Shortening intradermal rabies post-exposure prophylaxis regimens to 1 week: Results from a phase III clinical trial in children, adolescents and adults

BackgroundThis phase III clinical trial compared the immunogenicity and safety of a purified chick-embryo cell rabies vaccine (PCECV) administered according to a shortened post-exposure prophylaxis (PEP) 4-site/1-week intradermal regimen, compared with the currently recommended 2-site/Thai Red Cross (TRC) regimen.Methodology/Principal findingsThis controlled, open-label, multi-center study (NCT02177032) enrolled healthy individuals ≥1 year of age, randomized into 4 groups to receive intradermal PCECV according to one of the 2 regimens, with or without human rabies immunoglobulin (HRIG) administration at first visit (in adults only). Rabies virus neutralizing antibody (RVNA) concentrations and percentages of participants with RVNA concentrations ≥0.5 IU/mL (considered as adequate concentrations following PEP) were assessed up to day (D) 365 post-first vaccination. Non-inferiority of the 4-site/1-week regimen to the 2-site/TRC regimen was demonstrated if at D49, the lower limit of the 95% confidence interval (CI) for the difference between groups in the percentage of participants with adequate RVNA concentrations was >-5%. Of the 443 participants receiving the 4-site/1-week regimen, 88 adults received HRIG; 442 participants received the 2-site/TRC regimen (88 with HRIG). All participants achieved adequate RVNA concentrations by D14. At D49, the difference in percentage of participants with adequate RVNA concentrations between the 4-site/1-week and the 2-site/TRC groups was -1 (95%CI: -2.4–0.0); thus, non-inferiority was concluded. RVNA geometric mean concentrations were 18 IU/mL in 4-site/1-week groups and 12 IU/mL in 2-site/TRC groups at D14, and subsequently declined in all groups. RVNA concentrations were consistently lower in adults with HRIG administration than in those without. The 2 regimens had similar safety profiles. Of the 15 serious adverse events reported in 4-site/1-week groups and 19 in 2-site/TRC groups, none were vaccination-related.SignificanceThe data suggest that the 4-site/1-week regimen might be an alternative to current recommendations, with potential benefits in terms of improved cost-efficiency and compliance to vaccination.

背景 本项III期临床试验对比了两种方案的免疫原性与安全性：其一为采用缩短型暴露后预防（post-exposure prophylaxis, PEP）4位点/1周皮内给药方案的纯化鸡胚细胞狂犬病疫苗（purified chick-embryo cell rabies vaccine, PCECV），其二为当前推荐的2位点/泰国红十字会（Thai Red Cross, TRC）方案。
研究方法与主要结果 本项对照、开放标签、多中心研究（临床试验注册号：NCT02177032）纳入了年龄≥1岁的健康受试者，按2种给药方案（联合或不联合首次就诊时给予人狂犬病免疫球蛋白（human rabies immunoglobulin, HRIG），仅针对成人）随机分为4组，接受皮内接种PCECV。本研究于首次接种后第365天（D365）前，对狂犬病病毒中和抗体（rabies virus neutralizing antibody, RVNA）浓度，以及狂犬病病毒中和抗体浓度≥0.5 IU/mL（被视为暴露后预防后达标浓度）的受试者占比进行评估。若在首次接种后第49天（D49），达标RVNA浓度受试者占比的组间差值的95%置信区间（confidence interval, CI）下限大于-5%，则可证明4位点/1周方案非劣于2位点/TRC方案。
本研究共纳入接受4位点/1周方案的受试者443名，其中88名成人联合使用HRIG；接受2位点/TRC方案的受试者442名，其中88名联合使用HRIG。所有受试者均在首次接种后第14天（D14）前达到达标RVNA浓度。首次接种后第49天时，4位点/1周组与2位点/TRC组达标RVNA浓度受试者占比的差值为-1（95%CI：-2.4~0.0），因此判定两组具有非劣效性。首次接种后第14天时，4位点/1周组的RVNA几何平均浓度为18 IU/mL，2位点/TRC组为12 IU/mL，随后所有组的RVNA浓度均呈下降趋势。联合使用HRIG的成人受试者的RVNA浓度始终低于未联合使用者。两种方案的安全性谱相似。4位点/1周组共报告15例严重不良事件，2位点/TRC组报告19例，所有严重不良事件均与疫苗接种无关。
研究意义 本研究数据表明，4位点/1周方案可作为当前推荐方案的替代选择，在成本效益与疫苗接种依从性方面具有潜在优势。