scholarly journals Rational design of hepatitis C virus E2 core nanoparticle vaccines

2019 ◽  
Author(s):  
Linling He ◽  
Netanel Tzarum ◽  
Xiaohe Lin ◽  
Benjamin Shapero ◽  
Cindy Sou ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Vaccine Development ◽  
Variable Region ◽  
High Yield ◽  
Vaccine Strategy ◽  
Neutralizing Epitopes

ABSTRACTHepatitis C virus (HCV) envelope glycoproteins E1 and E2 are critical for cell entry with E2 being the major target of neutralizing antibodies (NAbs). Here, we present a comprehensive strategy for B cell-based HCV vaccine development through E2 optimization and nanoparticle display. We redesigned variable region 2 in a truncated form (tVR2) on E2 cores derived from genotypes 1a and 6a, resulting in improved stability and antigenicity. Crystal structures of three optimized E2 cores with human cross-genotype NAbs (AR3s) revealed how the modified tVR2 stabilizes E2 without altering key neutralizing epitopes. We then displayed these E2 cores on 24- and 60-meric nanoparticles and achieved high yield, high purity, and enhanced antigenicity. In mice, these nanoparticles elicited more effective NAb responses than soluble E2 cores. Next-generation sequencing (NGS) defined distinct B-cell patterns associated with nanoparticle-induced antibody responses, which cross-neutralized HCV by targeting the conserved neutralizing epitopes on E2.One Sentence SummaryAn HCV vaccine strategy is presented that displays redesigned E2 cores on nanoparticles as vaccine candidates for eliciting a broadly neutralizing B-cell response.

scholarly journals Proof of concept for rational design of hepatitis C virus E2 core nanoparticle vaccines

2020 ◽  
Vol 6 (16) ◽  
pp. eaaz6225 ◽  
Author(s):  
Linling He ◽  
Netanel Tzarum ◽  
Xiaohe Lin ◽  
Benjamin Shapero ◽  
Cindy Sou ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Vaccine Development ◽  
Variable Region ◽  
Improved Stability ◽  
Cell Patterns ◽  
Neutralizing Epitopes

Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are responsible for cell entry, with E2 being the major target of neutralizing antibodies (NAbs). Here, we present a comprehensive strategy for B cell–based HCV vaccine development through E2 optimization and nanoparticle display. We redesigned variable region 2 in a truncated form (tVR2) on E2 cores derived from genotypes 1a and 6a, resulting in improved stability and antigenicity. Crystal structures of three optimized E2 cores with human cross-genotype NAbs (AR3s) revealed how the modified tVR2 stabilizes E2 without altering key neutralizing epitopes. We then displayed these E2 cores on 24- and 60-meric nanoparticles and achieved substantial yield and purity, as well as enhanced antigenicity. In mice, these nanoparticles elicited more effective NAb responses than soluble E2 cores. Next-generation sequencing (NGS) defined distinct B cell patterns associated with nanoparticle-induced antibody responses, which target the conserved neutralizing epitopes on E2 and cross-neutralize HCV genotypes.

scholarly journals Convergent antibody responses associated with broad neutralization of hepatitis C virus and clearance of infection

2021 ◽  
Author(s):  
Nicole E. Skinner ◽  
Clinton O. Ogega ◽  
Nicole Frumento ◽  
Kaitlyn E. Clark ◽  
Srinivasan Yegnasubramanian ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
B Cell ◽  
Early Development ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
High Plasma ◽  
Spontaneous Clearance ◽  
Cell Repertoire ◽  
Molecular Features

