Synergistic anti-HCV broadly neutralizing human monoclonal antibodies with independent mechanisms

Madeleine C. Mankowski, Valerie J. Kinchen, Lisa N. Wasilewski, Andrew I. Flyak, Stuart Campbell Ray, James E. Crowe, Justin Bailey

Research output: Contribution to journalArticle

Abstract

There is an urgent need for a vaccine to combat the hepatitis C virus (HCV) pandemic, and induction of broadly neutralizing monoclonal antibodies (bNAbs) against HCV is a major goal of vaccine development. Even within HCV genotype 1, no single bNAb effectively neutralizes all viral strains, so induction of multiple neutralizing monoclonal antibodies (NAbs) targeting distinct epitopes may be necessary for protective immunity. Therefore, identification of optimal NAb combinations and characterization of NAb interactions can guide vaccine development. We analyzed neutralization profiles of 12 human NAbs across diverse HCV strains, assigning the NAbs to two functionally distinct clusters. We then measured neutralizing breadth of 35 NAb combinations against genotype 1 isolates, with each combination including one NAb from each neutralization cluster. Many NAbs displayed complementary neutralizing breadth, forming combinations with greater neutralization across diverse strains than any individual bNAb. Remarkably, one of the most broadly neutralizing combinations of two NAbs, designated HEPC74/HEPC98, also displayed enhanced potency, with interactions matching the Bliss independence model, suggesting that these NAbs inhibit HCV infection through independent mechanisms. Subsequent experiments showed that HEPC74 primarily blocks HCV envelope protein binding to CD81, while HEPC98 primarily blocks binding to scavenger receptor B1 and heparan sulfate. Together, these data identify a critical vulnerability resulting from the reliance of HCV on multiple cell surface receptors, suggesting that vaccine induction of multiple NAbs with distinct neutralization profiles is likely to enhance the breadth and potency of the humoral immune response against HCV.

Original languageEnglish (US)
Pages (from-to)E82-E91
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number1
DOIs
StatePublished - Jan 2 2018

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Neutralizing Antibodies
Hepacivirus
Monoclonal Antibodies
Vaccines
Genotype
Viral Envelope Proteins
Virus Activation
Scavenger Receptors
Heparitin Sulfate
Cell Surface Receptors
Pandemics
Virus Diseases
Humoral Immunity
Protein Binding
Epitopes
Immunity

Keywords

  • Antagonism
  • Hepatitis C virus
  • Neutralizing antibody
  • Neutralizing breadth
  • Synergy

ASJC Scopus subject areas

  • General

Cite this

Synergistic anti-HCV broadly neutralizing human monoclonal antibodies with independent mechanisms. / Mankowski, Madeleine C.; Kinchen, Valerie J.; Wasilewski, Lisa N.; Flyak, Andrew I.; Ray, Stuart Campbell; Crowe, James E.; Bailey, Justin.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 1, 02.01.2018, p. E82-E91.

Research output: Contribution to journalArticle

Mankowski, Madeleine C. ; Kinchen, Valerie J. ; Wasilewski, Lisa N. ; Flyak, Andrew I. ; Ray, Stuart Campbell ; Crowe, James E. ; Bailey, Justin. / Synergistic anti-HCV broadly neutralizing human monoclonal antibodies with independent mechanisms. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 1. pp. E82-E91.
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