Jenner Institute, University of Oxford, Oxford, UK; Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, University of Oxford, Oxford, UK.
Jenner Institute, University of Oxford, Oxford, UK.
Lancet Microbe. 2022 Sep;3(9):e663-e671. doi: 10.1016/S2666-5247(22)00126-4. Epub 2022 Jul 27.
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 × 10 viral particles), middle (2·5 × 10 viral particles), and high doses (5 x 10 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.
狂犬病每年导致约 60000 人死亡。ChAdOx2 RabG 是一种猴腺病毒载体狂犬病疫苗候选物，可能具有提供低成本单剂量狂犬病暴露前预防的潜力。这项首次人体研究旨在评估其在健康成年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 ChAdOx2 RabG 的单中心 1 期研究，采用单次肌内注射，非随机开放性标签剂量递增。健康成年人按顺序分配到接受低（5×10 病毒颗粒）、中（2.5×10 病毒颗粒）和高剂量（5×10 病毒颗粒）ChAdOx2 RabG 的组，并在接种后第 56 天进行随访。主要目的是评估安全性。次要目的是使用国际标准化的狂犬病病毒中和抗体测定评估免疫原性。在登记后 1 年的可选 1 期随访阶段，我们测量了抗体维持情况，然后给予了一种许可的狂犬病疫苗（模拟暴露后预防），并测量了回忆反应。该试验在 ClinicalTrials.gov 注册，NCT04162600，现已对新参与者关闭。
2020 年 1 月 2 日至 10 月 28 日，12 名成年人接受了低（n=3）、中（n=3）和高（n=6）剂量的 ChAdOx2 RabG。参与者报告的不良反应主要为轻至中度。没有严重不良事件。接种后 56 天内，3 名中剂量受者和 6 名高剂量受者的病毒中和抗体浓度超过公认的保护相关性（0.5IU/mL）（中位数 18.0IU/mL）。接种后 56 天内病毒中和抗体的中位峰值浓度分别为低剂量组 0.7IU/mL（范围 0.0-54.0IU/mL）、中剂量组 18.0IU/mL（0.7-18.0IU/mL）和高剂量组 18.0IU/mL（6.0-486.0IU/mL）。9 名参与者在 1 年后进行了额外的随访。在这 9 名参与者中，接受中剂量或高剂量 ChAdOx2 RabG 的 7 名参与者中有 6 名保持了病毒中和抗体滴度超过 0.5IU/mL。在第一剂许可狂犬病疫苗给药后 7 天内，9 名参与者的病毒中和抗体滴度超过 0.5IU/mL。
在这项研究中，ChAdOx2 RabG 表现出可接受的安全性和耐受性，并具有令人鼓舞的免疫原性，支持进一步的临床评估。
英国医学研究理事会和工程与物理科学研究理事会。
