CLINICAL TRIAL: IMPAACT P1088 (VERSION 10) A PHASE II STUDY TO ASSESS THE SAFET

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。 很有可能，2009年甲型H1N1流感在美国的持续疫情传播将在秋冬季节大幅增加，届时社会互动和气候条件变得更加有利于流感病毒的传播。虽然到目前为止的报告表明，健康的人通常患有轻微的疾病，但包括免疫缺陷在内的潜在医疗状况似乎增加了患严重疾病甚至死于甲型H1N1大流行的风险。因此，了解诺华A/H1N1 S OIV疫苗在感染艾滋病毒的儿童和青年中的安全性和免疫原性对于满足这一弱势群体的卫生保健需求至关重要。 由于季节性流感已被证明与年龄匹配的非感染者相比，在艾滋病毒感染者中会导致更严重的疾病，因此2009年甲型H1N1流感很可能会导致艾滋病毒感染者的显著发病率和可能的死亡率。发病率可能是流感病毒的直接结果，或者感染可能导致继发性细菌感染或患者S抗逆转录病毒治疗的依从性下降，原因是大流行性H1N1疾病可能会出现严重的恶心和呕吐。在这一人群中预防感染将是至关重要的。 众所周知，季节性流感感染会先影响社区中的儿童，然后才会在成人中传播。年轻人对疾病的易感性在2009年甲型H1N1流感中显得更加明显，因为三分之一的老年人有可测量的血清HAI或2009年甲型H1N1流感的中和抗体水平，而年轻人和儿童完全缺乏保护性效价。血清学数据与观察到的情况一致，即病毒的发病率和疾病严重程度在年龄较小的人群中似乎要高得多，这些人群相对受到50岁的保护。 目前正在努力评估2009年甲型H1N1流感疫苗在健康儿童中的应用。然而，感染艾滋病毒-1的儿童上学并参加所有活动，这些活动通常会使儿童面临感染流感的高风险。要保护感染艾滋病毒-1的儿童和青年免受2009年甲型H1N1流感的侵袭，需要了解这些新产品在这一人群中的安全性和免疫原性。 这项研究将评估两剂诺华A/H1N1 S OIV疫苗在美国和波多黎各感染艾滋病毒-1的儿童和青年中的安全性和免疫应答。由于研究对象之前从未接触过2009年甲型H1N1流感，因此被认为需要两剂疫苗。由于季节性流感疫苗通常会导致HIV-1感染者迟钝的反应，我们选择了更高剂量的抗原，30mcg，而不是目前正在进行的诺华A/H1N1 S-OIV疫苗在健康儿童中的试验中研究的15mcg剂量。我们还选择了根据年龄将我们的研究人群分为三组。选择这些小组是为了提供所有年龄段的信息，并知道没有足够的能力来比较不同年龄段的免疫反应。这项研究仅限于围产期感染HIV-1的儿童和青少年。 为了了解疾病和保护的机制，我们将调查该人群接种疫苗后的血清应答、应答持续时间和流感样疾病的发展情况。我们还建议研究疫苗的细胞介导性应答。针对2009年甲型H1N1流感病毒的细胞毒性T淋巴细胞(CTL)的产生尤其令人感兴趣，因为这种病毒在肺组织中的复制比季节性流感更好，而且CTL是病毒在肺部清除的主要媒介。对2009年甲型H1N1流感病毒的记忆B细胞将确保宿主对暴露于野生型病毒的充分反应。 总而言之，如果在感染蔓延之前没有有效的疫苗，2009年甲型H1N1流感很可能会感染相当大比例的艾滋病毒感染儿童和青少年。感染可能会在这一脆弱人群中导致严重疾病，因此，疫苗努力至关重要。必须在感染艾滋病毒-1的儿童中确定2009年甲型H1N1流感候选疫苗的免疫原性，以确保这一人群得到保护。缺乏保护性免疫反应将支持采取额外措施保护这一高危人群的必要性。 猪源H1N1流感灭活疫苗用于围产期感染HIV的儿童和青少年是安全有效的潜在疫苗，可预防或减轻H1N1流感的影响

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 2009 influenza A (H1N1) infection in the US will greatly increase in the fall-winter season when social interactions and climactic conditions become even more conducive to spread of influenza viruses. While reports to date suggest that healthy individuals typically have a mild illness, underlying medical conditions including immunodeficiency appear to increase risk for severe disease and even death with pandemic H1N1. Thus, knowledge of the safety and immunogenicity of the Novartis A/H1N1 S-OIV vaccine in HIV-infected children and youth is critically important to address the health care needs of this vulnerable population. Because seasonal influenza has been shown to cause more severe illness in HIV-infected individuals compared to that typical of age-matched uninfected people, it is likely that 2009 Influenza A (H1N1) will result in significant morbidity and possibly mortality in HIV infected individuals. Morbidity may be a direct result of the influenza virus or infection may result in secondary bacterial infections or decreased adherence to the patient s antiretroviral therapy due to the severe nausea and vomiting that may occur with pandemic H1N1 illness. Prevention of infection in this population will be critical. It is well established that seasonal influenza infection impacts children in a community before becoming widespread in adult populations. Susceptibility to disease among young populations appears even more pronounced with 2009 Influenza A (H1N1) as one third of older adults have measurable levels of serum