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背景咪喹莫特(Imiquimod)-Toll样受体7拮抗剂的预处理能改善老年人接种流感疫苗的免疫力,本研究将阐明咪喹莫特对年龄较低人群接种流感疫苗的影响。方法在此双盲-对照随机研究中,招募年龄在18~30岁志愿者,由玛丽女王医院(中国,香港)在2014年初注射2013~2014北半球三价流感疫苗。通过电脑产生随机数字,志愿者按照(1:1:1:1)的比例分为4组,病例组为局部涂抹咪喹莫特皮下注射流感疫苗(INF-Q-ID),3个对照组为局部涂抹水皮下注射流感疫苗(INF-C-ID)、局部涂抹水肌肉内注射流感疫苗(INF-C-IM)、局部涂抹咪喹莫特皮下注射盐水(SAL-Q-ID)。虽然注射的护理人员知道使用药物,但志愿者和研究者不知道分组,研究是双盲进行。采用血清血凝抑制和微量中和方法分析抗体滴度。在疫苗接种7d后,检测血清抗体水平,检测病毒包括三个疫苗株:A/California/2009H1N、A/Victoria/H3N2/2011、B/Massachusetts/2012/Yamagata,4个非疫苗株:A HK/485197/14 H3N2、A/WSN/1933 H1N1、A/HK/408027/09/H1N1、B/HK/418078/11/Victoria。研究采用意向性治疗分析,通过政府临床实验网站进行注册,注册号为NCT02103023。结果 2014年3月1日~5月31日,招募160名志愿者,随机分为4组,每组40人。A/California/H1N1毒株,INF-Q-ID组,39名志愿者抗体阳转,阳转率为98%;INF-CID组,25名志愿者阳性,阳转率为63%;INF-C-IM组,18名志愿者阳性,阳转率为45%;SAL-Q-ID组,无阳转。A/Victoria/H3N2毒株,INF-Q-ID组,30名志愿者抗体阳转,阳转率为75%;INF-C-ID组,4名志愿者阳性,阳转率为10%;INF-C-IM组,4名志愿者阳性,阳转率为10%;SAL-Q-ID组,无阳转。B/Massachusetts/2012/Yamagata毒株,INF-Q-ID组,36名志愿者抗体阳转,阳转率为90%;INF-C-ID组,27名志愿者阳性,阳转率为68%;INF-C-IM组,17名志愿者阳性,阳转率为43%;SALQ-ID组,1例阳转,阳转率为3%,3个疫苗株,4组抗体阳转率差异有统计学意义(P<0.0001)。此外,对7d和21d的血清进行检测,INF-Q-ID组非疫苗株阳转率均高于3个对照组(P<0.0001)。不良反应是罕见的,都是自限性的,4组之间差异无统计学意义。最常见的不良反应为1度红(grade1 redness)(INFQ-ID组5例,INF-C-ID组3例,INF-C-IM组1例,SAL-Q-ID组1例)、1度肿(grade 1 swelling)(INF-Q-ID组7例,INF-C-ID组5例,INF-C-IM组3例,SAL-Q-ID组2例)。结论在年龄较低人群中,局部涂抹咪喹莫特能改善皮下注射流感疫苗免疫效果,不仅改善对疫苗株免疫,同时增加对非疫苗株的免疫效果,特别是2015流行的存在抗原漂移H3N2病毒株。进一步的研究将探索局部涂抹咪喹莫特对注射其他疫苗的效果和安全性,促进保护性抗体产生。
Background The pretreatment of Imiquimod-Toll-like Receptor 7 antagonists improves the immunization of influenza vaccination in the elderly, and this study will illustrate the impact of imiquimod on influenza vaccination in the younger population. Methods In this double-blind, randomized, controlled trial, volunteers aged 18-30 were enrolled in the Northern Hemisphere Trivalent Flu vaccine from 2013 to 2014 in early 2014 by Queen Mary Hospital (Hong Kong, China). Random numbers were generated by computer. The volunteers were divided into four groups according to the ratio (1: 1: 1: 1). The cases were divided into two groups: INF-Q-ID and INF-Q- For topical water subcutaneous injection of influenza vaccine (INF-C-ID), Topical Water intramuscular influenza vaccine (INF-C-IM), topical imiquimod subcutaneous Saline (SAL-Q-ID). Although injecting nurses knew about the use of medication, volunteers and researchers did not know the grouping and the study was double-blind. Antibody titers were analyzed using serum hemagglutination inhibition and micro-neutralization methods. Serum antibody levels were tested 7 days after vaccination, and the virus was tested for three vaccine strains: A / California / 2009 H1N, A / Victoria / H3N2 / 2011, B / Massachusetts / 2012 / Yamagata and 4 non-vaccine strains: 485197/14 H3N2, A / WSN / 1933 H1N1, A / HK / 408027/09 / H1N1, B / HK / 418078/11 / Victoria. The study used intent-to-treat analysis and was registered on the government clinical trial website with the registration number NCT02103023. Results From March 1 to May 31, 2014, 160 volunteers were recruited and randomly divided into 4 groups of 40. In the group of INF-CID, positive rate of positive conversion was 63% in INF-CID group and positive rate of INF-Q-ID was 39% C-IM group, 18 volunteers were positive, positive conversion rate was 45%; SAL-Q-ID group, no positive. A / Victoria / H3N2 strain, INF-Q-ID group, 30 volunteers were positive for positive conversion of positive rate of 75%; INF-C-ID group, 4 volunteers were positive, positive conversion rate was 10% In the INF-C-IM group, four volunteers were positive with a positive rate of 10%. In the SAL-Q-ID group, there was no positive conversion. In the group of B / Massachusetts / 2012 / Yamagata and INF-Q-ID, 36 volunteers were positive for positive conversion and the positive conversion rate was 90%. In the INF-C-ID group, 27 volunteers were positive and the positive conversion rate was 68 %; In the INF-C-IM group, 17 volunteers were positive and the positive rate was 43%. In the SALQ-ID group, 1 was positive and the positive rate was 3% The difference was statistically significant (P <0.0001). In addition, the seroconversion rates of non-vaccine strains in INF-Q-ID group were higher than those in 3 control groups (P <0.0001). Adverse reactions are rare and self-limiting, with no significant difference between the 4 groups. The most common adverse reactions were grade 1 redness (5 in the INFQ-ID group, 3 in the INF-C-ID group, 1 in the INF-C-IM group and 1 in the SAL-Q-ID group) Grade 1 swelling (7 in the INF-Q-ID group, 5 in the INF-C-ID group, 3 in the INF-C-IM group and 2 in the SAL-Q-ID group). Conclusion In the younger population, topical application of imiquimod improves the immunization efficacy of the influenza vaccine administered subcutaneously, not only improving the immunization against the vaccine strain but also increasing the immune response to the non-vaccine strain, in particular the presence of the H3N2 antigen-drift virus present in 2015 Strain. Further research will explore the effect and safety of topical imiquimod injection on other vaccines and promote protective antibody production.