Safety and immunogenicity of a simian-adenovirus-vectored rabies vaccine: an open-label, non-randomised, dose-escalation, first-in-human, single-centre, phase 1 clinical trial.
Safety and immunogenicity of a simian-adenovirus-vectored rabies vaccine: an open-label, non-randomised, dose-escalation, first-in-human, single-centre, phase 1 clinical trial.
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DOI：
10.1016/s2666-5247(22)00126-4
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发表时间：
2022-09
期刊：
影响因子：
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通讯作者：
Douglas AD
中科院分区：
文献类型：
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作者：
Jenkin D;Ritchie AJ;Aboagye J;Fedosyuk S;Thorley L;Provstgaad-Morys S;Sanders H;Bellamy D;Makinson R;Xiang ZQ;Bolam E;Tarrant R;Ramos Lopez F;Platt A;Poulton I;Green C;Ertl HCJ;Ewer KJ;Douglas AD
狂犬病每年造成约6万人死亡。ChAdOx 2 RabG是一种猴腺病毒载体狂犬病候选疫苗，可能有潜力提供低成本的单剂量暴露前狂犬病预防。这项首次人体研究旨在评估其在健康成人中的安全性和免疫原性。我们在英国牛津临床疫苗学和热带医学中心进行了一项ChAdOx 2 RabG单次肌内给药的单中心I期研究，采用非随机开放标签剂量递增。将健康成人依次分配至接受低剂量（5 × 109个病毒颗粒）、中剂量（2 × 1010个病毒颗粒）和高剂量（5 × 1010个病毒颗粒）ChAdOx 2 RabG的组，并随访至接种后第56天。主要目的是评估安全性。次要目的是使用国际标准化狂犬病病毒中和抗体试验评估免疫原性。在入组后1年的可选随访阶段，我们测量了抗体维持率，然后接种了许可的狂犬病疫苗（模拟暴露后预防），并测量了回忆反应。该试验已在ClinicalTrials.gov注册，NCT 04162600，现在对新参与者关闭。在2020年1月2日至10月28日期间，12名成年人接受了低剂量（n=3），中等剂量（n=3）和高剂量（n=6）的ChAdOx 2 RabG。受试者报告主要为轻度至中度反应原性。未发生严重不良事件。在接种后56天内，3名中剂量接种者和6名高剂量接种者的病毒中和抗体浓度超过了公认的保护相关性（0.5 IU/mL）（中位数18.0 IU/mL）。低剂量组56天内的病毒中和抗体中位峰值浓度为0·7 IU/mL（范围0·0-54·0 IU/mL），中剂量组为18·0 IU/mL（0·7-18·0 IU/mL），高剂量组为18·0 IU/mL（6·0-486·0 IU/mL）。9名参与者在1年后返回接受额外随访。在这9名受试者中，7名接受中等剂量或高剂量ChAdOx 2 RabG的受试者中有6名的病毒中和抗体滴度保持在0·5 IU/mL以上。在首次接种许可的狂犬病疫苗后7天内，9名受试者的病毒中和抗体滴度超过0.5 IU/mL。在这项研究中，ChAdOx 2 RabG显示出可接受的安全性和耐受性特征，并具有令人鼓舞的免疫原性，支持进一步的临床评价。英国医学研究理事会和工程与物理科学研究理事会理事会。
Rabies kills around 60 000 people each year. ChAdOx2 RabG, a simian adenovirus-vectored rabies vaccine candidate, might have potential to provide low-cost single-dose pre-exposure rabies prophylaxis. This first-in-human study aimed to evaluate its safety and immunogenicity in healthy adults. We did a single-centre phase 1 study of ChAdOx2 RabG, administered as a single intramuscular dose, with non-randomised open-label dose escalation at the Centre for Clinical Vaccinology and Tropical Medicine, Oxford, UK. Healthy adults were sequentially allocated to groups receiving low (5 × 109 viral particles), middle (2·5 × 1010 viral particles), and high doses (5 x 1010 viral particles) of ChAdOx2 RabG and were followed up to day 56 after vaccination. The primary objective was to assess safety. The secondary objective was to assess immunogenicity with the internationally standardised rabies virus neutralising antibody assay. In an optional follow-up phase 1 year after enrolment, we measured antibody maintenance then administered a licensed rabies vaccine (to simulate post-exposure prophylaxis) and measured recall responses. The trial is registered with ClinicalTrials.gov, NCT04162600, and is now closed to new participants. Between Jan 2 and Oct 28, 2020, 12 adults received low (n=3), middle (n=3), and high doses (n=6) of ChAdOx2 RabG. Participants reported predominantly mild-to-moderate reactogenicity. There were no serious adverse events. Virus neutralising antibody concentrations exceeded the recognised correlate of protection (0·5 IU/mL) in three middle-dose recipients and six high-dose recipients within 56 days of vaccination (median 18·0 IU/mL). The median peak virus neutralising antibody concentrations within 56 days were 0·7 IU/mL (range 0·0–54·0 IU/mL) for the low-dose group, 18·0 IU/mL (0·7–18·0 IU/mL) for the middle-dose group, and 18·0 IU/mL (6·0–486·0 IU/mL) for the high-dose group. Nine participants returned for the additional follow-up after 1 year. Of these nine participants, virus neutralising antibody titres of more than 0·5 IU/mL were maintained in six of seven who had received middle-dose or high-dose ChAdOx2 RabG. Within 7 days of administration of the first dose of a licensed rabies vaccine, nine participants had virus neutralising antibody titres of more than 0·5 IU/mL. In this study, ChAdOx2 RabG showed an acceptable safety and tolerability profile and encouraging immunogenicity, supporting further clinical evaluation. UK Medical Research Council and Engineering and Physical Sciences Research Council.