AbstractEarly development of broadly neutralizing antibodies (bNAbs) targeting the hepatitis C virus (HCV) envelope glycoprotein E2 is associated with spontaneous clearance of infection, so induction of bNAbs is a major goal of HCV vaccine development. However, much remains to be learned at a molecular level about protective E2-reactive antibodies, since HCV infection persists in some individuals despite early development of broadly neutralizing plasma. To examine B cell repertoire features associated with broad neutralization and viral clearance, we performed RNA sequencing of the B cell receptors (BCRs) of HCV E2-reactive B cells of people with cleared or persistent HCV, including subjects with high or low plasma neutralizing breadth in both clearance and persistence groups. We identified many E2-reactive public BCR clonotypes, which are antibody clones with the same V and J-genes and identical CDR3 sequences, shared among subjects grouped by either clearance or neutralization status. The majority (89) of these public clonotypes were shared by two subjects with broad plasma neutralizing activity and cleared infection, but not found in subjects with high plasma neutralizing breadth and persistent infection. We cloned a potent, cross-reactive neutralizing monoclonal antibody (mAb) by pairing the most abundant public heavy and light chains from these two subjects, providing evidence that broadly E2-reactive public clonotypes arise in a subset of individuals with broadly neutralizing plasma and spontaneous clearance of infection. Further characterization of the molecular features and function of these antibodies can inform HCV vaccine development.

scholarly journals Design of a native-like secreted form of the hepatitis C virus E1E2 heterodimer

2021 ◽  
Vol 118 (3) ◽  
pp. e2015149118
Author(s):  
Johnathan D. Guest ◽  
Ruixue Wang ◽  
Khadija H. Elkholy ◽  
Andrezza Chagas ◽  
Kinlin L. Chao ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Vaccine Development ◽  
Immune Escape ◽  
Transmembrane Domains ◽  
Viral Envelope ◽  
Soluble Form ◽  
Furin Cleavage Site

Hepatitis C virus (HCV) is a major worldwide health burden, and a preventive vaccine is needed for global control or eradication of this virus. A substantial hurdle to an effective HCV vaccine is the high variability of the virus, leading to immune escape. The E1E2 glycoprotein complex contains conserved epitopes and elicits neutralizing antibody responses, making it a primary target for HCV vaccine development. However, the E1E2 transmembrane domains that are critical for native assembly make it challenging to produce this complex in a homogenous soluble form that is reflective of its state on the viral envelope. To enable rational design of an E1E2 vaccine, as well as structural characterization efforts, we have designed a soluble, secreted form of E1E2 (sE1E2). As with soluble glycoprotein designs for other viruses, it incorporates a scaffold to enforce assembly in the absence of the transmembrane domains, along with a furin cleavage site to permit native-like heterodimerization. This sE1E2 was found to assemble into a form closer to its expected size than full-length E1E2. Preservation of native structural elements was confirmed by high-affinity binding to a panel of conformationally specific monoclonal antibodies, including two neutralizing antibodies specific to native E1E2 and to its primary receptor, CD81. Finally, sE1E2 was found to elicit robust neutralizing antibodies in vivo. This designed sE1E2 can both provide insights into the determinants of native E1E2 assembly and serve as a platform for production of E1E2 for future structural and vaccine studies, enabling rational optimization of an E1E2-based antigen.

scholarly journals Flexible RSV prefusogenic fusion glycoprotein exposes multiple neutralizing epitopes that may collectively contribute to protective immunity

2020 ◽  
Author(s):  
Nita Patel ◽  
Jing-Hui Tian ◽  
Rhonda Flores ◽  
Kelsey Jacobson ◽  
Michelle Walker ◽  
...  
Keyword(s):  
B Cell ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Quaternary Structure ◽  
Vaccine Development ◽  
High Titer ◽  
Treatment Options ◽  
Fusion Glycoprotein ◽  
Syncytial Virus ◽  
Neutralizing Epitopes

