Plasma deconvolution identifies broadly neutralizing antibodies associated with hepatitis C virus clearance
Valerie J. Kinchen, Guido Massaccesi, Andrew I. Flyak, Madeleine C. Mankowski, Michelle D. Colbert, William O. Osburn, Stuart C. Ray, Andrea L. Cox, James E. Crowe Jr, Justin R. Bailey
Valerie J. Kinchen, Guido Massaccesi, Andrew I. Flyak, Madeleine C. Mankowski, Michelle D. Colbert, William O. Osburn, Stuart C. Ray, Andrea L. Cox, James E. Crowe Jr, Justin R. Bailey
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Research Article Immunology Virology

Plasma deconvolution identifies broadly neutralizing antibodies associated with hepatitis C virus clearance

Abstract

A vaccine for hepatitis C virus (HCV) is urgently needed. Development of broadly neutralizing plasma antibodies during acute infection is associated with HCV clearance, but the viral epitopes of these plasma antibodies are unknown. Identifying these epitopes could define the specificity and function of neutralizing antibodies (NAbs) that should be induced by a vaccine. Here, we present the development and application of a high-throughput method that deconvolutes polyclonal anti-HCV NAbs in plasma, delineating the epitope specificities of anti-HCV NAbs in acute-infection plasma of 44 humans with subsequent clearance or persistence of HCV. Remarkably, we identified multiple broadly neutralizing antibody combinations that were associated with greater plasma neutralizing breadth and with HCV clearance. These studies have the potential to inform new strategies for vaccine development by identifying broadly neutralizing antibody combinations in plasma associated with the natural clearance of HCV, while also providing a high-throughput assay that could identify these responses after vaccination trials.

Authors

Valerie J. Kinchen, Guido Massaccesi, Andrew I. Flyak, Madeleine C. Mankowski, Michelle D. Colbert, William O. Osburn, Stuart C. Ray, Andrea L. Cox, James E. Crowe Jr, Justin R. Bailey

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Figure 1

Deconvolution method.

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Deconvolution method. Neutralization of a panel of 19 HCVpp by 8 referen...
Neutralization of a panel of 19 HCVpp by 8 reference mAbs or 63 plasma samples was measured, generating a neutralization profile (i.e., ranking of relative neutralization of each HCVpp) for each reference mAb (“mAb rank”) and each plasma sample (“plasma rank”). Points on each graph represent the ranking of relative neutralization sensitivity of each of 19 HCVpp by plasma on the x axis and a reference mAb on the y axis. Reference mAb neutralization profiles were added in all possible proportions to generate an array of possible combined mAb neutralization profiles (“combined mAb rank”). The algorithm then identified the specific combined reference mAb neutralization profile with the minimum difference from each plasma neutralization profile, thereby delineating the most likely proportion of each reference mAb contributing to the neutralization profile of the plasma sample.