目标。评估经皮内注射的纯化鸡胚细胞狂犬疫苗(PCECV, Rabipur)增强剂量的免疫原性。
方法。在一项随机，开放标签的这种后续研究，II期临床试验中，两个模拟暴露后加强剂量PCECV进行了第0天给药，3皮内以703健康的学童，一，初次接种三年或五年后with either two or three ID doses of 0.1 mL PCECV. Blood was drawn immediately before and 7, 14 and 365 days after the first booster dose to determine rabies virus neutralizing antibody (RVNA) concentrations.
结果。的大约30倍的增加在RVNA浓度回忆应答被内升压后14天证实。All children (100%) developed adequate RVNA concentrations above 0.5 IU/mL. No vaccine related serious adverse events were seen in any of the vaccinees.
结论。使用PCECV的ID狂犬病预防对学童是安全的和免疫原性的，并且在两剂或三剂初级预防疫苗系列接种后的一、三和五年后，对两剂强化疫苗系列接种的遗忘反应被发现是足够的。
在这项长期随访中，对接受了两次(模拟的)暴露后PCECV增强剂量的泰国学童进行了调查，调查时间为接种初级疫苗准备系列疫苗五年后。有关研究的详情已于较早前描述[
13]。Briefly, subjects enrolled in the clinical trial included healthy schoolchildren, aged 5 to 8 at the time that the primary vaccination with two or three 0.1 mL ID doses of PCECV was administered. Subjects were followed for one, three, or five years after primary PrEP and then received two ID booster doses of 0.1 mL PCECV on days 0 and 3, simulating the current recommended PEP booster recommendations, that is, administering the 2-dose booster doses, without RIG, as if an exposure had occurred. The PCECV used for the primary vaccination series and for the 1-year and 3-year booster doses was Novartis Vaccines’ Rabipur, produced in India; batch no. 725 (potency 7.25 IU/mL). For the 5-year group, batch no. 1471 (potency 9.81 IU/mL) was used. The objectives of the study were to demonstrate long-term postbooster rabies virus-neutralizing antibody (RVNA) protection, defined as RFFIT antibody concentrations ≥0.5 IU/mL, one, three, and five years after the primary vaccination, to evaluate whether adequate RVNA concentrations is achieved in all subjects and to compare the immune responses of the 2-dose versus 3-dose ID regimen of PCECV. This study was conducted under the auspices of the Ministry of Public Health, Thailand, following the research principles set out in the Declaration of Helsinki and Good Clinical Practice guidelines. Approval of the study protocol was obtained by the Ethical Review Committee for Research in Human Subjects, Ministry of Health; all parents and legal guardians of subjects were informed of the study protocol prior to enrollment, and written informed consent was obtained from parents or legal guardians of all subjects prior to enrollment. The study was registered at ClinicalTrials.gov (identifier: NCT01107275). A flow diagram of study participants as suggested in the CONSORT Statement is given in Figure
1。
首次接种疫苗一年后，RVNA浓度下降(图)
2(一个)) with 7% and 35% of the vaccinees still having adequate RVNA concentrations above 0.5 IU/mL, in the 2-dose and 3-dose group, respectively, (Table
1)。与充足的RVNA浓度的科目，这一比例不随时间变化显著（图
2 (b)和
图2（c）);3年组的8%和40%，5年组的12%和46%，分别维持了足够的RVNA浓度(表)
1)。收到两个升压剂PCECV,后0天,第三天,RVNA浓度显著增加在所有学习小组,从而引起足够的RVNA浓度7天postbooster在100%,97%,和99%的儿童3-dose组和96%,73%,和91%的儿童服用组,一,三,五年后主要疫苗接种,分别。到第14天，每个儿童(100%)都达到了适当的RVNA浓度，无论初级疫苗接种和强化接种之间的时间间隔，或是否接受了2或3次初级剂量(表)
1)。因此，我们的目标是证明增强后RVNA的长期保护，定义为RFFIT抗体浓度在初级接种1、3和5年后≥0.5 IU/mL，并证明在所有受试者中RVNA达到了足够的浓度。加强治疗后14天，2剂量方案与3剂量方案在诱导充分反应方面效果相当(各组RVNA浓度均为100%)，而加强治疗后第7天，2剂量组的百分比较低。当比较实际RVNA浓度时，3剂量组的GMCs大约是2剂量组的3倍。这种差异在整个研究中都可以看到(图)