AbstractHuman respiratory syncytial virus (RSV) is a significant cause of lower respiratory tract infection in infants, young children, and older adults. There is no licensed vaccine and prophylactic treatment options are limited and not widely available in developing countries with the greatest disease burden. The RSV fusion (F) glycoprotein is a primary target of host immunity and thus a major focus for vaccine development. The native F glycoprotein structure is flexible and undergoes significant rearrangements from the metastable prefusion to a stable postfusion structure with neutralizing epitopes on intermediate structures. We hypothesize trimeric vaccine strategies that recapitulate the breathable F quaternary structure, and provide accessibility of B-cells to epitopes on intermediate conformations, may collectively contribute to protective immunity, while ridge prefusion F structures restrict access to key protective epitopes. To test this hypothesis, we used the near full-length native prefusogenic F as a backbone to construct three prefusion F variants with substitutions in the hydrophobic head cavity: 1) disulfide bond double mutant (DS), 2) space filling hydrophobic amino acid substitutions (Cav1), and 3) DS plus Cav1 substitutions (DS-Cav1). In this study, we compared the immunogenicity of prefusogenic F to the immunogenicity of the prefusion F variants in two animal models. Native prefusogenic F was significantly more immunogenic producing high titer antibodies to prefusogenic, prefusion, and postfusion F structures compared to animals immunized with prefusion F DS or DS-Cav1. Importantly, native prefusogenic F elicited antibodies that targeted neutralizing epitopes including prefusion-specific site zero (Ø) and V as well as conformation-independent neutralizing sites II and IV. Immunization with prefusion F DS or DS-Cav1 elicited antibodies primarily targeting antigenic sites Ø and V with little or no detectable antibodies to other key neutralizing sites. Animals immunized with native prefusogenic F also had significantly higher neutralizing antibodies that cross-neutralized RSV A and B subtypes while immunization with DS or DS-Cav1 elicited neutralizing antibodies primarily to the A subtype. We conclude that breathable trimeric vaccines that closely mimic the native F-structure, and incorporate strategies for B-cell accessibility to protective epitopes, are important considerations for vaccine design. F structures locked in a single conformation restrict B-cell access to neutralizing epitopes that may collectively contribute to destabilizing F-trimers important for broad protection. These results also have implications for vaccine strategies targeting other type 1 integral membrane proteins.

scholarly journals Conformational Flexibility in the Immunoglobulin-Like Domain of the Hepatitis C Virus Glycoprotein E2

mBio ◽  
2017 ◽  
Vol 8 (3) ◽  
Author(s):  
Ieva Vasiliauskaite ◽  
Ania Owsianka ◽  
Patrick England ◽  
Abdul Ghafoor Khan ◽  
Sarah Cole ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Binding Site ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Asymptomatic Infection ◽  
Effective Vaccine ◽  
Viral Glycoprotein ◽  
Direct Acting Antiviral ◽  
Glycoprotein E2

ABSTRACT The hepatitis C virus (HCV) glycoprotein E2 is the major target of neutralizing antibodies and is therefore highly relevant for vaccine design. Its structure features a central immunoglobulin (Ig)-like β-sandwich that contributes to the binding site for the cellular receptor CD81. We show that a synthetic peptide corresponding to a β-strand of this Ig-like domain forms an α-helix in complex with the anti-E2 antibody DAO5, demonstrating an inside-out flip of hydrophobic residues and a secondary structure change in the composite CD81 binding site. A detailed interaction analysis of DAO5 and cross-competing neutralizing antibodies with soluble E2 revealed that the Ig-like domain is trapped by different antibodies in at least two distinct conformations. DAO5 specifically captures retrovirus particles bearing HCV glycoproteins (HCVpp) and infectious cell culture-derived HCV particles (HCVcc). Infection of cells by DAO5-captured HCVpp can be blocked by a cross-competing neutralizing antibody, indicating that a single virus particle simultaneously displays E2 molecules in more than one conformation on its surface. Such conformational plasticity of the HCV E2 receptor binding site has important implications for immunogen design. IMPORTANCE Recent advances in the treatment of hepatitis C virus (HCV) infection with direct-acting antiviral drugs have enabled the control of this major human pathogen. However, due to their high costs and limited accessibility in combination with the lack of awareness of the mostly asymptomatic infection, there is an unchanged urgent need for an effective vaccine. The viral glycoprotein E2 contains regions that are crucial for virus entry into the host cell, and antibodies that bind to these regions can neutralize infection. One of the major targets of neutralizing antibodies is the central immunoglobulin (Ig)-like domain within E2. We show here that this Ig-like domain is conformationally flexible at the surface of infectious HCV particles and pseudoparticles. Our study provides novel insights into the interactions of HCV E2 with the humoral immune system that should aid future vaccine development. IMPORTANCE Recent advances in the treatment of hepatitis C virus (HCV) infection with direct-acting antiviral drugs have enabled the control of this major human pathogen. However, due to their high costs and limited accessibility in combination with the lack of awareness of the mostly asymptomatic infection, there is an unchanged urgent need for an effective vaccine. The viral glycoprotein E2 contains regions that are crucial for virus entry into the host cell, and antibodies that bind to these regions can neutralize infection. One of the major targets of neutralizing antibodies is the central immunoglobulin (Ig)-like domain within E2. We show here that this Ig-like domain is conformationally flexible at the surface of infectious HCV particles and pseudoparticles. Our study provides novel insights into the interactions of HCV E2 with the humoral immune system that should aid future vaccine development.