HAI or neutralizing antibody against the 2009 Influenza A (H1N1) while young adults and children completely lack protective titers. The serologic data is consistent with the observation that the attack rate and disease severity for the virus appears to be much higher in younger populations with relative protection of those >50 years of age. Efforts are currently underway to evaluate 2009 Influenza A (H1N1) vaccine in healthy children. However, HIV-1 infected children attend schools and participate in all the activities that typically put children at such high risk for infection with influenza. Protection of HIV-1 infected children and youth from 2009 Influenza A (H1N1) will require knowledge of safety and immunogenicity of these new products in this population. This study will assess the safety and immune response following each of the two doses of Novartis A/H1N1 S-OIV vaccine in HIV-1 infected children and youth in the US and Puerto Rico. Two doses are thought to be required because study subjects have had no prior exposure to 2009 Influenza A (H1N1). Because seasonal influenza vaccine often results in blunted response in HIV-1 infected persons, we have opted to investigate the higher dose of antigen, 30mcg, in comparison to the 15mcg dose that is currently being studied in ongoing trials of the Novartis A/H1N1 S-OIV vaccine in healthy children. We have also opted to stratify our study population into 3 groups based on age. The groups were selected to provide information across all age groups and with knowledge that there would be insufficient power to compare immune response across age groups. This study is limited to HIV-1 perinatally infected children and youth. In order to understand the mechanism of disease and protection, we will investigate the seroresponse, duration of response, and development of influenza-like illness following vaccine in this population. We also propose investigation of the cell-mediated response to vaccine. The generation of cytotoxic T lymphocyte (CTL) responses against 2009 Influenza A (H1N1) is of particular interest, because this virus replicates better in lung tissue than seasonal influenza and CTLs are the major mediator of viral clearance in the lungs. Memory B cells to 2009 Influenza A (H1N1) will ensure that the host responds adequately to exposure to the wild type virus. In summary, 2009 Influenza A (H1N1) is likely to infect a significant proportion of HIV-1 infected children and youth if an effective vaccine is not available before infection is widespread. Infection will likely lead to severe disease in this vulnerable population, therefore, vaccine efforts are critical. Immunogenicity of the candidate 2009 Influenza A (H1N1) vaccine must be established in HIV-1 infected children in order to assure that this population is protected. Lack of a protective immune response would support the need for additional measures to protect this high risk population. The Inactivated Swine-Origin H1N1 Influenza Vaccine is safe and effective as a potential vaccine to prevent or lessen the effects of H1N1 influenza when administered to HIV Perinatally Infected Children and Youth