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Can Broadly Neutralizing Monoclonal Antibodies Lead to a Hepatitis C Virus Vaccine?

ABSTRACT: While licensed vaccines elicit protective antibody responses against a variety of viral infections, an effective vaccine for hepatitis C virus (HCV) has remained elusive. The extraordinary genetic diversity of HCV and the ability of the virus to evade the immune response have hindered vaccine development efforts. However, recent studies have greatly expanded the number of well characterized broadly neutralizing human monoclonal antibodies (bNAbs) against HCV. These bNAbs target relatively conserved HCV epitopes, prevent HCV infection in animal models, and are associated with spontaneous clearance of human HCV infection. In this review, recent high-resolution bNAb epitope mapping and structural analysis of bNAb-epitope complexes that may serve as a guide for vaccine development are discussed along with major obstacles.

SUBMITTER: Kinchen VJ

PROVIDER: S-EPMC6421862 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Can Broadly Neutralizing Monoclonal Antibodies Lead to a Hepatitis C Virus Vaccine?

Kinchen Valerie J VJ Cox Andrea L AL Bailey Justin R JR

Trends in microbiology 20180424 10

While licensed vaccines elicit protective antibody responses against a variety of viral infections, an effective vaccine for hepatitis C virus (HCV) has remained elusive. The extraordinary genetic diversity of HCV and the ability of the virus to evade the immune response have hindered vaccine development efforts. However, recent studies have greatly expanded the number of well characterized broadly neutralizing human monoclonal antibodies (bNAbs) against HCV. These bNAbs target relatively conser ...[more]

PMID: 29703495

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Project description:IntroductionThe last 12 years have seen remarkable progress in the isolation and characterization of at least five different epitope classes of HIV-specific broadly neutralizing antibodies (bnAbs). Detailed analyses of these bnAb lineages, maturation pathways and epitopes have created new opportunities for vaccine development. In addition, interest exists in passive administration of monoclonal antibodies as a viable option for HIV prevention.DiscussionRecently, two antibody-mediated prevention (AMP) trials of a passively administered monoclonal antibody targeting the HIV envelope CD4 binding site, called VRC01, provided proof-of-concept that monoclonal antibody infusion could offer protection against HIV acquisition. While the trials failed to show overall protection against HIV acquisition, sub-analyses revealed that VRC01 infusion provided a 75% prevention efficacy against HIV strains that were susceptible to the antibody. The study also demonstrated that in vitro neutralizing activity, measured by the TZM-bl/pseudovirus assay, was able to predict HIV prevention efficacy in humans. In addition, the AMP trials defined a threshold protective concentration, or neutralization titer, for the VRC01 class of bnAbs, explaining the observed low overall efficacy and serving as a benchmark for the clinical testing of new bnAbs, bnAb cocktails and neutralizing antibody-inducing vaccines. Newer bnAbs that exhibit greater potency and breadth of neutralization in vitro than VRC01 are available for clinical testing. Combinations of best-in-class bnAbs with complementary magnitude, breadth and extent of complete neutralization are predicted to far exceed the prevention efficacy of VRC01. Some engineered bi- and trispecific mAbs exhibit similar desirable neutralizing activity and afford advantages for manufacturing and delivery. Modifications that prolong the serum half-life and improve genital tissue persistence offer additional advantages.ConclusionsIterative phase 1 trials are acquiring safety and pharmacokinetic data on dual and triple bnAbs and bi- and trispecific antibodies in preparation for future AMP studies that seek to translate findings from the VRC01 efficacy trials and achieve acceptable levels of overall prevention efficacy.

Project description:Hepatitis C virus (HCV) infection is a global health problem, with millions of chronically infected individuals at risk for cirrhosis and hepatocellular carcinoma. HCV vaccine development is vital in the effort toward disease control and eradication, an undertaking aided by an increased understanding of the mechanisms of resistance to broadly neutralizing antibodies (bNAbs). In this study, we identified HCV codons that vary deep in a phylogenetic tree of HCV sequences and showed that a polymorphism at one of these positions renders Bole1a, a computationally derived, ancestral genotype 1a HCV strain, resistant to neutralization by both polyclonal-HCV-infected plasma and multiple broadly neutralizing monoclonal antibodies with unique binding epitopes. This bNAb resistance mutation reduces replicative fitness, which may explain the persistence of both neutralization-sensitive and neutralization-resistant variants in circulating viral strains. This work identifies an important determinant of bNAb resistance in an ancestral, representative HCV genome, which may inform HCV vaccine development.Worldwide, more than 170 million people are infected with hepatitis C virus (HCV), the leading cause of hepatocellular carcinoma and liver transplantation in the United States. Despite recent significant advances in HCV treatment, a vaccine is needed. Control of the HCV pandemic with drug treatment alone is likely to fail due to limited access to treatment, reinfections in high-risk individuals, and the potential for resistance to direct-acting antivirals (DAAs). Broadly neutralizing antibodies (bNAbs) block infection by diverse HCV variants and therefore serve as a useful guide for vaccine development, but our understanding of resistance to bNAbs is incomplete. In this report, we identify a viral polymorphism conferring resistance to neutralization by both polyclonal plasma and broadly neutralizing monoclonal antibodies, which may inform HCV vaccine development.

Dataset Information

Can Broadly Neutralizing Monoclonal Antibodies Lead to a Hepatitis C Virus Vaccine?

Publications

Can Broadly Neutralizing Monoclonal Antibodies Lead to a Hepatitis C Virus Vaccine?

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