scholarly journals A Hepatitis C Virus Envelope Polymorphism Confers Resistance to Neutralization by Polyclonal Sera and Broadly Neutralizing Monoclonal Antibodies

2016 ◽  
Vol 90 (7) ◽  
pp. 3773-3782 ◽  
Author(s):  
Lisa N. Wasilewski ◽  
Ramy El-Diwany ◽  
Supriya Munshaw ◽  
Anna E. Snider ◽  
Jillian K. Brady ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Monoclonal Antibodies ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Resistance Mutation ◽  
The United States ◽  
Broadly Neutralizing Antibodies ◽  
Access To Treatment

ABSTRACTHepatitis 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.IMPORTANCEWorldwide, 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.

scholarly journals Hepatitis C virus association with peripheral blood B lymphocytes potentiates viral infection of liver-derived hepatoma cells

Blood ◽  
2009 ◽  
Vol 113 (3) ◽  
pp. 585-593 ◽  
Author(s):  
Zania Stamataki ◽  
Claire Shannon-Lowe ◽  
Jean Shaw ◽  
David Mutimer ◽  
Alan B. Rickinson ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
B Cells ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Cd40 Ligand ◽  
Hepatoma Cells ◽  
Productive Infection ◽  
Interleukin 4 ◽  
Extracellular Virus

Abstract Hepatitis C virus (HCV) primarily replicates within the liver, leading to hepatitis, fibrosis, and hepatocellular carcinoma. Infection is also associated with B-cell abnormalities, suggesting an association of the virus with B cells. The infectious JFH-1 strain of HCV can bind primary and immortalized B cells but fails to establish productive infection. However, B cell–associated virus readily infects hepatoma cells, showing an enhanced infectivity compared with extracellular virus. B cells express the viral receptors CD81, SR-BI, and the C-type lectins DC-SIGN and L-SIGN. Antibodies specific for SR-BI and DC-SIGN/L-SIGN reduced B-cell transinfection, supporting a role for these molecules in B-cell association with HCV. Stimulation of B cells with CD40 ligand and interleukin-4 promoted their ability to transinfect hepatoma cells. B cell–associated virus is resistant to trypsin proteolysis and HCV-specific neutralizing antibodies, consistent with particle internalization. HCV promoted the adhesion of primary B cells to Huh-7 hepatomas, providing a mechanism for B-cell retention in the infected liver. In summary, B cells may provide a vehicle for HCV to persist and transmit to the liver.

scholarly journals Mechanisms of Hepatitis C Virus Escape from Vaccine-Relevant Neutralizing Antibodies

