A5240 (VERSION 10) A PHASE II STUDY TO EVALUATE THE IMMUNOGENICITY AND SAFETY

A5240（版本 10）评估免疫原性和安全性的 II 期研究

• 批准号: 8356728
• 负责人: William Thomas Shearer
• 金额: $ 2.64万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8356728
• 关键词: Academic Medical Centers; Address; Adult; Affect; Antibodies; Biological Assay; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Cell Count; Cells; Cervical; Clinical Research; DNA; Data; Detection; Development; Female; Funding; Grant; HIV; HIV-1; Hepatitis A; Hepatitis B; Hepatitis B Vaccination; High Prevalence; Highly Active Antiretroviral Therapy; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papillomavirus 6; Immune response; Immunologics; Immunosuppression; Indiana; Individual; Infection; Infection prevention; Life; Liquid substance; Measures; Methods; National Center for Research Resources; Oral; Oral Examination; Oral cavity; Oral mucous membrane structure; Participant; Patients; Personal Communication; Population; Population Analysis; Prevalence; Principal Investigator; RNA; Research; Research Infrastructure; Research Personnel; Resources; Safety; Series; Serologic tests; Serum; Source; Specimen; Squamous Epithelium; Squamous cell carcinoma; United States National Institutes of Health; Vaccination; Vaccines; Variant; Viral Load result; Woman; clinically significant; cost; immunogenicity; oral cavity epithelium; phase 2 study; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. ABSTRACT HIV-infected individuals are living longer, and non-AIDS-defining conditions are likely to affect this population in increasing numbers. HPV infections are more prevalent and persistent in HIV-infected women, with a prevalence of 64% compared to 28% in HIV-negative women. However, in a study of 146 treatment na¿ve women initiating HAART, the prevalence of HPV types 16 and 18 was 16% and 11%, respectively, at baseline (personal communication, Kenneth Fife, Indiana University Medical Center, September 2007). Additionally, in the HER study, evaluating 767 HIV-infected and 390 non-infected women, the DNA prevalence of one or more of HPV types 6, 11, 16, and 18 was 15.9%; specifically, type 6 was 3.1%, 11 was 0.9%, 16 was 5.7%, and 18 was 6.1% (6.7% in HIV-negative women). Thus, although HIV-infected women have a much higher prevalence of these four types than HIV-negative women, the majority of them (84-89%) did not have the types contained in the vaccine. Preventing infection of the four vaccine HPV types could decrease the impact of HPV infection among HIV-infected individuals. To date, the immunogenicity and safety of an HPV vaccine in HIV-infected adults has not been studied. This study is an initial step in evaluating an HPV vaccine in adult HIV-infected females. Immunogencity Rationale HIV-infected individuals have been known to have a poor response to standard vaccination series like hepatitis A and B, compared with HIV-uninfected people. Investigators have analyzed patient specific predictors associated with poor response and found that low CD4+ cell count and detectable HIV viral load have been associated with poor response to hepatitis A and B vaccinations in some studies. In this study, we will evaluate the immunogenicity and safety of GARDASIL. Since this is a population analysis, the study is stratified by CD4+ cell count and HIV-1 RNA viral load to assess whether these factors affect the participants ability to generate antibodies. To address the potential effect of HIV serum viral load on the vaccine immunogenicity, there will be an equal number of females in each CD4+ cell count =350 cells/mm¿ stratum with an HIV-1 RNA viral load = or 10,000 copies/mL. This approach will allow assessing the vaccine immunogenicity among females with different levels of immunosuppression. Immunogenicity will be measured with serological testing for antibodies to HPV types 6, 11, 16, and 18 after the vaccination