PRNT60 by linear trend). On day 28 at the 2 × 107 PFU dose, the geometric mean IgG ELISA endpoint titre was 1624 (95% CI 1146–2302) and seroconversion was 95·7% (95% CI 85·5–98·8); the geometric mean neutralising antibody titre by PRNT60 was 250 (176–355) and seroconversion was 95·7% (85·5–98·8). These robust immunological responses were sustained for 1 year. Interpretation rVSV∆G-ZEBOV-GP was well tolerated and stimulated a rapid onset of binding and neutralising antibodies, which were maintained through to day 360. The immunogenicity results support selection of the 2 × 107 PFU dose. Funding Biomedical Advanced Research and Development Authority, US Department of Health and Human Services.
We report the first safety and immunogenicity trial of the
Plasmodium falciparum malaria blood stage vaccine candidate, FMP1/AS02A consisting of the FMP1 antigen, an
Escherichia coli-expressed ...His-tagged fusion protein from the 42
kDa C-terminal fragment from the 3D7 clone of the merozoite surface protein 1 formulated in the AS02A adjuvant. An open label, prospective, single-center Phase I dose escalation trial of FMP1/AS02A was conducted in 15 adult malaria-naïve human volunteers to assess safety, reactogenicity, and immunogenicity. The vaccine was safe and well-tolerated and no serious adverse events were observed. The vaccine induced high-titer ELISA and IFA responses in all volunteers. Proliferative and ELISPOT responses were induced to vaccine antigen. Biologically active antibodies were induced as measured by GIA. This study establishes the foundation to further evaluate and measure the vaccine's ability to reduce morbidity and mortality in target populations directly affected by
P. falciparum malaria.
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