2)。
有趣的是，RVNA浓度和产生足够滴度的患者百分比多年来没有显著变化。在5年前接种疫苗的受试者中，观察到的RVNA浓度与1年和3年前接种疫苗的受试者大致相同。在两剂PEP系列后，无论起始PrEP系列后的时间如何，在所有受试者中均观察到可比较的免疫应答。一个更相关的考虑是，初始初级疫苗系列中包括了多少剂量:接受三剂量初级疫苗系列的受试者比仅接受两剂量初级疫苗系列的受试者有更高的RVNA浓度和更高的增强反应(图)
2)。However, although GMTs of RVNA concentrations in the group that received a two-dose PrEP series were significantly lower throughout the study, in this group all subjects achieved adequate RVNA concentrations above 0.5 IU/mL, when two booster doses were given up to five years after primary vaccination. The fact that all subjects reached adequate RVNA concentrations by day 14, regardless of the time interval between primary series, and booster doses or the number of doses in the primary series is reassuring. However, the overall lower RVNA concentrations in the 2-dose group resulted in a lower percentage of adequate RVNA concentrations on day 7. In particular, in the 2-dose group adequate immune responses were only seen in 73% of children (3-year data), compared to 97–100% in the 3-dose groups. This leaves a vulnerable period of a few days in more than few subjects after a 2-dose primary vaccination series. Whether this would lead to treatment failure and development of rabies remains questionable. In PEP of previously unvaccinated subjects, adequate RVNA concentrations do not develop before day 14 either. Clearly here RIG is recommended to cover the lag period. However, in reality RIG is only administered in 2 to 10% of all cases, where it would be indicated [
18]，并且治疗失败被认为极为罕见。为了安全起见，然而，如RIG的给药被认为是不必要的或推荐的先前接种的受试者，3-剂量初级接种方案可能被认为是更适合于个人的保护。
在持续的风险世界卫生组织建议，诊断实验室工作人员，狂犬病研究人员，和其他人（其中狂犬病毒持续存在，而且浓度较高，以及在哪里狂犬病特定风险可能难以识别）应该有自己的血清效价评估每六months for the presence of RVNA and receive a single booster vaccination when their RVNA concentrations fall below 0.5 IU/mL [
4]。For the general population living in endemic countries, it is sufficient to receive a routine ID booster series with 0.1 mL of PCECV without routine serology testing, which is expensive and difficult to perform. Due to the fact that immune memory is established in persons that have been vaccinated with a TCV, an anamnestic immune response is induced after a PEP-booster series using 0.1 mL of a TCV (PCECV) ID booster doses, as demonstrated in this study up to five years after completion of the primary vaccination.
现时的预防接种建议包括注射三剂狂犬病疫苗
4], a PrEP vaccination series using two or three doses of 0.1 mL PCECV administered ID is safe and immunogenic in school children, and anamnestic responses occurred in all subjects after two booster doses were administered up to five years later. This indicates that when an exposure occurs, two booster doses of vaccine administered ID three days apart may be appropriate in previously immunized persons that may have received only two initial doses of a PrEP series although three initial doses lead to higher immune responses and longer lasting protection. Reduced PrEP regimens would reduce the cost of protecting vulnerable populations against rabies and would promote better compliance, thus supporting opportunities to conduct mass PrEP rabies vaccination in children, the population most at risk of dying of this dreaded disease.