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BackgroundGlobal efforts are needed to elucidate the epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the underlying cause of coronavirus disease 2019 (COVID-19), including seroprevalence, risk factors, and long-term sequelae, as well as immune responses after vaccination across populations and the social dimensions of prevention and treatment strategies.MethodsIn the United States, the National Cancer Institute in partnership with the National Institute of Allergy and Infectious Diseases, established the SARS-CoV-2 Serological Sciences Network (SeroNet) as the nation's largest coordinated effort to study coronavirus disease 2019. The network comprises multidisciplinary researchers bridging gaps and fostering collaborations among immunologists, epidemiologists, virologists, clinicians and clinical laboratories, social and behavioral scientists, policymakers, data scientists, and community members. In total, 49 institutions form the SeroNet consortium to study individuals with cancer, autoimmune disease, inflammatory bowel diseases, cardiovascular diseases, human immunodeficiency virus, transplant recipients, as well as otherwise healthy pregnant women, children, college students, and high-risk occupational workers (including healthcare workers and first responders).ResultsSeveral studies focus on underrepresented populations, including ethnic minorities and rural communities. To support integrative data analyses across SeroNet studies, efforts are underway to define common data elements for standardized serology measurements, cellular and molecular assays, self-reported data, treatment, and clinical outcomes.ConclusionsIn this paper, we discuss the overarching framework for SeroNet epidemiology studies, critical research questions under investigation, and data accessibility for the worldwide scientific community. Lessons learned will help inform preparedness and responsiveness to future emerging diseases.

Spontaneous clearance of acute hepatitis C virus (HCV) infection is associated with single nucleotide polymorphisms (SNPs) on the MHC class II. We fine-mapped the MHC region in European (n = 1,600; 594 HCV clearance/1,006 HCV persistence) and African (n = 1,869; 340 HCV clearance/1,529 HCV persistence) ancestry individuals and evaluated HCV peptide binding affinity of classical alleles. In both populations, HLA-DQβ1Leu26 (p valueMeta = 1.24 × 10-14) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQβ1Pro55 (p valueMeta = 8.23 × 10-11) located in the peptide binding region was positively associated, independently of HLA-DQβ1Leu26. These two amino acids are not in linkage disequilibrium (r2 < 0.1) and explain the SNPs and classical allele associations represented by rs2647011, rs9274711, HLA-DQB1∗03:01, and HLA-DRB1∗01:01. Additionally, HCV persistence classical alleles tagged by HLA-DQβ1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC50 nM of persistence versus clearance; 2,321 nM versus 761.7 nM, p value = 1.35 × 10-38). In summary, MHC class II fine-mapping revealed key amino acids in HLA-DQβ1 explaining allelic and SNP associations with HCV outcomes. This mechanistic advance in understanding of natural recovery and immunogenetics of HCV might set the stage for much needed enhancement and design of vaccine to promote spontaneous clearance of HCV infection.

BackgroundSpontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors.MethodsTo identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group.ResultsA male-specific region near the adenosine diphosphate-ribosylation factor-like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10-07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10-06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor.ConclusionsThese novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development.

