Lang J, Gravenstein S, Briggs D, Miller B, Froeschle J, Dukes C, Le Mener V, Lutsch C
Pasteur Mérieux Connaught, Lyon, France.
Biologicals. 1998 Mar;26(1):7-15. doi: 10.1006/biol.1997.0117.
A double-blind, controlled, randomized trial was conducted to evaluate the safety and immunogenicity of a new human rabies immune globulin (HTRIG). This product, manufactured by Pasteur Merieux Connaught, PMC, has undergone a heat-treatment step (10 h at 60 degrees C) and removal of mercurothiolate. The corresponding unheated product available from the same manufacturer (human rabies immune globulin, HRIG, IMOGAM RABIES[spr2]) was used for comparison. These two rabies immune globulins (RIGs) were administered either alone or in association with the human diploid cell rabies vaccine (HDCV, IMOVAX[spr2] RABIES, PMC) according to a standard, post-exposure rabies prophylaxis schedule. Sixty-four healthy adults were randomly assigned to four groups of 16 to receive either HRIG/placebo, HTRIG/placebo, HRIG/HDCV or HTRIG/HDCV. RIG was administered at the recommended dose of 20 IU/kg by three intramuscular (i.m.) injections in the gluteus. HDCV or placebo was given on day (D) 0, D3, D7, D14, and D28 into the deltoid by the intramuscular (i.m.) route. Any local reaction from D0 to D3 at the immune globulin injection site, and any systemic reaction from D0 to D42, were monitored by subject diaries. Rabies-neutralizing serum antibody levels were assessed by the rapid fluorescent focus inhibition test (RFFIT) before treatment and on D3, D7, D14, D28, D35, and D42. No serious adverse reactions and, in particular, no allergic-type reactions were reported. The safety profiles of HTRIG and HRIG were similar, except that complaints of pain, or tenderness at the injection site were half as common in the HTRIG group. Most of the local reactions were mild or moderate. After the administration of HTRIG/placebo or HRIG/placebo, 60% of subjects had detectable rabies antibodies levels, but by D42 all titres were below the seroprotective level (i.e. below 0.5 IU/ml). In the groups HTRIG/HDCV and HRIG/HDCV, the antibody titres rose markedly from D7, and reached a maximum value of 19 IU/ml (95% CI, 11 to 38 IU/ml) and 31 IU/ml (95% CI, 20 to 48 IU/ml), respectively, on day 14. All subjects who received RIG and vaccine maintained a protective antibody level from D14 to D42. No significant difference in immunogenicity results between these two groups (HTRIG/HDCV and HRIG/HDCV) was observed, and no interference of immune globulin with vaccine was reported. The safety and immunogenicity profiles of PMC HTRIG appear comparable with the current reference product. The heat-treatment step will enhance the safety by further reducing the probability of virus transmission through immune globulin treatment. The low levels of rabies antibodies obtained by intramuscular administration of either PMC HTRIG or of PMC HRIG support the recommendations that call for local infiltration of wounds with RIG.
开展了一项双盲、对照、随机试验，以评估一种新型人狂犬病免疫球蛋白（HTRIG）的安全性和免疫原性。该产品由巴斯德梅里厄康诺特公司（PMC）生产，已经历热处理步骤（60℃下10小时）并去除硫柳汞。使用同一制造商提供的相应未加热产品（人狂犬病免疫球蛋白，HRIG，IMOGAM RABIES[spr2]）作为对照。这两种狂犬病免疫球蛋白（RIGs）根据标准的暴露后狂犬病预防方案单独给药或与人二倍体细胞狂犬病疫苗（HDCV，IMOVAX[spr2] RABIES，PMC）联合给药。64名健康成年人被随机分为四组，每组16人，分别接受HRIG/安慰剂、HTRIG/安慰剂、HRIG/HDCV或HTRIG/HDCV。RIG以20 IU/kg的推荐剂量通过在臀肌中进行三次肌肉注射给药。HDCV或安慰剂在第0天（D）、D3、D7、D14和D28通过肌肉注射途径注射到三角肌中。通过受试者日记监测免疫球蛋白注射部位从D0到D3的任何局部反应以及从D0到D42的任何全身反应。在治疗前以及D3、D7、D14、D28、D35和D42通过快速荧光灶抑制试验（RFFIT）评估狂犬病中和血清抗体水平。未报告严重不良反应，尤其是未报告过敏型反应。HTRIG和HRIG的安全性概况相似，只是HTRIG组中注射部位疼痛或压痛的主诉发生率为HRIG组的一半。大多数局部反应为轻度或中度。在给予HTRIG/安慰剂或HRIG/安慰剂后，60%的受试者具有可检测到的狂犬病抗体水平，但到D42时所有滴度均低于血清保护水平（即低于0.5 IU/ml）。在HTRIG/HDCV和HRIG/HDCV组中，抗体滴度从D7开始显著上升，在第14天分别达到最大值19 IU/ml（95%CI，11至38 IU/ml）和31 IU/ml（95%CI，20至48 IU/ml）。所有接受RIG和疫苗的受试者从D14到D42维持了保护性抗体水平。未观察到这两组（HTRIG/HDCV和HRIG/HDCV）在免疫原性结果上有显著差异，并且未报告免疫球蛋白对疫苗的干扰。PMC HTRIG的安全性和免疫原性概况似乎与当前的参考产品相当。热处理步骤将通过进一步降低病毒通过免疫球蛋白治疗传播的可能性来提高安全性。通过肌肉注射PMC HTRIG或PMC HRIG获得的低水平狂犬病抗体支持了要求用RIG局部浸润伤口的建议。
