b型流行性感冒嗜血杆菌结合疫苗(磷酸多核糖基核糖醇-白喉毒素突变体197)的安全性和免疫原性研究

Study on Safety and Immunogenicity of Haemophilus Influenzae Type b Conjugate Vaccine (Polyribosylribitol Phosphate-Cross Reacting Material 197)

目的评价b型流行性感冒嗜血杆菌结合疫苗(Haemophilus Influenzae Typeb Conjugate Vaccine,Hib)[磷酸多核糖基核糖醇-白喉毒素突变体197(Polyribosylribitol Phosphate-Cross Reacting Material197,PRP-CRM197)]在中国儿童使用的安全性、免疫原性和加强免疫后的抗体应答。方法研究分三个阶段:第一阶段为I期安全性研究,先入组20名16～20月龄的幼儿,接种1剂Hib PRP-CRM197;15d后入组20名2～4月龄的婴儿,按间隔1个月的程序接种3剂Hib PRP-CRM197。每剂接种后收集30d内的安全性数据。第二个阶段为Ⅲ期基础免疫,入组916名2～4月龄受试者,随机分配到试验组(611人)和对照组(305人),分别接种3剂Hib PRP-CRM197或Hib PRP-T(Tetanus Toxoid,TT;破伤风类毒素)对照疫苗,每剂间隔1个月。第三个阶段为Ⅲ期加强免疫,对基础免疫完成3剂疫苗接种的受试者,于1周岁后加强免疫1剂。在Ⅲ期临床研究中,收集安全性和免疫原性的数据。抗-PRP抗体测定采用酶联免疫吸附试验。结果Ⅰ期安全性研究发现,Hib PRP-CRM197在两个年龄组(婴儿和幼儿)都有良好的耐受性。基础免疫和加强免疫的Ⅲ期临床研究表明,Hib PRP-CRM197的安全性和HibPRP-T相似。在完成基础免疫后1个月,实验组和对照组的所有受试者均达到了短期血清保护性抗-PRP抗体水平[≥0.15微克/毫升(g/ml)],且分别有99%和97%的受试者达到了长期血清保护性抗-PRP抗体水平(≥1.0g/ml)。在完成加强免疫后,所有受试者均达到了短期和长期的血清保护性抗体水平。与HibPRP-T组相比,接种HibPRP-CRM197始终产生更高的抗体几何平均浓度。结论 Hib PRP-CRM197疫苗在基础免疫和加强免疫后,都显示了良好的耐受性和快速的抗-PRP抗体应答。Hib PRP-CRM197的免疫原性不劣于HibPRP-T,且安全性也相似。Hib PRP-CRM197可用于中国儿童抗Hib感染的常规免疫接种。临床试验注册国家食品药品监督管理局《药物临床批件》2008L03160。

Objective To evaluate the safety, immunogenicity and booster effect of a Haemophilus influenzae type b （Hib） conjugated vaccine （polyribosylribitol phosphate -cross reacting material 197, PRP-CRM197） against Hib for Chinese children. Methods The Hib PRP-CRMI97 was evaluated in three trials. The first （phase I） safety study were conducted in two Firstly, 20 toddlers aged 16-20 months were enrolled and received one dose of PRP-CRMl97 vaccine; 15 days later, 20 infants aged 2-4 months were enrolled and received 3 doses of PRP-CRM197 vaccine with 1 months interval. Safety data only were collected up to 30 days post each dose of vaccination. The second trial, a phase III study, primary immunization enrolled randomly 916 subjects who were the age of 2-4 months to receive either PRP- CRM197 （N=611 ） or PRP-T （tetanus toxoid） vaccine as control group （N=305） administered three doses with one month interval. In a third （phase III） trial, booster immunization, the subjects received a booster dose of vaccine for toddlers （12 to 18 months of age）after completed 3 doses . In the phase III studies, safety and immunogenicity data were collected. The immunogenicity was measured via anti-PRP enzyme-linked immunosorbant assay. Results The safety study of phase I found that the PRP-CRM197 was well tolerated in both age groups （infants and toddlers）. The trial of phase III for three-dose primary immunization schedule and booster dosle demonstrated the safety of PRP-CRM197 are similar to that of PRP-T. All subjects achieved short-term seroprotective anti-PRP antibody levels （ ≥ 0.15μg/ml） following primary immunization with two kind of vaccines; 99% and 97% of subjects achieved long-term （≥ 1.0gg/ml） seroprotection in the PRP-CRM197 and PRP-T vaccine groups respectively, one month after completion of the primary vaccination series. All subjects receiving booster mmunization amorig trial group and control group got short-term and long-term seroprotective antibody. Administration of PRP-CRM197 consistently resulted in higher geometric mean concentrations （GMC） of antibody compared with that of PRP-T. Conclusion PRP-CRM197 shown that both kind of vaccine has good tolerated and fast response of anti-PRP antibody after both the primary and booster vaccinations. Immunogenicity responses and the safety for both kind of vaccines are similar. PRP-CRM197 is suitable for routine immunization against Hib disease among the Chinese children. Clinical Trial Registration State Food and Drug Administration Approval Number： 2008L03160. Trial registration： （www.clinciahrials.gov） NCT00808392.