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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在社会互动和气候条件特别有利于流感病毒传播的秋冬季，美国甲型H1N1 S OIV感染的持续疫情传播极有可能大幅增加。育龄妇女缺乏与大流行毒株的HA相互作用并中和它的抗体，因此她们缺乏对这种流感病毒的可衡量的保护。 孕妇患流感并发症的风险增加。对于同时感染艾滋病毒-1的孕妇来说，这种风险可能会增加，特别是如果她们的艾滋病毒感染控制不佳，减少这些妇女因大流行毒株而可能出现的并发症的最可行的方法是接种针对这种毒株制备的安全和免疫原性疫苗。季节性流感疫苗过去对感染HIV-1的患者有效，尽管它们在怀孕队列中没有得到充分的评估。 在HAART之前接种艾滋病毒感染者的TIV疫苗与4-18%的艾滋病毒病毒载量的一过性增加有关。这可能与T细胞活化和/或细胞免疫功能下调有关。在服用抗逆转录病毒药物(ART)的个体中，HIV病毒载量的增加不太常见，接种时CD4+计数为200-500个/毫升，通常被认为没有临床意义。据报道，包括破伤风类毒素在内的其他疫苗对艾滋病毒感染者也有类似的不良反应。这些影响并不构成接种疫苗的禁忌，但在研究感染艾滋病毒的孕妇的免疫接种时，重要的是确定问题的严重性或缺乏问题，因为产妇艾滋病毒病毒载量与艾滋病毒垂直传播之间存在高度关联。 在大规模接种疫苗之前，正在对安全性进行评估，以确保灭活猪源H1N1流感疫苗对感染HIV-1的孕妇是安全的。疗效评估不是该方案的主要目标。将评估HAI抗体反应的大小，因为这些反应的大小(在接种季节性流感疫苗的未感染和非怀孕疫苗中)与对流感感染和/或疾病的保护相关。 免疫学评估将重点放在： 1)达到预定保护水平的疫苗数量(根据季节性流感疫苗确定的HAI检测为1：40)。 2)诱导特异性B、T细胞免疫(CMI)。 3)这些反应的持久性。 对流感特异性记忆B细胞进行评估是因为它们是抗体持久性的关键因素。有或没有HAART的HIV-1感染者对疫苗的反应往往产生较低滴度的特定抗体，并且比未感染HIV-1的人损失特定抗体的速度更快。抗体丢失的发病机制尚不完全清楚，但与记忆B细胞的生成缺陷有关。正在对细胞免疫进行评估，因为它可能在流感感染的康复过程中发挥重要作用，而这种对新型疫苗的反应可能在感染艾滋病毒-1的孕妇中尤其成问题。此外，对于一种可能主要在下呼吸道复制的病毒，重要的是验证疫苗是否产生了细胞毒性T淋巴细胞(CTL)，因为动物模型已经明确地建立了流感特异性CTL与流感病毒从肺部清除之间的关联。P1086将包括分娩后3个月和6个月(受试者的子组)的免疫学测量，从而提供对免疫反应持久性的评估。 分别在分娩时(脐带血)、3个月和6个月时测量婴儿的胎盘抗体转移率和母体抗体的持久性。在感染HIV-1的妇女中，通过胎盘的抗体转移可能受到损害，原因是疫苗反应中产生的特异性抗体较少，以及她们高滴度的非特异性抗体竞争胎盘中的抗体转运部位。因此，确定经胎盘向婴儿传递流感特异性免疫球蛋白的水平以及该抗体在婴儿出生后6个月内的持久性是极其重要的。在前6个月，婴儿不能接种季节性TIV疫苗，由于缺乏安全数据，通常也不建议进行抗病毒预防。然而，在特殊情况下，可以考虑在较年轻的人群中进行抗病毒预防。因此，为了向这一决定提供信息，我们将确定感染艾滋病毒-1的母亲所生婴儿因其母亲接种了灭活猪源H1N1流感疫苗而获得潜在被动保护的程度。

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.