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.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供 该子项目的主要支持。 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源的子项目可能列出的总成本。 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 抽象的 HIV 感染者的寿命更长，并且非艾滋病定义的疾病可能会越来越多地影响该人群，HPV 感染在 HIV 感染女性中更为普遍和持久，其患病率为 64%，而 HIV 感染者的患病率为 28%。然而，在一项针对 146 名治疗的研究中，阴性女性。在 5 名开始 HAART 的女性中，基线时 HPV 16 型和 18 型的患病率分别为 16% 和 11%（个人通讯，Kenneth Fife，印第安纳大学医学中心，2007 年 9 月）此外，在 HER 研究中，评估了 767 名 HIV 患者。 -感染者和 390 名未感染者的 HPV 6、11、16 和 18 型中一种或多种的 DNA 患病率15.9%；具体而言，6 型为 3.1%，11 型为 0.9%，16 型为 5.7%，18 型为 6.1%（HIV 阴性女性为 6.7%），因此，尽管 HIV 感染女性的患病率要高得多。与 HIV 阴性女性相比，大多数（84-89%）没有接种疫苗中所含的四种类型的 HPV 疫苗。可以减少 HPV 感染对 HIV 感染者的影响 迄今为止，尚未对 HPV 疫苗对 HIV 感染者的免疫原性和安全性进行研究。女性。 免疫原性原理 与未感染 HIV 的人相比，HIV 感染者对甲型肝炎和乙型肝炎等标准疫苗接种反应较差。研究人员分析了与反应不佳相关的患者特异性预测因子，发现 CD4+ 细胞计数较低且可检测到 HIV 病毒。在一些研究中，负荷与甲型和乙型肝炎疫苗接种反应不佳有关。在本研究中，我们将评估 GARDASIL 的免疫原性和安全性，因为这是一项人群分析，因此该研究按以下因素进行分层。 CD4+ 细胞计数和 HIV-1 RNA 病毒载量来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 = 350 个细胞/mm3 中将有相同数量的女性。 HIV-1 RNA 病毒载量 = 或 10,000 拷贝/mL 的层此方法将允许评估具有不同免疫抑制水平的女性中的疫苗免疫原性。 免疫原性将通过抗体的血清学测试来测量 疫苗接种系列后的 HPV 6、11、16 和 18 型血清学检测将由默克使用抗 HPV 6、11、16 和 18 竞争性 Luminex 免疫测定 (HPV-4 cLIA) 进行。因为这些检测对于每种 HPV 类型都是独特的，因此不同类型的检测下限以及与其他检测的比较是不合适的。血清转化被定义为抗体滴度水平高于每种 HPV 类型的截止值，经默克 (Merck) 验证。Dias 等人描述了确定血清状态截止值的方法。 还将通过评估对 HPV 疫苗接种的细胞免疫反应以及与 HPV 反应的发展和程度的相关性来测量免疫原性，测量每个 CD4+ 细胞计数层的反应将允许在各层之间进行更仔细的比较。较高的病毒载量水平与较高的病毒载量相关。 CD4+ 和 CD8+ 细胞计数激活标记物可能与较少的免疫反应相关，因此，将在该方案中定义的美国参与者子集中测量细胞免疫反应。 收集口腔 HPV 数据的基本原理 自HAART 引入以来，HPV 相关的 OW 患病率似乎有所增加，但迄今为止，OW 患病率增加与鳞状上皮中 HPV 复制增加之间的相关性尚未探讨。口腔上皮脱落与 OW 甚至鳞状细胞癌后续发展的关系尚不清楚。 因此，研究参与者将接受口腔检查，并在 OW 上收集细胞刷标本，以探索 OW 的基线患病率及其在研究期间的发展情况。此外，将在方案中定义的美国参与者子集中收集试点数据，以探索 OW 的发病情况。接种疫苗之前和之后口腔细胞和体液中 HPV 的流行情况以及疫苗对跨毒株 HPV 变异的影响（仅疫苗针对的某些 HPV 类型不是口腔中通常分离的 HPV 类型）还将测量疫苗接种前后口腔和宫颈区室脱落以及 HPV 毒株变异。