Safety and immunogenicity of an egg-based inactivated Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomized, placebo-controlled, phase 1/2 trial in Vietnam.
Safety and immunogenicity of an egg-based inactivated Newcastle disease virus vaccine expressing SARS-CoV-2 spike: Interim results of a randomized, placebo-controlled, phase 1/2 trial in Vietnam.
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表达SARS-COV-2尖峰的基于鸡蛋的灭活纽卡斯尔病毒疫苗的安全性和免疫原性：越南随机，安慰剂对照，1/2期试验的临时结果。
DOI：
10.1016/j.vaccine.2022.04.078
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发表时间：
2022-06-09
期刊：
影响因子：
5.5
通讯作者：
Scharf, Rami
中科院分区：
文献类型：
--
作者：
Anh Duc Dang;Thiem Dinh Vu;Ha Hai Vu;Van Thanh Ta;Anh Thi Van Pham;Mai Thi Ngoc Dang;Be Van Le;Thai Huu Duong;Duoc Van Nguyen;Lawpoolsri, Saranath;Chinwangso, Pailinrut;McLellan, Jason S.;Hsieh, Ching-Lin;Garcia-Sastre, Adolfo;Palese, Peter;Sun, Weina;Martinez, Jose L.;Gonzalez-Dominguez, Irene;Slamanig, Stefan;Carreno, Juan Manuel;Tcheou, Johnstone;Krammer, Florian;Raskin, Ariel;Huong Minh Vu;Thang Cong Tran;Huong Mai Nguyen;Mercer, Laina D.;Raghunandan, Rama;Lal, Manjari;White, Jessica A.;Hjorth, Richard;Innis, Bruce L.;Scharf, Rami
需要在低收入和中等收入国家生产负担得起的2019冠状病毒病（COVID-19）疫苗。NDV-HXP-S是一种表达严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）Wuhan-Hu-1刺突蛋白的鸡胚灭活纽卡斯尔病病毒（NDV）疫苗。通过去除多碱基弗林蛋白酶切割位点，引入NDV融合蛋白的跨膜结构域和胞质尾区，并引入六个脯氨酸以稳定在融合前状态，稳定刺突蛋白并掺入NDV病毒粒子中。疫苗生产和临床开发在越南、泰国和巴西启动。本文介绍了在河内医科大学（越南）进行的随机化、剂量递增、设盲、安慰剂对照、I/II期试验第一阶段的中期结果。年龄在18-59岁、未怀孕、自我报告SARS-CoV-2感染阴性史的健康成年人符合条件。受试者随机接受五种治疗之一，肌肉注射两次，间隔28天：1 μg +/-CpG 1018（一种toll样受体9激动剂），单独3 μg，单独10 μg或安慰剂。参与者和评估结局的人员对治疗设盲。主要结局为每次疫苗接种后7天内征集的不良事件（AE）和28天内受试者报告的AE。研究者进一步审查了受试者报告的AE。次要结局是免疫原性指标（抗刺突免疫球蛋白G [IgG]和假型病毒中和）。根据方案，本中期分析评估了治疗暴露个体首次接种后56天（第57天）的安全性和第二次接种后14天（第43天）的免疫原性。2021年3月15日至4月23日，共筛查224人，入组120人（每组25人接种主动疫苗，20人接种安慰剂）。所有受试者均接受两次给药。在接受活性疫苗或安慰剂的患者中，最常见的征集性AE主要是轻度的，包括注射部位疼痛或压痛（<58%）、疲劳或不适（<22%）、头痛（<21%）和肌痛（<14%）。在任何活性疫苗组中均未观察到较高比例的征集性AE。疫苗接种后28天内报告疫苗相关AE的比例在疫苗组中为4%-8%，对照组为5%。未发生疫苗相关严重不良事件。10 μg制剂组的免疫应答最高，其次是1 μg + CpG 1018、3 μg和1 μg制剂。第二次免疫后14天，抗同源性武汉-沪-1假病毒的50%中和抗体的几何平均浓度（GMC）范围为56.07 IU/mL（1 μg，95% CI 37.01，84.94）至246.19 IU/mL（10 μg，95% CI 151.97，398.82），84%至96%的疫苗组较基线增加≥ 4倍。将其与一组人恢复期血清进行比较（N = 29，72.93 95% CI 33.00-161.14）。关注的B.1.617.2（Delta）变体的活病毒中和作用降低，但与目前使用的疫苗的观察结果一致。由于佐剂显示出适度的益处，对于lyg +/-CpG 1018，GMC比率为2.56（95%CI，1.4-4.6），因此决定不继续用该疫苗研究它。NDV-HXP-S具有可接受的安全性特征和强免疫原性。将3 μg剂量与6 μg剂量一起沿着推进至2期。由于对生产能力的潜在影响，未选择10 μg剂量进行II期评价。ClinicalTrials.gov NCT 04830800。
Production of affordable coronavirus disease 2019 (COVID-19) vaccines in low- and middle-income countries is needed. NDV-HXP-S is an inactivated egg-based Newcastle disease virus (NDV) vaccine expressing the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Wuhan-Hu-1. The spike protein was stabilized and incorporated into NDV virions by removing the polybasic furin cleavage site, introducing the transmembrane domain and cytoplasmic tail of the fusion protein of NDV, and introducing six prolines for stabilization in the prefusion state. Vaccine production and clinical development