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

点击翻译按钮获取中文摘要

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.