BackgroundA safe and effective vaccine to prevent chronic hepatitis C virus (HCV) infection is a critical component of efforts to eliminate the disease.MethodsIn this phase 1-2 randomized, double-blind, placebo-controlled trial, we evaluated a recombinant chimpanzee adenovirus 3 vector priming vaccination followed by a recombinant modified vaccinia Ankara boost; both vaccines encode HCV nonstructural proteins. Adults who were considered to be at risk for HCV infection on the basis of a history of recent injection drug use were randomly assigned (in a 1:1 ratio) to receive vaccine or placebo on days 0 and 56. Vaccine-related serious adverse events, severe local or systemic adverse events, and laboratory adverse events were the primary safety end points. The primary efficacy end point was chronic HCV infection, defined as persistent viremia for 6 months.ResultsA total of 548 participants underwent randomization, with 274 assigned to each group. There was no significant difference in the incidence of chronic HCV infection between the groups. In the per-protocol population, chronic HCV infection developed in 14 participants in each group (hazard ratio [vaccine vs. placebo], 1.53; 95% confidence interval [CI], 0.66 to 3.55; vaccine efficacy, -53%; 95% CI, -255 to 34). In the modified intention-to-treat population, chronic HCV infection developed in 19 participants in the vaccine group and 17 in placebo group (hazard ratio, 1.66; 95% CI, 0.79 to 3.50; vaccine efficacy, -66%; 95% CI, -250 to 21). The geometric mean peak HCV RNA level after infection differed between the vaccine group and the placebo group (152.51×103 IU per milliliter and 1804.93×103 IU per milliliter, respectively). T-cell responses to HCV were detected in 78% of the participants in the vaccine group. The percentages of participants with serious adverse events were similar in the two groups.ConclusionsIn this trial, the HCV vaccine regimen did not cause serious adverse events, produced HCV-specific T-cell responses, and lowered the peak HCV RNA level, but it did not prevent chronic HCV infection. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT01436357.).

There is an urgent need for innovative methods to reduce transmission of bloodborne pathogens like HIV and HCV among people who inject drugs (PWID). We investigate if PWID who acquire non-pathogenic bloodborne viruses like anelloviruses and pegiviruses might be at greater risk of acquiring a bloodborne pathogen. PWID who later acquire HCV accumulate more non-pathogenic viruses in plasma than matched controls who do not acquire HCV infection. Additionally, phylogenetic analysis of those non-pathogenic virus sequences reveals drug use networks. Here we find first in Baltimore and confirm in San Francisco that the accumulation of non-pathogenic viruses in PWID is a harbinger for subsequent acquisition of pathogenic viruses, knowledge that may guide the prioritization of the public health resources to combat HIV and HCV.

Clearance of acute infection with hepatitis C virus (HCV) is associated with the chr19q13.13 region containing the rs368234815 (TT/ΔG) polymorphism. We fine-mapped this region to detect possible causal variants that may contribute to HCV clearance. First, we performed sequencing of IFNL1-IFNL4 region in 64 individuals sampled according to rs368234815 genotype: TT/clearance (N = 16) and ΔG/persistent (N = 15) (genotype-outcome concordant) or TT/persistent (N = 19) and ΔG/clearance (N = 14) (discordant). 25 SNPs had a difference in counts of alternative allele >5 between clearance and persistence individuals. Then, we evaluated those markers in an association analysis of HCV clearance conditioning on rs368234815 in two groups of European (692 clearance/1 025 persistence) and African ancestry (320 clearance/1 515 persistence) individuals. 10/25 variants were associated (P

Temesgen E. Andargie, Katerina Roznik, Neelam Redekar, Tom Hill, Weiqiang Zhou, Zainab Apalara, Hyesik Kong, Oren Gordon, Rohan Meda, Woojin Park, Trevor S. Johnston, Yi Wang, Sheila Brady, Hongkai Ji, [...]

BackgroundWhile opioid agonist therapy (OAT) reduces the risk of hepatitis C virus (HCV) acquisition among people who inject drugs (PWID), protective effects may be attenuated in females. We used pooled data from an international collaboration of prospective cohorts to assess sex disparities in HCV incidence among PWID exposed to OAT.MethodsIndependent predictors of HCV infection were identified using Cox regression models with random effects after accounting for the clustering effect of study sites. Unadjusted and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) are presented in sex-specific analyses.ResultsAmong 701 participants exposed to OAT, HCV incidence was 16.5/100 person-years of observation (PYO) (95% CI, 13.1-20.7) in females and 7.6/100 PYO (95% CI, 6.0-9.5) in males (female:male adjusted HR [aHR], 1.80 [95% CI, 1.37-2.22]; P < .001). Factors associated with HCV acquisition among females exposed to OAT included nonwhite race (aHR, 1.79 [95% CI, 1.25-2.56]; P = .001), unstable housing (aHR, 4.00 [95% CI, 3.62-4.41]; P < .001), daily or more frequent injection (aHR, 1.45 [95% CI, 1.01-2.08]; P = .042), and receptive syringe sharing (aHR, 1.43 [95% CI, 1.33-1.53]; P < .001).ConclusionsFemale PWID exposed to OAT are twice as likely as their male counterparts to acquire HCV. While there is a need for better understanding of sex differences in immune function and opioid pharmacokinetic and pharmacodynamic parameters, structural and behavioral interventions that target women are required to bolster the efficacy of OAT in preventing HCV transmission.