Vaccines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 291
Author(s):  
Rodrigo Velázquez-Moctezuma ◽  
Elias H. Augestad ◽  
Matteo Castelli ◽  
Christina Holmboe Olesen ◽  
Nicola Clementi ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Cell Vaccine ◽  
Special Focus ◽  
Direct Modification ◽  
Chronic Hcv

Hepatitis C virus (HCV) is a major causative agent of acute and chronic hepatitis. It is estimated that 400,000 people die every year from chronic HCV infection, mostly from severe liver-related diseases such as cirrhosis and liver cancer. Although HCV was discovered more than 30 years ago, an efficient prophylactic vaccine is still missing. The HCV glycoprotein complex, E1/E2, is the principal target of neutralizing antibodies (NAbs) and, thus, is an attractive antigen for B-cell vaccine design. However, the high genetic variability of the virus necessitates the identification of conserved epitopes. Moreover, the high intrinsic mutational capacity of HCV allows the virus to continually escape broadly NAbs (bNAbs), which is likely to cause issues with vaccine-resistant variants. Several studies have assessed the barrier-to-resistance of vaccine-relevant bNAbs in vivo and in vitro. Interestingly, recent studies have suggested that escape substitutions can confer antibody resistance not only by direct modification of the epitope but indirectly through allosteric effects, which can be grouped based on the breadth of these effects on antibody susceptibility. In this review, we summarize the current understanding of HCV-specific NAbs, with a special focus on vaccine-relevant bNAbs and their targets. We highlight antibody escape studies pointing out the different methodologies and the escape mutations identified thus far. Finally, we analyze the antibody escape mechanisms of envelope protein escape substitutions and polymorphisms according to the most recent evidence in the HCV field. The accumulated knowledge in identifying bNAb epitopes as well as assessing barriers to resistance and elucidating relevant escape mechanisms may prove critical in the successful development of an HCV B-cell vaccine.

scholarly journals Role of the E2 Hypervariable Region (HVR1) in the Immunogenicity of a Recombinant Hepatitis C Virus Vaccine

2018 ◽  
Vol 92 (11) ◽  
Author(s):  
John L. M. Law ◽  
Michael Logan ◽  
Jason Wong ◽  
Juthika Kundu ◽  
Darren Hockman ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Hypervariable Region ◽  
Vaccine Antigen ◽  
Current Evidence ◽  
Pseudotyped Virus ◽  
Wild Type ◽  
Neutralization Activity ◽  
Neutralizing Epitopes

ABSTRACTCurrent evidence supports a protective role for virus-neutralizing antibodies in immunity against hepatitis C virus (HCV) infection. Many cross-neutralizing monoclonal antibodies have been identified. These antibodies have been shown to provide protection or to clear infection in animal models. Previous clinical trials have shown that a gpE1/gpE2 vaccine can induce antibodies that neutralize thein vitroinfectivity of all the major cell culture-derived HCV (HCVcc) genotypes around the world. However, cross-neutralization appeared to favor certain genotypes, with significant but lower neutralization against others. HCV may employ epitope masking to avoid antibody-mediated neutralization. Hypervariable region 1 (HVR1) at the amino terminus of glycoprotein E2 has been shown to restrict access to many neutralizing antibodies. Consistent with this, other groups have reported that recombinant viruses lacking HVR1 are hypersensitive to neutralization. It has been proposed that gpE1/gpE2 lacking this domain could be a better vaccine antigen to induce broadly neutralizing antibodies. In this study, we examined the immunogenicity of recombinant gpE1/gpE2 lacking HVR1 (ΔHVR1). Our results indicate that wild-type (WT) and ΔHVR1 gpE1/gpE2 antigens induced antibodies targeting many well-characterized cross-genotype-neutralizing epitopes. However, while the WT gpE1/gpE2 vaccine can induce cross-genotype protection against various genotypes of HCVcc and/or HCV-pseudotyped virus (HCVpp), antisera from ΔHVR1 gpE1/gpE2-immunized animals exhibited either reduced homologous neutralization activity compared to that of the WT or heterologous neutralization activity similar to that of the WT. These data suggest that ΔHVR1 gpE1/gpE2 is not a superior vaccine antigen. Based on previously reported chimpanzee protection data using WT gpE1/gpE2 and our current findings, we are preparing a combination vaccine including wild-type recombinant gpE1/gpE2 for clinical testing in the future.IMPORTANCEAn HCV vaccine is an unmet medical need. Current evidence suggests that neutralizing antibodies play an important role in virus clearance, along with cellular immune responses. Previous clinical data showed that gpE1/gpE2 can effectively induce cross-neutralizing antibodies, although they favor certain genotypes. HCV employs HVR1 within gpE2 to evade host immune control. It has been hypothesized that the removal of this domain would improve the production of cross-neutralizing antibodies. In this study, we compared the immunogenicities of WT and ΔHVR1 gpE1/gpE2 antigens as vaccine candidates. Our results indicate that the ΔHVR1 gpE1/gpE2 antigen confers no advantages in the neutralization of HCV compared with the WT antigen. Previously, we showed that this WT antigen remains the only vaccine candidate to protect chimpanzees from chronic infection, contains multiple cross-neutralizing epitopes, and is well tolerated and immunogenic in humans. The current data support the further clinical development of this vaccine antigen component.

