Plasma deconvolution identifies broadly neutralizing antibodies associated with hepatitis C virus clearance
Valerie J. Kinchen, … , James E. Crowe Jr, Justin R. Bailey
Valerie J. Kinchen, … , James E. Crowe Jr, Justin R. Bailey
Published August 13, 2019
Citation Information: J Clin Invest. 2019;129(11):4786-4796. https://doi.org/10.1172/JCI130720.
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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 6

Deconvolution of NAbs in plasma of subjects with subsequent clearance or persistence of HCV infection.

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Deconvolution of NAbs in plasma of subjects with subsequent clearance or...
Reference mAbs are on the x axis with plasma samples on the y axis. Each plasma sample is from a different subject. Plasma neutralization profiles each were averaged from 2 independent experiments. Reference mAb profiles were averaged from 5 independent experiments. Values shown are the proportion of each plasma neutralizing response attributed to each reference mAb. Proportions greater than 0.1 are shown and marked with different colors for each NAb type, with higher values shaded darker. Plasma samples are grouped by subject outcome. Neutralizing breadth was calculated as the number out of 19 HCVpp neutralized greater than 50% by a 1:100 dilution of plasma. P values are for the Pearson correlation between the plasma sample neutralization profile and the best-fit combined reference mAb neutralization profile. Only subjects with significant correlation (P < 0.05) between combined mAb neutralization profile and plasma neutralization profile are shown (persistence n = 29, clearance n = 15). Results for subjects with a poor deconvolution fit are shown in Supplemental Figure 4.