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Analytical Advances in the Ex Vivo Challenge Efficacy Assay.

ABSTRACT: The ex vivo challenge assay is being increasingly used as an efficacy endpoint during early human clinical trials of HIV prevention treatments. There is no standard methodology for the ex vivo challenge assay, although the use of different data collection methods and analytical parameters may impact results and reduce the comparability of findings between trials. In this analysis, we describe the impact of data imputation methods, kit type, testing schedule and tissue type on variability, statistical power, and ex vivo HIV growth kinetics. Data were p24 antigen (pg/ml) measurements collected from clinical trials of candidate microbicides where rectal (n?=?502), cervical (n?=?88), and vaginal (n?=?110) tissues were challenged with HIV-1_BaL ex vivo. Imputation of missing data using a nonlinear mixed effect model was found to provide an improved fit compared to imputation using half the limit of detection. The rectal virus growth period was found to be earlier and of a relatively shorter duration than the growth period for cervical and vaginal tissue types. On average, only four rectal tissue challenge assays in each treatment and control group would be needed to find a one log difference in p24 to be significant (alpha?=?0.05), but a larger sample size was predicted to be needed for either cervical (n?=?21) or vaginal (n?=?10) tissue comparisons. Overall, the results indicated that improvements could be made in the design and analysis of the ex vivo challenge assay to provide a more standardized and powerful assay to compare efficacy of microbicide products.

SUBMITTER: Richardson-Harman N

PROVIDER: S-EPMC5372762 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Analytical Advances in the Ex Vivo Challenge Efficacy Assay.

Richardson-Harman Nicola N Parody Robert R Anton Peter P McGowan Ian I Doncel Gustavo G Thurman Andrea Ries AR Herrera Carolina C Kordy Kattayoun K Fox Julie J Tanner Karen K Swartz Glenn G Dezzutti Charlene S CS

AIDS research and human retroviruses 20161216 4

The ex vivo challenge assay is being increasingly used as an efficacy endpoint during early human clinical trials of HIV prevention treatments. There is no standard methodology for the ex vivo challenge assay, although the use of different data collection methods and analytical parameters may impact results and reduce the comparability of findings between trials. In this analysis, we describe the impact of data imputation methods, kit type, testing schedule and tissue type on variability, statis ...[more]

PMID: 27841671

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Project description:BACKGROUND:Eosinophils are immunomodulatory leucocytes that contribute to the pathogenesis of Th2-driven asthma and allergic lung diseases. OBJECTIVE:Our goal was to identify unique properties of eosinophils recruited to the lungs and airways of mice in response to challenge with asthma-associated fungal allergens. METHODS:Mice were challenged intranasally on days 0, 3 and 6 with a filtrate of Alternaria alternata. Recruited eosinophils were enumerated in bronchoalveolar lavage fluid. Eosinophils were also isolated from lungs of mice sensitized and challenged with Aspergillus fumigatus and evaluated ex vivo in tissue culture. RESULTS:Eosinophils persist in the airways for several weeks in response to brief provocation with A. alternata in wild-type, Gm-csf- and eotaxin-1-gene-deleted mice, while eosinophils are recruited but do not persist in the absence of IL-13. Eosinophils isolated from the lungs A. alternata-challenged mice are cytokine-enriched compared to those from IL5tg mice, including 800-fold higher levels of eotaxin-1. Furthermore, eosinophils from the lungs and spleen of fungal allergen-challenged wild-type mice are capable of prolonged survival ex vivo, in contrast to eosinophils from both untreated and fungal allergen-challenged IL5tg mice, which undergo rapid demise in the absence of exogenous cytokine support. TNF-? (but not IL5, IL-3, eotaxin-1 or GM-CSF) was detected in supernatants of ex vivo eosinophil cultures from the lungs of fungal allergen-challenged wild-type mice. However, neither TNF-? gene deletion nor anti-TNF-? neutralizing antibodies had any impact sustained eosinophil survival ex vivo. CONCLUSION AND CLINICAL RELEVANCE:Eosinophils are phenotypically and functionally heterogeneous. As shown here, eosinophils from fungal allergen-challenged wild-type mice maintain a distinct cytokine profile, and, unlike eosinophils isolated from IL5tg mice, they survive ex vivo in the absence of exogenous pro-survival cytokine support. As treatments for asthma currently in development focus on limiting eosinophil viability via strategic cytokine blockade, the molecular mechanisms underlying differential survival merit further investigation.

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Analytical Advances in the Ex Vivo Challenge Efficacy Assay.

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Analytical Advances in the Ex Vivo Challenge Efficacy Assay.

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