Safety and immunogenicity of the rVSVΔG-ZEBOV-GP Ebola virus vaccine candidate in healthy adults: a phase 1b randomised, multicentre, double-blind, placebo-controlled, dose-response study
Safety and immunogenicity of the rVSVΔG-ZEBOV-GP Ebola virus vaccine candidate in healthy adults: a phase 1b randomised, multicentre, double-blind, placebo-controlled, dose-response study
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DOI：
10.1016/s1473-3099(17)30313-4
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发表时间：
2017-08-01
影响因子：
56.3
通讯作者：
Monath, Thomas P.
中科院分区：
文献类型：
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作者：
Heppner, D. Gray, Jr.;Kemp, Tracy L.;Monath, Thomas P.
2014年扎伊尔埃博拉病毒爆发凸显了对安全、有效、快速起效的疫苗的需求。我们报告了重组水泡性口炎病毒-扎伊尔型埃博拉病毒包膜糖蛋白疫苗的安全性和免疫原性（rVSV Δ G-ZEBOV-GP）在两个连续的队列中在6log（10）剂量范围内进行。一项剂量反应研究，我们招募并随机分配健康成人（年龄18-61岁）在美国的8个研究中心接受单次疫苗或安慰剂注射，通过肌内注射给药。在队列1中，参与者被分配接受3 × 10（3）、3 × 10（4）、3 × 10（5）或3 × 10（6）PFU剂量的rVSV Delta G-ZEBOV-GP或安慰剂。在组群2中，参与者被分配接受3 X 10（6）、9 X 10（6）、2 X 10（7）或I X 10（8）PFU剂量的rVSV Delta G-ZEBOV-GP或安慰剂。研究统计员通过计算机生成的随机化列表将受试者集中分配至疫苗组或安慰剂组。主要安全性结局是改良意向治疗人群（所有随机分配的接受疫苗或安慰剂的参与者）中14天内不良事件的发生率，免疫原性的主要结局是符合方案人群中第28天的IgG ELISA抗体滴度。加强对关节炎和皮炎的监测，直至第56天。该研究注册于ClinicalTrials.gov，编号为NCT 02314923。结果在2014年12月26日至2015年6月8日期间，513名参与者被招募并随机分配;其中一名参与者因静脉切开术不成功而未进行免疫接种。在队列1中，256名参与者接受疫苗（3 x 10（3）[n= 64]，3 x 10（4）[n= 64]，3 x 10（5）[n= 64]或3 x 10（6）PFU [n= 64]），74名接受安慰剂。在队列2中，162名参与者接受疫苗（3 x 10（6）[n= 20]，9 x 10（6）[n= 47]，2 x 10（7）[n= 47]或1 x 10（8）PFU [n= 48]），20名接受安慰剂。大多数不良事件发生在接种后第一天，强度为轻度至中度，持续时间较短，在高疫苗剂量（9 × 10（6）PFU及以上）时更频繁。在2 × 10（7）PFU剂量（用于III期试验）下，与安慰剂相比，前14天内最常见的局部不良事件是手臂疼痛（57.4% [27/47] vs 7.4% [7/94]）和局部压痛（59.6% [28/47] vs 8.5% [8/94]）。与安慰剂相比，2 × 10（7）PFU剂量组在前14天内最常见的全身不良事件是头痛（46.8% [22/47] vs 27.7% [26/94]），疲乏（38.3% [18/47] vs 19.1% [18/94]），肌痛（34.0% [16/47] vs 10.6% [10/94]），主观发热（29.8% [14/47] vs 2.1% [2/94]），寒战或寒战（27.7% [13/47] vs 7.4% [7/94]），出汗（23.4% [11/47] vs 3.2% [3/94]），关节疼痛（19.1% [9/47] vs 7.4% [7/94]）、客观发热（14.9% [7/47] vs 1.1% [1/94]）和关节压痛或肿胀（14.9% [7/47] vs 2.1% [2/94]）。4.5%（19/418）的疫苗接种者（中位发病12.0天[IQR 10-14];中位持续时间8.0天[6-15]）与3.2%（3/94）的对照组（中位发病15.0天[6-20];中位持续时间47.0天[37-339]）发生了自限性疫苗接种后关节炎，无明显的剂量关系。5.7%（24/418）的疫苗接种者发生了接种后皮炎（中位发病时间为9.0天[IQR 2-12];中位持续时间为7.0天[4-9]），而对照组为3.2%（3/94）（中位发病时间为5.0天[3-53];中位持续时间为33.0天[5-370]）。低水平、一过性、剂量依赖性病毒血症与早期反应原性一致。到第14天，在大多数参与者中观察到抗体应答。IgG和中和抗体滴度与剂量相关（IgG ELISA的p= 0.0003，60%空斑减少中和试验[PRNT 60]的p< 0.0001，线性趋势）。在第28天，2 × 10（7）PFU剂量下，IgG ELISA终点滴度的几何平均值为1624（95% CI 1146-2302），血清转化率为95.7%（95% CI 85.5-98.8）; PRNT 60的中和抗体滴度几何平均值为250（176-355），血清转化率为95.7%（85.5-98.8）。rVSV Delta G-ZEBOV-GP的耐受性良好，并刺激结合和中和抗体的快速发生，其维持至第360天。免疫原性结果支持选择2 × 10（7）PFU剂量。
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 Delta G-ZEBOV-GP) across a 6 log(10) 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 x 10(3), 3 x 10(4), 3 x 10(5), or 3 x 10(6) PFU doses of rVSV Delta G-ZEBOV-GP or placebo. In cohort 2, participants were assigned to receive 3 x 10(6), 9 x 10(6), 2 x 10(7), or 1 x 10(8) PFU doses of rVSV Delta 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 x 10(3) [n= 64], 3 x 10(4) [n= 64], 3 x 10(5) [n= 64], or 3 x 10(6) PFU [n= 64]) and 74 received placebo. In cohort 2, 162 participants received vaccine (3 x 10(6) [n= 20], 9 x 10(6) [n= 47], 2 x 10(7) [n= 47], or 1 x 10(8) 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 x 10(6) PFU and greater). At the 2 x 10(7) 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 x 10(7) 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 x 10(7) 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 Delta 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 x 10(7) PFU dose.