hrHPV DNA载量 分型和E6蛋白对宫颈癌前病变进展的预测作用

目的:探讨预测高危型人乳头瘤病毒(high risk human papillomavirus,hrHPV)阳性和宫颈上皮内瘤样病变1级(cervical in-traepithelial neoplasia grade 1,CIN1)妇女进展的生物学标志物。方法:2010年10月至2012年8月在山西省、河南省和江西省招募7 543名妇女,采用hrHPV DNA检测和E6蛋白检测(Onco E6)等方法进行宫颈癌筛查,任一结果阳性者转诊阴道镜并取活检,于1年后随访。纳入基线hrHPV阳性或病理诊断CIN1者。结果:共纳入794例满足条件妇女,1年后88例妇女病理级别发生进展。基线hrHPV DNA中高载量者进展的风险是低载量者的2.9倍(95%CI为1.8~4.8),hrHPV16/18/45、E6蛋白阳性者进展的风险分别是阴性者的2.4倍(95%CI为1.5~3.9)、2.9倍(95%CI为1.5~5.9),其进展至宫颈上皮内瘤样病变2级及以上(cervical intraepi-thelial neoplasia grade 2 or worse,CIN2+)的绝对风险分别为4.9%(95%CI为3.2~7.4)、9.0%(95%CI为5.5~14.3)、18.8%(95%CI为10.2~31.9)。hrHPV16/18/45中高载量且E6蛋白(Onco E6)阳性妇女进展的绝对风险高达32.4%(11/34)。结论:hrHPV DNA中高载量、hrHPV16/18/45分型以及E6蛋白(Onco E6)可作为妇女hrHPV阳性和CIN1进展的生物学标志物,特别是hrHPV中高载量且E6蛋白(Onco E6)阳性妇女,临床应给予密切随访。中国医学科学院医学与健康科技创新工程重大协同创新项目(编号:2016-I2M-1-019)资助~

Efficacy, Safety, and Immunogenicity of an Escherichia coliProduced Bivalent Human Papillomavirus Vaccine: An Interim Analysis of a Randomized Clinical Trial

HPV是一种常见的生殖道感染病毒，高危型HPV持续性感染能够导致几乎所有的宫颈癌，其中HPV 16型和18型危害最大，可导致约70%的宫颈癌。预防性HPV疫苗有望减少甚至最终消灭由疫苗型别导致的宫颈癌，降低HPV相关的疾病负担。该研究是在全国4个中心5个现场的18-45岁健康女性中进行的多中心、随机、双盲、对照（戊肝疫苗）的三期临床试验，该研究结果证实我校自主研发的双价人乳头瘤病毒疫苗（大肠杆菌）具有良好的安全性、免疫原性和免疫持久性，可有效地预防HPV 16型和/或18型相关的宫颈高度癌前病变及持续性感染。 该论文报告了我校和厦门万泰沧海生物技术有限公司自主研发的双价人乳头瘤病毒疫苗（大肠杆菌）三期临床试验的期中分析结果。这是第一个进入临床试验并提交药品注册申请的国产人乳头瘤病毒疫苗（HPV疫苗），有望成为世界上第四个上市的HPV疫苗，受到世界卫生组织和盖茨基金会等国际组织的高度关注。 中国医学科学院肿瘤医院乔友林教授、我校吴婷教授、广西壮族自治区疾病预防控制中心李荣成主任医师、江苏省疾病预防控制中心胡月梅主任医师、北京大学人民医院魏丽惠教授、中国食品药品检定研究院李长贵研究员、中国医学科学院肿瘤医院陈汶教授为该论文的共同第一作者，我校张军教授、夏宁邵教授和中国医学科学院肿瘤医院乔友林教授为该论文的共同通讯作者。【Abstract】Background The high cost and insufficient supply of human papillomavirus (HPV) vaccines have slowed the pace of controlling cervical cancer. A phase 3 clinical trial was conducted to evaluate the efficacy, safety and immunogenicity of a novel Escherichia coli-produced bivalent HPV-16/18 vaccine. Methods A multi-centre, randomized, double-blind trial started on November 22, 2012, in China. In total, 7372 eligible women aged 18-45 years were age-stratified and randomly assigned to receiving 3 doses of the test or control (hepatitis E) vaccine at months 0, 1 and 6. Co-primary endpoints included high-grade genital lesions and persistent infection (over 6 months) associated with HPV-16/18. The primary analysis was performed on a per-protocol susceptible population of individuals who were negative for relevant HPV type-specific neutralizing antibodies (at day 0) and DNA (at day 0 through month 7) and who received 3 doses of the vaccine. This report presents data from a pre-specified interim analysis used for regulatory submission. Results In the per-protocol cohort, the efficacies against high-grade genital lesions and persistent infection were 100.0% (95% confidence interval [CI] = 55.6% to 100.0%, 0/3306 in the vaccine group vs. 10/3296 in the control group) and 97.8% (95% CI = 87.1% to 99.9%, 1/3240 vs. 45/3246), respectively. The side effects were mild. No vaccine-related serious adverse events were noted. Robust antibody responses for both types were induced and persisted for at least 42 months. Conclusions The Escherichia coli-produced HPV-16/18 vaccine is well tolerated and highly efficacious against HPV-16/18 associated high-grade genital lesions and persistent infection in women.This work was supported by grants from the Chinese National High-tech R&D Program (863 program, 2012AA02A408), the Chinese National Major Scientific and Technological Special Project for “Significant New Drug Development” (2018ZX09308010 and 2012ZX09101316), the National Natural Science Foundation of China (81673240 and U1705283), the Fujian Provincial Major Scientific and Technological Project (2015YZ0002), the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (CIFMS, 2017-I2M-B&R-03, and 2016-I2M-1-019) and Xiamen Innovax. 该研究获得了国家高技术研究发展计划（863计划）、新药创制国家科技重大专项、国家自然科学基金、福建省科技重大专项、中国医学科学院医学与健康科技创新工程基金以及厦门万泰沧海生物技术有限公司的资助

