Browsing by Author "Hjelle, Brian"
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Publication A non-randomized multicentre trial of human immune plasma for treatment of hantavirus cardiopulmonary syndrome caused by Andes virus(International Medical Press, 2015) Vial, Pablo; Valdivieso, Francisca; Calvo, Mario; Rioseco, María; Riquelme, Raúl; Araneda, Andrés; Tomicic, Vinko; Graf, Jerónimo; Paredes, Laura; Fiorenzano, Matías; Bidart, Teresa; Cuiza, Analía; Marco, Claudia; Hjelle, Brian; Ye, Chunyan; Hanfelt-Goade, Daniel; Vial, Cecilia; Rivera, Juan; Mertz, Gregory; Hantavirus Study Group in Chile; Delgado, IrisBACKGROUND: In Chile, Andes virus (ANDV) is the sole aetiological agent of hantavirus cardiopulmonary syndrome (HCPS) with mean annual incidence of 55 cases, 32% case fatality rate (CFR) and no specific treatment. Neutralizing antibody (NAb) titres at hospital admission correlate inversely with HCPS severity. We designed an open trial to explore safety and efficacy and evaluate pharmacokinetics of immune plasma as a treatment strategy for this disease. METHODS: We performed plasmapheresis on donors at least 6 months after HCPS and measured NAb titres through a focus-reduction neutralization test. Subjects admitted to 10 study sites with suspected/confirmed HCPS were eligible for treatment with immune plasma by intravenous infusion at an ANDV NAb dose of 5,000 U/kg. HCPS was confirmed through immunoglobulin M serology or reverse transcriptase-PCR. The main outcome was mortality within 30 days. RESULTS: From 2008-2012, we enrolled and treated 32 cases and confirmed HCPS in 29. CFR of hantavirus plasma-treated cases was 4/29 (14%); CFR of non-treated cases in the same period in Chile was 63/199 (32%; P=0.049, OR=0.35, CI=0.12, 0.99); CFR of non-treated cases at the same study sites between 2005-2012 was 18/66 (27%; (P=0.15, OR=0.43, CI=0.14, 1.34) and CFR in a previous methylprednisolone treatment study was 20/60 (33%; P=0.052, OR=0.32, CI=0.10, 1.00). We detected no serious adverse events associated to plasma infusion. Plasma NAb titres reached in recipients were variable and viral load remained stable. CONCLUSIONS: Human ANDV immune plasma infusion appears safe for HCPS. We observed a decrease in CFR in treated cases with borderline significance that will require further studies for confirmation.Item Highly Differentiated, Resting Gn-Specific Memory CD8+ T Cells Persist Years after Infection by Andes Hantavirus(2010) Manigold, Tobias; Mori, Andres; Graumann, Rebecca; Llop, Elena; Simon, Valeska; Ferres, Marcela; Valdivieso, Francisca; Castillo, Constanza; Hjelle, Brian; Vial, PabloIn man, infection with South American Andes virus (ANDV) causes hantavirus cardiopulmonary syndrome (HCPS). HCPS due to ANDV is endemic in Southern Chile and much of Argentina and increasing numbers of cases are reported all over South America. A case-fatality rate of about 36% together with the absence of successful antiviral therapies urge the development of a vaccine. Although T-cell responses were shown to be critically involved in immunity to hantaviruses in mouse models, no data are available on the magnitude, specificity and longevity of ANDV-specific memory T-cell responses in patients. Using sets of overlapping peptides in IFN-c ELISPOT assays, we herein show in 78 Chilean convalescent patients that Gnderived epitopes were immunodominant as compared to those from the N- and Gc-proteins. Furthermore, while the relative contribution of the N-specific response significantly declined over time, Gn-specific responses remained readily detectable ex vivo up to 13 years after the acute infection. Tetramer analysis further showed that up to 16.8% of all circulating CD3+ CD8+ T cells were specific for the single HLA-B*3501-restricted epitope Gn465–473 years after the acute infection. Remarkably, Gn465–473–specific cells readily secreted IFN-c, granzyme B and TNF-a but not IL-2 upon stimulation and showed a ‘revertant’ CD45RA+ CD272CD282CCR72CD1272 effector memory phenotype, thereby resembling a phenotype seen in other latent virus infections. Most intriguingly, titers of neutralizing antibodies increased over time in 10/17 individuals months to years after the acute infection and independently of whether they were residents of endemic areas or not. Thus, our data suggest intrinsic, latent antigenic stimulation of Gn-specific T-cells. However, it remains a major task for future studies to proof this hypothesis by determination of viral antigen in convalescent patients. Furthermore, it remains to be seen whether Gn-specific T cells are critical for viral control and protective immunity. If so, Gn-derived immunodominant epitopes could be of high value for future ANDV vaccinesItem Neutralizing antibodies in survivors of Sin Nombre and Andes hantavirus infection(Centers for Disease Control and Prevention, 2006) Valdivieso, Francisca; Vial, Pablo; Ferres, Marcela; Ye, Chunyan; Goade, Diane; Cuiza, Analía; Hjelle, BrianWe evaluated titers of homotypic and heterotypic neutralizing antibodies (NAbs) to Andes and Sin Nombre hantaviruses in plasma samples from 20 patients from Chile and the United States. All but 1 patient had high titers of NAb. None of the plasma samples showed high titers against the heterologous virus.