Safety and immunogenicity of the live-attenuated hRVFV-4s vaccine against Rift Valley fever in healthy adults: a dose-escalation, placebo-controlled, first-in-human, phase 1 randomised clinical trial.

IF 36.4 1区 医学 Q1 INFECTIOUS DISEASES Lancet Infectious Diseases Pub Date : 2024-11-01 Epub Date: 2024-07-25 DOI:10.1016/S1473-3099(24)00375-X
Isabel Leroux-Roels, Chittappen Kandiyil Prajeeth, Amare Aregay, Niranjana Nair, Guus F Rimmelzwaan, Albert D M E Osterhaus, Simone Kardinahl, Sabrina Pelz, Stephan Bauer, Valentino D'Onofrio, Azhar Alhatemi, Bart Jacobs, Fien De Boever, Sharon Porrez, Gwenn Waerlop, Carine Punt, Bart Hendriks, Ellemieke von Mauw, Sandra van de Water, Jose Harders-Westerveen, Barry Rockx, Lucien van Keulen, Jeroen Kortekaas, Geert Leroux-Roels, Paul J Wichgers Schreur
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Although animals are primarily infected via mosquito bites, humans mainly become infected following contact with infected tissues or fluids of infected animals. There is an urgent need for adequate countermeasures, especially for humans, because effective therapeutics or vaccines are not yet available. Here we assessed the safety, tolerability, and immunogenicity of a next-generation, four-segmented, live-attenuated vaccine candidate, referred to as hRVFV-4s, in humans.</p><p><strong>Methods: </strong>A first-in-human, single-centre, randomised, double-blind, placebo-controlled trial was done in Belgium in which a single dose of hRVFV-4s was administered to healthy volunteers aged 18-45 years. Participants were randomly assigned using an interactive web response system. The study population encompassed 75 participants naive to Rift Valley fever virus infection, divided over three dosage groups (cohorts) of 25 participants each. All participants were followed up until 6 months. Using a staggered dose escalating approach, 20 individuals of each cohort were injected in the deltoid muscle of the non-dominant arm with either 10<sup>4</sup> (low dose), 10<sup>5</sup> (medium dose), or 10<sup>6</sup> (high dose) of 50% tissue culture infectious dose of hRVFV-4s as based on animal data, and five individuals per cohort received formulation buffer as a placebo. Primary outcome measures in the intention-to-treat population were adverse events and tolerability. Secondary outcome measures were vaccine-induced viraemia, vaccine virus shedding, Rift Valley fever virus nucleocapsid antibody responses (with ELISA), and neutralising antibody titres. Furthermore, exploratory objectives included the assessment of cellular immune responses by ELISpot. The trial was registered with the EU Clinical Trials Register, 2022-501460-17-00.</p><p><strong>Findings: </strong>Between August and December, 2022, all 75 participants were vaccinated. 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引用次数: 0

Abstract

Background: Rift Valley fever virus, a pathogen to ruminants, camelids, and humans, is an emerging mosquito-borne bunyavirus currently endemic to Africa and the Arabian Peninsula. Although animals are primarily infected via mosquito bites, humans mainly become infected following contact with infected tissues or fluids of infected animals. There is an urgent need for adequate countermeasures, especially for humans, because effective therapeutics or vaccines are not yet available. Here we assessed the safety, tolerability, and immunogenicity of a next-generation, four-segmented, live-attenuated vaccine candidate, referred to as hRVFV-4s, in humans.

Methods: A first-in-human, single-centre, randomised, double-blind, placebo-controlled trial was done in Belgium in which a single dose of hRVFV-4s was administered to healthy volunteers aged 18-45 years. Participants were randomly assigned using an interactive web response system. The study population encompassed 75 participants naive to Rift Valley fever virus infection, divided over three dosage groups (cohorts) of 25 participants each. All participants were followed up until 6 months. Using a staggered dose escalating approach, 20 individuals of each cohort were injected in the deltoid muscle of the non-dominant arm with either 104 (low dose), 105 (medium dose), or 106 (high dose) of 50% tissue culture infectious dose of hRVFV-4s as based on animal data, and five individuals per cohort received formulation buffer as a placebo. Primary outcome measures in the intention-to-treat population were adverse events and tolerability. Secondary outcome measures were vaccine-induced viraemia, vaccine virus shedding, Rift Valley fever virus nucleocapsid antibody responses (with ELISA), and neutralising antibody titres. Furthermore, exploratory objectives included the assessment of cellular immune responses by ELISpot. The trial was registered with the EU Clinical Trials Register, 2022-501460-17-00.

Findings: Between August and December, 2022, all 75 participants were vaccinated. No serious adverse events or vaccine-related severe adverse events were reported. Pain at the injection site (51 [85%] of 60 participants) was most frequently reported as solicited local adverse event, and headache (28 [47%] of 60) and fatigue (28 [47%] of 60) as solicited systemic adverse events in the active group. No vaccine virus RNA was detected in any of the blood, saliva, urine, or semen samples. Rift Valley fever virus nucleocapsid antibody responses were detected in most participants who were vaccinated with hRVFV-4s (43 [72%] of 60 on day 14) irrespective of the administered dose. In contrast, a clear dose-response relationship was observed for neutralising antibodies on day 28 with four (20%) of 20 participants responding in the low-dose group, 13 (65%) of 20 responding in the medium-dose group, and all participants (20 [100%] of 20) responding in the high-dose group. Consistent with the antibody responses, cellular immune responses against the nucleocapsid protein were detected in all dose groups, whereas a more dose-dependent response was observed for the Gn and Gc surface glycoproteins. Neutralising antibody titres declined over time, whereas nucleocapsid antibody responses remained relatively stable for at least 6 months.

