Kulkarni Prasad S, Potey Anirudha Vyankatesh, Kapse Dhananjay, Bhamare Chetanraj, Gawande Avinash, Munshi Renuka, Pawar Sudhir, Gogtay Nithya J, Agarwal Anurag, Tambe Muralidhar, Thakre Sushama, Samuel Clarence J, Khan Shahzada Mohmed Salim, S Ravish H, Rana Devang, Singh Neha, Kamath Veena, Bhalla Hira Lal, Poonawalla Cyrus S, Mani Reeta S, Gunale Bhagwat
Serum Institute of India, Pune, India.
Serum Institute of India, Pune, India.
Lancet. 2025 Aug 9;406(10503):627-635. doi: 10.1016/S0140-6736(25)00735-4.
Rabies is almost invariably fatal. A rabies monoclonal antibody (RmAb) was approved in India in 2016 for passive prophylaxis. This post-marketing study aimed to evaluate the long-term safety, immunogenicity, and efficacy of a post-exposure prophylaxis (PEP) regimen containing RmAb.
This phase 4, open-label, randomised, active-controlled study was conducted at 15 tertiary care hospitals in India. Patients aged 2 years or older with WHO category 3 rabies exposure by a suspected rabid animal were eligible if the exposure occurred less than 72 h before enrolment, or less than 24 h before enrolment for exposures to the face, neck, hand, or fingers. Participants were randomly assigned (3:1) to receive either RmAb (Rabishield; Serum Institute of India, Pune, India) plus a purified Vero cell rabies vaccine (PVRV; Rabivax-S) or equine rabies immunoglobulin (ERIG; Equirab) plus PVRV as PEP. In each treatment group, patients were further randomly assigned (1:1) to receive PVRV either intradermally or intramuscularly. Study group allocation was done using a permuted block design with random block sizes of eight. A central randomisation list was generated before the study start and randomisation was performed with an interactive web response system. Participants and site personnel were not masked to group assignment. RmAb (3·33 IU/kg) and ERIG (40 IU/kg) were infiltrated into and around the wounds only on day 0 as per WHO 2018 recommendations. PVRV was administered 1·0 mL intramuscularly (days 0, 3, 7, 14, and 28) or 0·1 mL plus 0·1 mL intradermally (days 0, 3, 7, and 28). The primary outcome was treatment-related serious adverse events up to 365 days after immunisation, analysed in the safety analysis set (all participants who received at least one dose of vaccine with treatment). Geometric mean concentrations of rabies virus neutralising antibody were measured in a subset of patients. This study is registered with Clinical Trial Registry-India (CTRI/2019/06/019622) and is completed.
4059 participants were enrolled between Aug 21, 2019, and March 31, 2022, and randomly assigned. A total of 3994 participants (3001 male, 993 female) were treated (2996 RmAb plus PVRV, 998 ERIG plus PVRV), of which 3622 (90·7%) participants completed the 1-year follow-up. 11 adverse events were considered causally related to RmAb plus PVRV and 17 were considered causally related to the ERIG plus PVRV regimen. Most adverse events were mild and transient. Seven serious adverse events occurred in the RmAb group and all were causally unrelated. One causally related serious adverse event was reported in the ERIG group. On day 14, the geometric mean concentrations increased to 16·05 IU/mL (95% CI 13·25-19·44) in the RmAb group and 13·48 IU/mL (9·51-19·11) in the ERIG group (point estimate 1·19 [95% CI 0·82-1·72]). No patient developed rabies during the 1-year follow-up period.
RmAb was safe and well tolerated and showed protective efficacy against rabies. A PEP regimen containing RmAb plus PVRV was immunogenic with long-term persistence of immune response.
Serum Institute of India.
狂犬病几乎无一例外是致命的。一种狂犬病单克隆抗体（RmAb）于2016年在印度获批用于被动预防。这项上市后研究旨在评估包含RmAb的暴露后预防（PEP）方案的长期安全性、免疫原性和疗效。
这项4期、开放标签、随机、活性对照研究在印度的15家三级护理医院进行。2岁及以上被疑似患有狂犬病的动物造成WHO 3级狂犬病暴露的患者符合条件，前提是暴露发生在入组前不到72小时，或者暴露于面部、颈部、手部或手指的情况下在入组前不到24小时。参与者被随机分配（3:1）接受RmAb（Rabishield；印度血清研究所，印度浦那）加纯化的Vero细胞狂犬病疫苗（PVRV；Rabivax-S）或马狂犬病免疫球蛋白（ERIG；Equirab）加PVRV作为PEP。在每个治疗组中，患者进一步被随机分配（1:1）接受皮内或肌肉注射PVRV。研究组分配采用置换区组设计，随机区组大小为8。在研究开始前生成中央随机化列表，并使用交互式网络响应系统进行随机化。参与者和研究点人员未对分组情况进行盲法处理。根据WHO 2018年建议，仅在第0天将RmAb（3.33 IU/kg）和ERIG（40 IU/kg）注入伤口及其周围。PVRV通过肌肉注射1.0 mL（第0、3、7、14和28天）或皮内注射0.1 mL加0.1 mL（第0、3、7和28天）给药。主要结局是免疫接种后365天内与治疗相关的严重不良事件，在安全性分析集（所有接受至少一剂疫苗治疗的参与者）中进行分析。在一部分患者中测量了狂犬病病毒中和抗体的几何平均浓度。本研究已在印度临床试验注册中心（CTRI/2019/06/019622）注册并已完成。
2019年8月21日至2022年3月31日期间共纳入4059名参与者并进行随机分配。总共3994名参与者（3001名男性，993名女性）接受了治疗（2996名接受RmAb加PVRV，998名接受ERIG加PVRV），其中3622名（90.7%）参与者完成了1年随访。11例不良事件被认为与RmAb加PVRV有因果关系，17例被认为与ERIG加PVRV方案有因果关系。大多数不良事件为轻度且短暂。RmAb组发生7例严重不良事件，均与治疗无关。ERIG组报告了1例与治疗相关的严重不良事件。在第14天，RmAb组的几何平均浓度升至16.05 IU/mL（95%CI 13.25 - 19.44），ERIG组为13.48 IU/mL（9.51 - 19.11）（点估计1.19 [9,5%CI 0.82 - 1.72]）。在1年随访期内无患者发生狂犬病。
RmAb安全且耐受性良好，并显示出对狂犬病的保护效力。包含RmAb加PVRV的PEP方案具有免疫原性，免疫反应可长期持续。
印度血清研究所。
