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 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. In an ongoing study at the University of Colorado Denver and The Childrens Human Immunodeficiency Program comparing immune responses to seasonal influenza vaccines in HIV-1 infected and uninfected pregnant women showed that HIV-1 infected pregnant women had significant antibody increases in response to seasonal influenza vaccines. We, therefore, surmise that HIV-1 infected pregnant women may produce specific antibodies in response to the administration of the pandemic inactivated swine-origin H1N1 influenza vaccine. However, we anticipate the antibodies will be of lower titer than uninfected non-pregnant populations. Both HIV-1 infected and pregnant women are risk factors for having lower immune defenses. The study team anticipates widespread infection with swine-origin H1N1 influenza virus during the study. Therefore, it is imperative that this study be completed as soon as possible. It is critical that this study evaluates a vaccine dose that is most likely to produce a high titer protective response in this high risk population. Since women of childbearing age have had no prior exposure to the pandemic strain of influenza it will be necessary to immunize with two doses of the vaccine. This study will assess the safety and immune response following each of the two doses of inactivated swine-origin H1N1 influenza vaccine. A higher titer dose vaccine (30mcg) will be evaluated, since the target populations are at risk for sub-optimal responses to the lower dose of vaccine. Time constraints and available subject sample size will not support a dose-ranging study. It is also likely that in this population the risk-benefit ratio supports use of the higher dose of vaccine. Data are not currently available on either dose of the inactivated swine-origin H1N1 influenza vaccine;however, in view of prior influenza vaccine studies in pregnant women suggesting lower response rates and HIV-1 infected individuals having confirmed lower responses, we feel it is justified to use the higher titer dose. If any data becomes available to indicate if a dose of 30mcg is not optimal, we will consider amending the protocol to evaluate another dose. 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.
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