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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 摘要 感染艾滋病毒的人寿命更长，而非艾滋病定义的疾病可能会越来越多地影响这一人群。人乳头瘤病毒感染在感染艾滋病毒的妇女中更为普遍和持久，其患病率为%，而在艾滋病毒阴性的妇女中为28%。然而，在一项对146名接受HAART治疗的未接受治疗的妇女的研究中，16型和18型HPV的患病率在基线时分别为16%和11%(私人交流，Kenneth Fife，印第安纳大学医学中心，2007年9月)。此外，在HER的研究中，评估了767名艾滋病毒感染者和390名非感染者，其中一种或多种HPV 6型、11型、16型和18型的DNA流行率为15.9%；具体地说，6型为3.1%，11型为0.9%，16型为5.7%，18型为6.1%(HIV阴性妇女为6.7%)。因此，尽管艾滋病毒感染妇女的这四种类型的流行率比艾滋病毒阴性妇女高得多，但她们中的大多数(84-89%)没有疫苗中包含的类型。预防感染四种HPV疫苗可以减少HPV感染对艾滋病毒感染者的影响。到目前为止，人类乳头瘤病毒疫苗在感染艾滋病毒的成年人中的免疫原性和安全性尚未得到研究。这项研究是在成年感染艾滋病毒的女性中评估HPV疫苗的第一步。 免疫原性原理 众所周知，与未感染艾滋病毒的人相比，艾滋病毒感染者对甲型和乙型肝炎等标准疫苗系列的反应较差。研究人员分析了与不良反应相关的患者特异性预测因素，发现在一些研究中，低CD4+细胞计数和可检测到的艾滋病毒载量与甲型和乙型肝炎疫苗的不良反应有关。在本研究中，我们将评估Gardasil的免疫原性和安全性。由于这是一项人群分析，这项研究按CD4+细胞计数和HIV-1RNA病毒载量进行分层，以评估这些因素是否影响参与者产生抗体的能力。 为了解决艾滋病毒血清病毒载量对疫苗免疫原性的潜在影响，在每个CD4+细胞计数=350个细胞/毫米层中将有相等数量的女性，艾滋病毒-1RNA病毒载量=或10,000拷贝/毫升。这种方法将允许在免疫抑制程度不同的女性中评估疫苗的免疫原性。 免疫原性将通过抗体的血清学检测来衡量。 接种系列疫苗后，HPV6型、11型、16型和18型。血清学检测将由默克公司使用抗HPV 6、11、16和18竞争性Luminex免疫分析(HPV-4 CLIA)进行。这些检测的标度对每种HPV类型都是独一无二的，具有HPV类型特定的检测下限。跨类型和与其他化验方法进行比较是不合适的。默克公司证实，血清转换的定义是每种HPV类型的抗体滴度水平超过截止值。Dias等人描述了确定血清抗体界值的方法。 免疫原性也将通过评估对HPV疫苗的细胞免疫反应以及与HPV反应的发展和程度的相关性来衡量。测量每个CD4+细胞计数层的反应将允许在不同层之间进行更仔细的比较。较高的病毒载量水平与较高的CD4+和CD8+细胞计数激活标志物相关，并可能与较低的免疫反应有关。因此，细胞免疫反应将在方案中定义的美国参与者子集中进行测量。 收集口腔内HPV数据的基本原理 自从引入HAART以来，HPV相关性OW的患病率似乎有所增加。然而，到目前为止，OW的患病率增加和HPV在鳞状上皮中复制增加之间的相关性尚未被探索。此外，口腔上皮中HPV脱落对口腔癌甚至鳞状细胞癌后续发展的临床意义还知之甚少。 因此，研究参与者将接受口腔检查，并在OW上收集细胞刷子样本，以探讨OW的基线患病率及其在研究期间的发展。此外，将在该方案中定义的美国参与者子集中收集试点数据，以探索接种疫苗前后口腔细胞和液体中HPV的流行率，以及疫苗对跨株HPV变异的影响(只有一些疫苗针对的HPV类型不是通常在口腔中分离的HPV类型)。比较接种疫苗前后口腔和颈部的HPV感染情况及HPV株的变异情况。还将检测疫苗反应中产生的HPV特异性口腔粘膜抗体。

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.