series. The serological testing will be done by Merck, using an anti-HPV 6, 11, 16, and 18 competitive Luminex Immuno-Assay (HPV-4 cLIA). The scales for these assays are unique to each HPV type, with HPV type-specific lower limit of detection. Comparisons across types and to other assays are not appropriate. Seroconversion is defined as the development of antibody titer levels above a cutoff for each HPV type, as validated by Merck. The methods for determining serostatus cutoffs are described in Dias et al. Immunogenecity will also be measured by assessing cellular immune responses to HPV vaccination and correlations with the development and magnitude of HPV responses. Measuring responses in each CD4+ cell count stratum will allow for more careful comparisons across the strata. Higher viral load levels are associated with higher CD4+ and CD8+ cell count activation markers and may be associated with less immunologic response. Therefore, cellular immune responses will be measured in the subset of U.S. participants defined in the schema. Rationale for collecting data on HPV in the oral cavity The prevalence of HPV-associated OW appears to have increased since the introduction of HAART. However, to date, the correlation between an increased prevalence of OW and increased replication of HPV in squamous epithelium has not been explored. Furthermore, the clinical significance of HPV shedding from the oral epithelium with respect to subsequent development of OW or even squamous cell carcinoma is poorly understood. Therefore, study participants will undergo oral examinations and cytobrush specimens will be collected on OW to explore the baseline prevalence of OW and their development during the study. Furthermore, pilot data will be collected in the subset of U.S. participants defined in the schema to explore the prevalence of HPV in oral cells and fluids prior to and after administration of the vaccine and the effect of the vaccine on cross-strain HPV variation (only some of the HPV types targeted by the vaccine are not the HPV types typically isolated in the oral cavity). Oral and cervical compartmental shedding and strain variation of HPV before and after vaccine administration will be compared. HPV specific oral mucosal antibodies generated in response to the vaccine will be measured as well.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 抽象的 艾滋病毒感染者的寿命更长，非辅助状况可能会影响数量越来越多的人群。 HPV感染在HIV感染的女性中更为普遍，持续存在，患病率为64％，而HIV阴性妇女为28％。但是，在一项针对HAART启动HAART的146名妇女治疗的研究中，HPV类型16和18的患病率分别为16％和11％，在基线时（个人通讯，肯尼斯·法夫，印第安纳大学医学中心，2007年9月）。此外，在她的研究中，评估了767名HIV感染和390名未感染的妇女，一种或多种HPV类型6、11、16和18的DNA患病率为15.9％；具体而言，6型为3.1％，11型为0.9％，16型为5.7％，而艾滋病毒阴性女性为6.1％（6.7％）。尽管这四种类型的艾滋病毒感染妇女的患病率比艾滋病毒阴性妇女高得多，但其中大多数（84-89％）没有疫苗中包含的类型。防止四种疫苗HPV类型的感染可能会降低HIV感染的个体中HPV感染的影响。迄今为止，尚未研究HPV疫苗在HIV感染的成年人中的免疫原性和安全性。这项研究是评估成人HIV感染的女性中HPV疫苗的第一步。 免疫原理 与HIV未感染的人相比，众所周知，感染HIV的个体对标准疫苗接种系列（如乙型肝炎和B）的反应较差。研究人员已经分析了与反应不佳有关的患者特定预测因素，发现低CD4+细胞计数和可检测到的HIV病毒载量与某些研究中对乙型肝炎和B疫苗的反应不佳有关。在这项研究中，我们将评估Gardasil的免疫原性和安全性。由于这是人群分析，因此通过CD4+细胞计数和HIV-1 RNA病毒载量对研究进行分层，以评估这些因素是否影响参与者产生抗体的能力。 为了解决HIV血清病毒载量对疫苗免疫原性的潜在影响，每个CD4+细胞计数中的女性数量= 350细胞= 350个细胞/mm？tratum，具有HIV-1 RNA病毒载荷=或10,000份/ml。这种方法将允许评估不同水平免疫抑制的女性中的疫苗免疫原性。 免疫原性将通过血清学测试来测量 疫苗接种系列后的HPV类型6、11、16和18。血清学测试将使用默克（Merck）进行抗HPV 6、11、16和18竞争性Luminex免疫测定（HPV-4 CLIA）。这些测定的尺度是每种HPV类型所独有的，HPV类型特异性的检测下限。跨类型和其他测定的比较是不合适的。血清转化定义为默克验证的每种HPV类型的截止量高于截止的抗滴定水平的发展。 Dias等人描述了确定血清抗体截止的方法。 免疫原性还将通过评估与HPV疫苗接种的细胞免疫回报，并与HPV反应的发育和幅度相关。测量每个CD4+细胞计数层中的响应将使整个Stratta进行更仔细的比较。较高的病毒载荷水平与较高的CD4+和CD8+细胞计数激活标记有关，并且可能与免疫学反应较少有关。因此，将在模式中定义的美国参与者子集中测量细胞免疫响应反应。 用于在口腔中收集HPV数据的理由 自引入HAART以来，与HPV相关的OW的患病率似乎有所增加。但是，迄今为止，尚未探索OW患病率的增加与鳞状上皮中HPV复制增加之间的相关性。此外，对随后的OW甚至鳞状细胞癌的发展，口服上皮脱落的HPV脱落的临床意义知之甚少。 因此，研究参与者将接受口腔检查，并且将在OW上收集细胞刺激标本，以探索研究期间OW的基线患病率及其发展。此外，将在架构中定义的美国参与者子集中收集初步数据，以探索疫苗给药前后口腔细胞和烟道中HPV的普遍性，以及疫苗对疫苗的影响HPV跨疫苗的影响（仅通过疫苗靶向的HPV类型中的某些HPV类型都不是HPV类型的HPV类型的HPV类型。将比较疫苗给药前后HPV的口服和宫颈分室脱落和应变变化。还将测量针对疫苗产生的HPV特异性口服粘膜抗体。