CLINICAL TRIAL: IMPAACT P1086 (VS 10) A PHASE II STUDY TO ASSESS THE SAFETY AN

临床试验：IMPAACT P1086 (VS 10) 评估安全性的 II 期研究

• 批准号: 8166748
• 负责人: William Thomas Shearer
• 金额: $ 1.24万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166748
• 关键词: Adverse effects; Animal Model; Antibodies; Antibody Formation; Antiviral Agents; Biological Assay; CD4 Lymphocyte Count; Cells; Cellular Immunity; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Cytotoxic T-Lymphocytes; Data; Defect; Down-Regulation; Elements; Epidemic; Evaluation; Family suidae; Female of child bearing age; Funding; Generations; Grant; HIV; HIV Infections; HIV immunization; HIV-1; Highly Active Antiretroviral Therapy; IMPAACT; Immune System Diseases; Immune response; Immunoglobulin G; Immunologics; Individual; Infant; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Institution; Life; Lower respiratory tract structure; Lung; Mass Vaccinations; Maternal antibody; Measurable; Measurement; Measures; Memory B-Lymphocyte; Mothers; Pathogenesis; Patients; Placenta; Play; Pregnant Women; Production; Prophylactic treatment; Protocols documentation; Recovery; Research; Research Personnel; Resources; Risk; Role; ST14 gene; Safety; Seasons; Site; Social Interaction; Source; Subgroup; T-Cell Activation; T-Lymphocyte; Tetanus Toxoid; Umbilical Cord Blood; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Vertical Disease Transmission; Viral Load result; Virus; Woman; age group; clinically significant; cohort; efficacy evaluation; falls; immunogenic; influenza virus vaccine; influenzavirus; novel vaccines; pandemic disease; phase 2 study; pregnant; response; seasonal influenza