was initiated in Vietnam, Thailand, and Brazil. Here the interim results from the first stage of the randomized, dose-escalation, observer-blind, placebo-controlled, phase 1/2 trial conducted at the Hanoi Medical University (Vietnam) are presented. Healthy adults aged 18–59 years, non-pregnant, and with self-reported negative history for SARS-CoV-2 infection were eligible. Participants were randomized to receive one of five treatments by intramuscular injection twice, 28 days apart: 1 μg +/- CpG1018 (a toll-like receptor 9 agonist), 3 μg alone, 10 μg alone, or placebo. Participants and personnel assessing outcomes were masked to treatment. The primary outcomes were solicited adverse events (AEs) during 7 days and subject-reported AEs during 28 days after each vaccination. Investigators further reviewed subject-reported AEs. Secondary outcomes were immunogenicity measures (anti-spike immunoglobulin G [IgG] and pseudotyped virus neutralization). This interim analysis assessed safety 56 days after first vaccination (day 57) in treatment-exposed individuals and immunogenicity through 14 days after second vaccination (day 43) per protocol. Between March 15 and April 23, 2021, 224 individuals were screened and 120 were enrolled (25 per group for active vaccination and 20 for placebo). All subjects received two doses. The most common solicited AEs among those receiving active vaccine or placebo were all predominantly mild and included injection site pain or tenderness (<58%), fatigue or malaise (<22%), headache (<21%), and myalgia (<14%). No higher proportion of the solicited AEs were observed for any group of active vaccine. The proportion reporting vaccine-related AEs during the 28 days after either vaccination ranged from 4% to 8% among vaccine groups and was 5% in controls. No vaccine-related serious adverse event occurred. The immune response in the 10 μg formulation group was highest, followed by 1 μg + CpG1018, 3 μg, and 1 μg formulations. Fourteen days after the second vaccination, the geometric mean concentrations (GMC) of 50% neutralizing antibody against the homologous Wuhan-Hu-1 pseudovirus ranged from 56.07 IU/mL (1 μg, 95% CI 37.01, 84.94) to 246.19 IU/mL (10 μg, 95% CI 151.97, 398.82), with 84% to 96% of vaccine groups attaining a ≥ 4-fold increase over baseline. This was compared to a panel of human convalescent sera (N = 29, 72.93 95% CI 33.00–161.14). Live virus neutralization to the B.1.617.2 (Delta) variant of concern was reduced but in line with observations for vaccines currently in use. Since the adjuvant has shown modest benefit, GMC ratio of 2.56 (95% CI, 1.4–4.6) for 1 μg +/- CpG1018, a decision was made not to continue studying it with this vaccine. NDV-HXP-S had an acceptable safety profile and potent immunogenicity. The 3 μg dose was advanced to phase 2 along with a 6 μg dose. The 10 μg dose was not selected for evaluation in phase 2 due to potential impact on manufacturing capacity. ClinicalTrials.gov NCT04830800.
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