Comparison of methods for determination of immunogenicity of recombinant human papillomavirus vaccine

目的评价重组人乳头瘤病毒(HuMAn PAPIllOMAVIruS,HPV)疫苗免疫原性2种检测方法的相关性。方法应用间接酶联免疫吸附(ElISA)法和假病毒中和(PSEudOVIrIOn-bASEd nEuTrAlIzATIOn ASSAy,PbnS)法对26份阴性血清样本、34份自然感染HPV16或HPV18的血清样本及30份接种HPV16/18型双价疫苗后7个月的血清样本进行抗体滴度检测,并采用PEArMAn进行相关性分析。结果 3组样本的抗HPV16型和HPV18型抗体滴度的2次检测结果比值显示,试验室内重复性较好;2种方法检测血清样本抗HPV16型抗体滴度的总体相关系数为0.826,抗HPV18型为0.921;自然感染HPV的血清样本抗HPV16型抗体滴度的相关系数为0.519,抗HPV18型为0.613;接种HPV16/18型双价疫苗后的血清样本抗HPV16型抗体滴度的相关系数为0.671,抗HPV18型为0.879。结论间接ElISA法和PbnS法在检测血清样本中抗HPV16/18型抗体滴度时均具有较好的重复性和相关性,其中以接种疫苗后的血清样本中抗体滴度相关性最佳,为HPV疫苗免疫原性的检测及剂量探索试验提供了参考依据。Objective To assess the correlation between two methods for determination of immunogenicity of recombinant human papillomavirus(HPV) vaccine.Methods Enzyme-linked immunosorbent assay(ELISA) and pseudovirion-based neutralization assay(PBNS) were used to measure the anti-HPV 16 or anti-HPV 18 antibody levels in 26 negative serum samples,34 serum samples naturally infected with HPV16 or HPV18 and 30 serum samples 7 months after immunization with HPV16 / 18 bivalent vaccine,between which the correlation was analyzed by Pearman method.Results The ratio of results of two tests for HPV16 and HPV18 antibody titers in three groups of samples showed high intra-reproducibility.The total correlation coefficient of test results of HPV16 antibody titers by two methods was 0.826,while that of HPV18 antibody was 0.921.The correlation coefficient for HPV 16 antibody titer in naturally infected samples was 0.519,while that for HPV18 antibody titer was 0.613.However,the correlation coefficient for HPV 16 antibody titer in serum samples after immunization with HPV16 / 18 bivalent vaccine was 0.671,while that for HPV 18 antibody titer was 0.879.Conclusion Both ELISA and PBNS showed high reproducibility and correlation for determination of HPV16 / 18 antibody titers in serum samples,especially for those in samples after vaccination.It provided a reference for determination of immunogenicity and optimization of dosage of HPV vaccine.国家高技术研究发展计划(2012AA02A402); Themajorpro-jectofInternationalScienceandTechnologyCollaborativeProgram(2010DFB30100

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

HPV1618假病毒中和抗体检测方法的验证

通讯作者：李长贵 E-mail：[email protected] 作者简介：赵慧（1980-），女，助理研究员 主要从事病毒疫苗质量控制工作目的 应用假病毒中和法建立检测血清HPV16/18中和抗体滴度检测方法并进行验证。方法 分别采用不同批次假病毒以及不同代次细胞对不同滴度的HPV16/18阳性血清进行多次平行检测，考察这些因素对检验结果的影响；同时通过对抗HPV16/18双价阳性血清、抗HPV16单价阳性血清和抗HPV18单价阳性血清的检测进一步评估中和抗体检测法的准确性、特异性及重复性。结果 不同批次假病毒和不同代次细胞对检验结果的影响均在四倍范围内，此外该检测法的准确性、特异性、重复性均在可接受标准范围之内。结论建立的假病毒法可满足中和抗体效价检测的要求，可用于评价疫苗的免疫效果。国家高技术研究发展计划（2012AA02A402）；国际科技合作项目 (2010DFB30100

新疆北部覆膜滴灌棉田的碳交换日、生长季变化特征/Diurnal and seasonal variation of carbon dioxide exchange over a film-mulched cotton field under drip irrigation in northern Xinjiang[J]