scholarly journals Broadly Neutralizing Antibodies Targeting New Sites of Vulnerability in Hepatitis C Virus E1E2

2019 ◽  
Vol 93 (14) ◽  
Author(s):  
Michelle D. Colbert ◽  
Andrew I. Flyak ◽  
Clinton O. Ogega ◽  
Valerie J. Kinchen ◽  
Guido Massaccesi ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Infected Individual ◽  
Hcv Infection ◽  
Broadly Neutralizing Antibodies ◽  
Genotype 1A ◽  
Antigenic Sites

ABSTRACTIncreasing evidence indicates that broadly neutralizing antibodies (bNAbs) play an important role in immune-mediated control of hepatitis C virus (HCV) infection, but the relative contribution of neutralizing antibodies targeting antigenic sites across the HCV envelope (E1 and E2) proteins is unclear. Here, we isolated thirteen E1E2-specific monoclonal antibodies (MAbs) from B cells of a single HCV-infected individual who cleared one genotype 1a infection and then became persistently infected with a second genotype 1a strain. These MAbs bound six distinct discontinuous antigenic sites on the E1 protein, the E2 protein, or the E1E2 heterodimer. Three antigenic sites, designated AS108, AS112 (an N-terminal E1 site), and AS146, were distinct from previously described antigenic regions (ARs) 1 to 5 and E1 sites. Antibodies targeting four sites (AR3, AR4-5, AS108, and AS146) were broadly neutralizing. These MAbs also displayed distinct patterns of relative neutralizing potency (i.e., neutralization profiles) across a panel of diverse HCV strains, which led to complementary neutralizing breadth when they were tested in combination. Overall, this study demonstrates that HCV bNAb epitopes are not restricted to previously described antigenic sites, expanding the number of sites that could be targeted for vaccine development.IMPORTANCEWorldwide, more than 70 million people are infected with hepatitis C virus (HCV), which is a leading cause of hepatocellular carcinoma and liver transplantation. Despite the development of potent direct acting antivirals (DAAs) for HCV treatment, a vaccine is urgently needed due to the high cost of treatment and the possibility of reinfection after cure. Induction of multiple broadly neutralizing antibodies (bNAbs) that target distinct epitopes on the HCV envelope proteins is one approach to vaccine development. However, antigenic sites targeted by bNAbs in individuals with spontaneous control of HCV have not been fully defined. In this study, we characterize 13 monoclonal antibodies (MAbs) from a single person who cleared an HCV infection without treatment, and we identify 3 new sites targeted by neutralizing antibodies. The sites targeted by these MAbs could inform HCV vaccine development.

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