Patients with chemotherapy-induced granulocytopenia for neoplastic diseases and those receiving cyclosporin A plus corticosteroids for prevention and treatment of organ transplant rejection are two immunologically distinct patient populations with high risks for development of invasive pulmonary aspergillosis. In order to compare the pathogenesis of aspergillosis in these two high-risk populations and to further characterize the role of cyclosporin A in development of pulmonary aspergillosis, we studied the patterns of infection and inflammation in two clinically applicable rabbit models of invasive pulmonary aspergillosis. There were striking differences in the patterns of infection and inflammation of invasive pulmonary aspergillosis according to the type of underlying immune defect. Among rabbits challenged with the same intratracheal inoculum, there was a 100% mortality for invasive pulmonary aspergillosis in profoundly granulocytopenic rabbits in comparison with a 100% mortality for invasive pulmonary aspergillosis in profoundly granulocytopenic rabbits in comparison with a 100% survival in rabbits immunosuppressed with cyclosporin A plus methylprednisolone (CsA+MP). Lesions of pulmonary aspergillosis in granulocytopenic rabbits consisted predominantly of coagulative necrosis, intraalveolar hemorrhage, and scant mononuclear inflammatory infiltrate. By comparison, pulmonary foci in rabbits immunosuppressed by CsA+MP consisted mainly of neutrophilic and monocytic infiltrates, inflammatory necrosis, and scant intraalveolar hemorrhage. There was extensive infiltration by hyphae with angioinvasion in granulocytopenic rabbits, whereas conidia in various stages of germination predominated in CsA+MP treated animals in which there was a paucity of hyphae or angioinvasion. Extrapulmonary disease predominated in granulocytopenic rabbits. Methylprednisolone was the major immunosuppressive drug in rabbits treated with CsA+MP. Cyclosporin A alone did not increase the progression of pulmonary aspergillosis and did so only when used chronically with methylprednisolone.

Virus-like particles (VLPs) can be rapidly developed from influenza virus genetic sequences in order to supply vaccine after the onset of a pandemic. The safety and immunogenicity of one or two doses of a recombinant A (H1N1) 2009 influenza VLP vaccine was evaluated in a two-stage, Phase 2, randomized, double-blind, placebo-controlled study conducted in 4563 healthy adults, 18-64 years of age, during the H1N1 2009 pandemic in Mexico. In Part A, 1013 subjects were randomized into four treatment groups (5 μg, 15 μg, or 45 μg hemagglutinin [HA] VLP vaccine or placebo) and vaccinated 21 days apart, with sera collected on Days 1, 14 and 36 for hemagglutination inhibition (HAI) testing. After review of safety and immunogenicity data from Part A, additional subjects were immunized with a single dose of 15 μg VLP vaccine (N=2537) or placebo (N=1011) and assessed for safety in Part B. Results showed the H1N1 2009 VLP vaccine was safe and well-tolerated. Systemic solicited events were similar between placebo and VLP vaccinated groups with no vaccine-related serious adverse events. Dose response trends for solicited local adverse events were observed, with higher incidences of local pain, swelling, tenderness, and redness reported in the higher VLP dose groups (15 μg and 45 μg) compared to the placebo and 5 μg VLP groups following both vaccinations. Although the majority of local AEs were mild in severity, a dose trend in events of moderate or greater severity was also noted for these solicited events. The VLP vaccine groups demonstrated robust HAI immune responses after a single vaccination, with high rates of seroprotection (≥ 40 HAI titer) in 82-92% of all subjects and in 64-85% of subjects who were seronegative at the time of immunization. HAI geometric mean titers (GMTs), geometric mean ratios (GMRs) and seroconversion rates were also all statistically higher in the VLP groups compared to placebo for both post-baseline time points. Based on these data, additional clinical trials are in development to evaluate influenza vaccine candidate antigens manufactured using Spodoptera frugiperda (Sf9)/baculovirus-based VLP technology.

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HIV-infected children (n = 243), ≥5 to <18 years old, receiving stable antiretroviral therapy, were stratified by immunologic status and randomly assigned to receive intranasal live attenuated

We investigated the safety and efficacy of amphotericin B colloidal dispersion (ABCD) for the treatment of invasive pulmonary aspergillosis in persistently granulocytopenic rabbits. Treatment groups included ABCD in dosages of 1, 5, and 10 mg/kg/day intravenously or conventional desoxycholate amphotericin B (DAmB) at 1 mg/kg/day intravenously. Antifungal activity was directly related to increasing dosage of ABCD as determined by the concentration ofAspergillusfumigatus organisms in lungs and the frequency of hemorrhagic pulmonary lesions. At 5 and 10 mg/kg/day, there was a significant reduction in the tissue burden of A. fumigatus as measured by percent culture-positive lobes and CFU per gram of tissue (P c 0.001), whereas at 1 mg/kg/day the tissue burden ofA.fimigatus was not significantly different from that in untreated controls. Microbiological clearance was significantly greater at 1 mg of DAmB per kg per day than at 1 mg of ABCD per kg per day (P c 0.001). There was no difference in microbiological clearance of bronchoalveolar lavage fluid among the treatment groups as measured by CFU per milliliter. As determined by survival, ABCD at 5.0 mg/kg/day was more effective than DAmB at 1.0 mg/kg/day and ABCD at 10 mg/kg/day. ABCD at 10 mg/kg/day was more nephrotoxic than the lower dosages of ABCD and resulted in higher mortality. Impairment of glomerular filtration developed as a direct function increasing the ABCD dosage (r = 0.77; P < 0.001). In summary, this study found dose-dependent antifungal activity and nephrotoxicity of ABCD against invasive pulmonary aspergillosis in persistently granulocytopenic rabbits and showed that the optimal dosage of ABCD for antifungal activity and safety was 5 mg/kg/day.