利用涡动相关系统测定新疆石河子棉区覆膜滴灌棉田的CO2通量,分析2010年棉花各生育期净生态系统碳交换(NEE)的日变化特征,并将NEE拆分为生态系统总生产力(GEP)和生态系统呼吸(Reco),分析三者的生长季变化特征及其影响因素.结果表明:在播种期和苗期,棉田白天和夜间的NEE变化幅度都较小；其他生育期NEE白天呈‘V’形变化,夜间为正值且变化小.NEE的日变化主要受太阳总辐射影响.GEP、Reco和NEE的生长季变化趋势与叶面积指数变化相对一致,最大日累积量均出现在花铃期,分别为11.8,8.0和-6.2 g C·m-2·d-1.播种期、苗期、蕾期、花铃期和吐絮期的日平均NEE分别为2.6,1.6,-1.2,-2.8和0.5 g C·m-2·d-1.整个生长季棉田NEE累积量为-122.2 g C·m-2,表现为碳汇.由偏相关分析可得,GEP,Reco和NEE的生长季变化与气温的相关系数最高,其次为饱和水汽压差,再次为太阳总辐射和土壤温度,结果表明气温是影响棉田GEP,Reco和NEE生长季变化的主要气象因素.气温对棉田GEP,Reco和净碳吸收起促进作用,而饱和水汽压差对其起限制作用

Aripiprazole versus other atypical antipsychotics for schizophrenia

BACKGROUND: In most western industrialised countries, second generation (atypical) antipsychotics are recommended as first line drug treatments for people with schizophrenia. In this review we specifically examine how the efficacy and tolerability of one such agent - aripiprazole - differs from that of other comparable second generation antipsychotics. OBJECTIVES: To evaluate the effects of aripiprazole compared with other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychoses. SEARCH METHODS: We searched the Cochrane Schizophrenia Group Trials Register (November 2011), inspected references of all identified studies for further trials, and contacted relevant pharmaceutical companies, drug approval agencies and authors of trials for additional information. SELECTION CRITERIA: We included all randomised clinical trials (RCTs) comparing aripiprazole (oral) with oral and parenteral forms of amisulpride, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone or zotepine for people with schizophrenia or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random-effects model. Where possible, we calculated illustrative comparative risks for primary outcomes. For continuous data, we calculated mean differences (MD), again based on a random-effects model. We assessed risk of bias for each included study. MAIN RESULTS: We included 12 trials involving 6389 patients. Aripiprazole was compared to olanzapine, risperidone and ziprasidone. All trials were sponsored by an interested drug manufacturer. The overall number of participants leaving studies early was 30% to 40%, limiting validity (no differences between groups).When compared with olanzapine no differences were apparent for global state (no clinically important change: n = 703, 1 RCT, RR short-term 1.00 95% CI 0.81 to 1.22; n = 317, 1 RCT, RR medium-term 1.08 95% CI 0.95 to 1.22) but mental state tended to favour olanzapine (n = 1360, 3 RCTs, MD total Positive and Negative Syndrome Scale (PANSS) 4.68 95% CI 2.21 to 7.16). There was no significant difference in extrapyramidal symptoms (n = 529, 2 RCTs, RR 0.99 95% CI 0.62 to 1.59) but fewer in the aripiprazole group had increased cholesterol levels (n = 223, 1 RCT, RR 0.32 95% CI 0.19 to 0.54) or weight gain of 7% or more of total body weight (n = 1095, 3 RCTs, RR 0.39 95% CI 0.28 to 0.54).When compared with risperidone, aripiprazole showed no advantage in terms of global state (n = 384, 2 RCTs, RR no important improvement 1.14 95% CI 0.81 to 1.60) or mental state (n = 372, 2 RCTs, MD total PANSS 1.50 95% CI -2.96 to 5.96).One study compared aripiprazole with ziprasidone (n = 247) and both the groups reported similar change in the global state (n = 247, 1 RCT, MD average change in Clinical Global Impression-Severity (CGI-S) score -0.03 95% CI -0.28 to 0.22) and mental state (n = 247, 1 RCT, MD change PANSS -3.00 95% CI -7.29 to 1.29).When compared with any one of several new generation antipsychotic drugs the aripiprazole group showed improvement in global state in energy (n = 523, 1 RCT, RR 0.69 95% CI 0.56 to 0.84), mood (n = 523, 1 RCT, RR 0.77 95% CI 0.65 to 0.92), negative symptoms (n = 523, 1 RCT, RR 0.82 95% CI 0.68 to 0.99), somnolence (n = 523, 1 RCT, RR 0.80 95% CI 0.69 to 0.93) and weight gain (n = 523, 1 RCT, RR 0.84 95% CI 0.76 to 0.94). Significantly more people given aripiprazole reported symptoms of nausea (n = 2881, 3 RCTs, RR 3.13 95% CI 2.12 to 4.61) but weight gain (7% or more of total body weight) was less common in people allocated aripiprazole (n = 330, 1 RCT, RR 0.35 95% CI 0.19 to 0.64). Aripiprazole may have value in aggression but data are limited. This will be the focus of another review. AUTHORS' CONCLUSIONS: Information on all comparisons are of limited quality, are incomplete and problematic to apply clinically. Aripiprazole is an antipsychotic drug with a variant but not absent adverse effect profile. Long-term data are sparse and there is considerable scope for another update of this review as new data emerges from the many Chinese studies as well as from ongoing larger, independent pragmatic trials