Naturally acquired HPV antibodies against subsequent homotypic infection: A large-scale prospective cohort study

宫颈癌是全球15-44岁女性中第二常见的癌症，其主要病因是高危型HPV的感染，尤其是HPV 16型和18型的感染，在我国与约84%的宫颈癌有关。早期研究显示因自然免疫获得抗体的女性再次感染同型HPV的风险降低较为有限（约35%），但在这些研究中多依据IgG抗体而非中和抗体作为自然免疫指标进行保护效果分析。我校研究人员利用国产双价HPV疫苗III期临床试验中未接种HPV疫苗且HPV DNA为阴性的3600余名18-45岁健康女性队列，分别采用中和抗体和IgG抗体作为获得自然免疫的指标，分析其在之后5.5年的随访期间再次感染同型HPV的风险。该研究首次在大样本长期随访队列中以中和抗体作为免疫指标评价HPV自然免疫效果，获得了客观准确的HPV自然免疫数据，丰富了HPV自然史研究，为HPV疫苗接种策略的制订提供了重要依据。我校博士生姚星妹、中国医学科学院肿瘤医院陈汶教授和北京大学人民医院赵超教授为该论文共同第一作者。我校吴婷教授、张军教授、夏宁邵教授和中国医学科学院肿瘤医院乔友林教授、赵方辉教授为该论文的共同通讯作者。Background: Although recent studies have suggested that naturally acquired Human papillomavirus (HPV) antibodies are partly protective against subsequent homotypic infection, the extent of protection remains indecisive. Here, we evaluate the protective effect of neutralizing and IgG antibodies simultaneously. Methods: In a cohort of 3634 women aged 18-45 years from the control arm of a phase III trial of the HPV-16/18 bivalent vaccine, participants were tested for neutralizing antibodies by pseudovirion-based neutralization assay (PBNA) and IgG antibodies by enzyme-linked immunosorbent assay (ELISA) at baseline. HPV-16/18 incident and persistent infections were identified using cervical specimens periodically collected during the 5.5 years of follow-up. The protective effects of HPV-16/18 neutralizing and IgG antibodies against homotypic infection were assessed using a Cox proportional hazard model. Findings: For the persistent infection (PI) endpoints of HPV-16/18 lasting for over 6/12 months, a prevalence of type-specific neutralizing antibodies was highly protective (6-month PI: hazard ratio (HR) = 0.16,95% confidence interval (CI): 0.04, 0.65; 12-month PI: HR = 0.23, 95% CI: 0.06, 0.94), whereas a prevalence of IgG antibodies was associated with minor and non-significant protection (6-month PI: HR = 0.66, 95% CI: 0.40, 1.09; 12-month PI: HR = 0.66, 95% CI: 0.36, 1.20). After increasing the cut-off value to the median IgG level, the risk of 6-month PI was significantly lower in seropositive vs seronegative women (HR = 0.38, 95% CI: 0.18, 0.83). Interpretation: Naturally acquired antibodies are associated with a substantially reduced risk of subsequent homotypic infection.We thank all the study participants and research staff of the HPV-003 Study Group for their contributions to the present study. In addition, we also thank Dr. Allan Hildesheim of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute, National Institutes of Health for his helpful comments on this study.该研究获得国家自然科学基金、福建省卫生教育联合攻关计划项目、厦门市科技重大专项、中国医学科学院医学科学创新基金和厦门万泰沧海生物技术有限公司的支持。Funding: NSFC; The Fujian Province Health Education Joint Research Project; Xiamen Science and Technology Major Project; CIFMS; and Xiamen Innovax