Interpretation: The hRVFV-4s vaccine showed a high safety profile and excellent tolerability across all tested dose regimens, eliciting robust immune responses, particularly with the high-dose administration. The findings strongly support further clinical development of this candidate vaccine for human use.

Funding: The Coalition for Epidemic Preparedness Innovations with support from the EU Horizon 2020 programme.

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健康成年人接种 hRVFV-4s 减毒活疫苗预防裂谷热的安全性和免疫原性:一项剂量递增、安慰剂对照、首次在人体内进行的 1 期随机临床试验。
背景:裂谷热病毒是反刍动物、骆驼和人类的病原体,是一种新出现的蚊媒布尼亚病毒,目前在非洲和阿拉伯半岛流行。虽然动物主要通过蚊子叮咬感染,但人类主要是在接触受感染动物的组织或体液后感染。由于目前还没有有效的治疗方法或疫苗,因此迫切需要采取适当的对策,尤其是针对人类的对策。在此,我们评估了新一代四段减毒活疫苗(简称 hRVFV-4s)在人体中的安全性、耐受性和免疫原性:比利时首次开展了一项单中心、随机、双盲、安慰剂对照试验,给 18-45 岁的健康志愿者注射单剂量 hRVFV-4s。参与者通过交互式网络响应系统进行随机分配。研究对象包括 75 名未感染裂谷热病毒的参与者,分为三个剂量组(队列),每组 25 人。所有参与者都接受了为期 6 个月的随访。采用交错剂量递增法,每组 20 人分别在非优势臂三角肌注射 104(低剂量)、105(中等剂量)或 106(高剂量)50% 组织培养感染剂量的 hRVFV-4s(基于动物数据),每组 5 人接受缓冲制剂作为安慰剂。意向治疗人群的主要结果指标是不良事件和耐受性。次要结果指标是疫苗诱发的病毒血症、疫苗病毒脱落、裂谷热病毒核壳抗体反应(采用 ELISA)和中和抗体滴度。此外,探索性目标还包括通过 ELISpot 评估细胞免疫反应。该试验已在欧盟临床试验登记处登记,编号为2022-501460-17-00.研究结果:2022年8月至12月期间,75名参与者全部接种了疫苗。未报告严重不良事件或与疫苗相关的严重不良事件。注射部位疼痛(60 位参与者中有 51 位[85%])是最常见的局部不良事件,头痛(60 位参与者中有 28 位[47%])和疲劳(60 位参与者中有 28 位[47%])是活动组中最常见的全身不良事件。在血液、唾液、尿液或精液样本中均未检测到疫苗病毒 RNA。大多数接种了 hRVFV-4s 疫苗的参与者(60 人中有 43 人 [72%] 在接种第 14 天出现了裂谷热病毒核壳抗体反应,与接种剂量无关)都检测到了裂谷热病毒核壳抗体反应。相反,在第 28 天,中和抗体出现了明显的剂量反应关系,低剂量组 20 名参与者中有 4 人(20%)出现了反应,中剂量组 20 名参与者中有 13 人(65%)出现了反应,而高剂量组所有参与者(20 人中有 20 人[100%])都出现了反应。与抗体反应一致的是,所有剂量组都检测到了针对核壳蛋白的细胞免疫反应,而针对 Gn 和 Gc 表面糖蛋白的反应则更多地取决于剂量。随着时间的推移,中和抗体滴度下降,而核壳抗体反应在至少 6 个月内保持相对稳定:hRVFV-4s疫苗在所有测试剂量方案中都表现出较高的安全性和良好的耐受性,尤其是在大剂量给药的情况下,可引起较强的免疫反应。研究结果有力地支持了该候选疫苗的进一步临床开发:疫情防备创新联盟,由欧盟地平线 2020 计划提供支持。
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来源期刊
Lancet Infectious Diseases
Lancet Infectious Diseases 医学-传染病学
CiteScore
60.90
自引率
0.70%
发文量
1064
审稿时长
6-12 weeks
期刊介绍: The Lancet Infectious Diseases was launched in August, 2001, and is a lively monthly journal of original research, review, opinion, and news covering international issues relevant to clinical infectious diseases specialists worldwide.The infectious diseases journal aims to be a world-leading publication, featuring original research that advocates change or sheds light on clinical practices related to infectious diseases. The journal prioritizes articles with the potential to impact clinical practice or influence perspectives. Content covers a wide range of topics, including anti-infective therapy and immunization, bacterial, viral, fungal, and parasitic infections, emerging infectious diseases, HIV/AIDS, malaria, tuberculosis, mycobacterial infections, infection control, infectious diseases epidemiology, neglected tropical diseases, and travel medicine. Informative reviews on any subject linked to infectious diseases and human health are also welcomed.
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