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. It is very likely that the continuing epidemic spread of H1N1 S-OIV infection in the US will greatly increase in the fall-winter season when social interactions and climactic conditions are especially conducive to spread of influenza viruses. Women of childbearing age lack antibody that will interact with the HA of the pandemic strain and neutralize it, and thus they lack measurable protection against this influenza virus. Pregnant women are at an increased risk for the complications of influenza. This risk is likely to increase for pregnant women that are also infected with HIV-1, especially if their HIV infection is poorly controlled, most feasible approach to mitigate potential complications from the pandemic strain in these women is to administer a safe and immunogenic vaccine prepared against this strain. Seasonal influenza vaccines have been efficacious in HIV-1 infected patients in the past, although they have not been sufficiently evaluated in a pregnant cohort. TIV vaccination of HIV-infected individuals before HAART has been associated with transient increases in HIV viral load in 4-18% of individuals. This may be related to T cell activation, and/or down regulation of cell-mediated immunity. Increases in HIV viral load are less common in individuals on antiretrovirals (ART), with CD4+ counts of 200-500 cells/ml at vaccination, and generally are not considered clinically significant. Other vaccines, including tetanus toxoid, reportedly have similar adverse effects in HIV-infected individuals. These effects do not constitute a contraindication to vaccination, but it is important to establish the magnitude of the problem or the lack thereof when studying immunization of HIV-infected pregnant women, because of the high association between the maternal HIV viral load and HIV vertical transmission. Safety is being evaluated prior to mass vaccination to be certain that inactivated swine-origin H1N1 influenza vaccine is safe in HIV-1 infected pregnant women. Efficacy evaluation is not a primary objective of this protocol. HAI antibody responses will be evaluated as the magnitude of these responses has been correlated (in uninfected and non-pregnant vaccines that received seasonal influenza vaccines) with protection against influenza infection and/or disease. The immunologic assessment will focus on: 1)The number of vaccines achieving a predefined protective level (1:40 in the HAI assay as established per seasonal influenza vaccine). 2)Induction of specific B and T cell-mediated immunity (CMI). 3)Persistence of these responses. Influenza-specific memory B cells are evaluated because they are key elements for antibody persistence. HIV-1 infected individuals with or without HAART tends to produce lower titers of specific antibodies in response to vaccines and also lose specific antibodies faster than HIV-1 uninfected individuals. The pathogenesis of the antibody loss is incompletely understood, but is related to a defect in the generation of memory B cells. Cell-mediated immunity is being evaluated because it may play a large role in recovery from influenza infection, and this response to a novel vaccine may be especially problematic in HIV-1 infected pregnant women. Furthermore, with a virus that may predominantly replicate in the lower respiratory tract, it is important to verify that cytotoxic T lymphocytes (CTL) are being generated by the vaccine, because animal models have clearly established an association between influenza-specific CTL and clearance of influenza viruses from the lungs. P1086 will include immunologic measurements at 3 months and 6 months (in a subgroup of subjects) after delivery, thereby providing an evaluation of the persistence of immune responses. Transplacental antibody transfer and persistence of maternal antibodies in the infant are measured at delivery (cord blood) and 3 months and 6 months, respectively. Transplacental antibody transfer may be impaired in HIV-1 infected women by low production of specific antibodies in response to the vaccine and by their high titer of nonspecific IgG, which competes for the IgG transport sites in the placenta. Hence, it is extremely important to determine the level of transplacental influenza-specific IgG transfer to the infant and persistence of this antibody during the first 6 months of life. During these first 6 months, infants cannot be vaccinated with the seasonal TIV vaccine, nor is antiviral prophylaxis generally recommended due to lack of safety data. Antiviral prophylaxis in the younger age group may be considered, however, under special circumstances. Thus, to inform this decision we will determine the extent to which infants born to HIV-1 infected mothers receive potential passive protection as a result of their mothers having been immunized with an inactivated swine-origin H1N1 influenza vaccine.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 在秋冬季节，社交互动和高潮条件特别有利于流感病毒的传播，H1N1 S-OIV感染的持续流行传播很可能会大大增加。 生育年龄的妇女缺乏与大流行应变相互作用并中和的抗体，因此她们缺乏针对这种流感病毒的可测量保护。 孕妇患流感并发症的风险增加。对于也感染了HIV-1的孕妇，这种风险可能会增加，尤其是如果她们的HIV感染受到控制不佳，最可行的方法可以减轻这些女性大流行菌株的潜在并发症，那就是给予针对这种菌株制备的安全和免疫原性疫苗。过去，季节性流感疫苗在过去的HIV-1感染患者中有效，尽管在怀孕的队列中尚未得到足够的评估。 在HAART之前，HIV感染的个体的TIV疫苗接种与4-18％的个体的HIV病毒载量增加有关。这可能与T细胞激活和/或下调细胞介导的免疫力有关。 HIV病毒载量的增加在抗逆转录病毒（ART）的个体中不太常见，疫苗接种时CD4+计数为200-500细胞/mL，通常认为临床上不显着。 据报道，包括破伤风毒素在内的其他疫苗在HIV感染的个体中也有类似的不良反应。这些作用并不构成疫苗接种的禁忌症，但是在研究感染HIV感染的孕妇免疫的问题的大小或缺乏疫苗的幅度很重要，因为孕产妇HIV病毒载量与HIV垂直传播之间存在很高的关联。 在大规模疫苗接种之前，正在评估安全性，以确保在HIV-1感染的孕妇中灭活猪原生H1N1流感疫苗是安全的。功效评估不是该协议的主要目标。 HAI抗体反应将被评估为这些反应的幅度已相关联（在接收季节性流感疫苗的未感染和非怀孕疫苗中），并保护了对流感感染和/或疾病的保护。 免疫学评估将重点关注： 1）达到预定义的保护水平的疫苗数量（在HAI测定中为1:40所确定的每个季节性流感疫苗已确定）。 2）诱导特异性B和T细胞介导的免疫（CMI）。 3）这些反应的持久性。 评估流感特定的记忆B细胞是因为它们是抗体持久性的关键要素。 HIV-1感染有或没有HAART的个体倾向于对疫苗产生较低的特定抗体滴度，并且比HIV-1未感染的个体更快地失去特定抗体。抗体损失的发病机理尚不完全理解，但与记忆B细胞的产生缺陷有关。正在评估细胞介导的免疫力，因为它可能在从流感感染中恢复中起着很大作用，而这种对新型疫苗的反应在HIV-1感染的孕妇中可能尤其有问题。此外，由于病毒可能主要在下呼吸道中复制，因此必须验证细胞毒性T淋巴细胞（CTL）是由疫苗产生的，因为动物模型清楚地确定了流感特异性的CTL和来自Lungs流感的CTL之间的关联。 P1086将在分娩后3个月零6个月（在受试者的亚组中）进行免疫测量，从而评估免疫反应的持续性。 分别在分娩时（脐带血）和3个月零6个月测量婴儿母体抗体的移植抗体转移和持久性。在HIV-1感染的女性中，通过对疫苗的响应及其非特异性IgG的高滴度，可能会损害HIV-1感染的女性的移植抗体转移，该抗体的高滴度与胎盘中的IgG运输部位竞争。因此，确定在生命的前6个月中，确定移植型流感特异性IgG转移到婴儿的持久性和持久性非常重要。在最初的六个月中，婴儿无法接种季节性TIV疫苗，由于缺乏安全性数据，通常不建议使用抗病毒预防。但是，在特殊情况下，可以考虑年轻年龄段的抗病毒预防。因此，为了告知这一决定，我们将确定HIV-1感染母亲出生的婴儿在多大程度上因母亲被灭活的猪原生H1N1流感疫苗免疫而受到了潜在的被动保护。