Background & aimsSpontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance, but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry.MethodsWe performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina (San Diego, CA) arrays and statistically imputed to the 1000 Genomes Project. For each ancestry group, the association of single-nucleotide polymorphisms with HCV clearance was tested by log-additive analysis, and then a meta-analysis was performed.ResultsIn the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4-IFNL3 (19q13.2) (P = 5.99 × 10-50) and the MHC locus 6p21.32 (P = 1.15 × 10-21). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P = 1.80 × 10-07). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared with individuals carrying none or 1 of the clearance-associated variants.ConclusionsIn a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4-IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection.

Introduction Multisystem inflammatory syndrome in children (MIS-C) is a rare yet life-threatening hyperinflammatory condition induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (1). MIS-C shares clinical features [...], Multisystem inflammatory syndrome in children (MIS-C) is a rare but life- threatening hyperinflammatory condition induced by infection with severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) that causes pediatric COVID-19 (pCOVID-19). The relationship of the systemic tissue injury to the pathophysiology of MIS-C is poorly defined. We leveraged the high sensitivity of epigenomics analyses of plasma cell-free DNA (cfDNA) and plasma cytokine measurements to identify the spectrum of tissue injury and glean mechanistic insights. Compared with pediatric healthy controls (pHCs) and patients with pCOVID-19, patients with MIS-C had higher levels of cfDNA primarily derived from innate immune cells, megakaryocyte-erythroid precursor cells, and nonhematopoietic tissues such as hepatocytes, cardiac myocytes, and kidney cells. Nonhematopoietic tissue cfDNA levels demonstrated significant interindividual variability, consistent with the heterogenous clinical presentation of MIS-C. In contrast, adaptive immune cell-derived cfDNA levels were comparable in MIS-C and pCOVID-19 patients. Indeed, the cfDNA of innate immune cells in patients with MIS-C correlated with the levels of innate immune inflammatory cytokines and nonhematopoietic tissue- derived cfDNA, suggesting a primarily innate immunity-mediated response to account for the multisystem pathology. These data provide insight into the pathogenesis of MIS-C and support the value of cfDNA as a sensitive biomarker to map tissue injury in MIS-C and likely other multiorgan inflammatory conditions.

Background:The objective of this study was to assess differences in hepatitis C virus (HCV) incidence by sex in people who inject drugs (PWID), using a large international multicohort set of pooled biological and behavioral data from prospective observational studies of incident human immunodeficiency virus (HIV) and HCV infections in high-risk cohorts (the InC3 Collaborative). Methods:HCV infection date was estimated based on a hierarchy of successive serological (anti-HCV), virological (HCV RNA), and clinical (symptoms and/or liver function tests) data. We used a Cox proportional hazards model to calculate the crude and adjusted female to male (F:M) hazard ratio (HR) for HCV incidence using biological sex as the main exposure. Results:A total of 1868 PWID were observed over 3994 person-years of observation (PYO). Unadjusted F:M HR was 1.38 (95% confidence interval [CI], 1.15-1.65) and remained significant after adjusting for behavioral and demographic risk factors (1.39 [95% CI, 1.12-1.72]). Although syringe and equipment sharing were associated with the highest HCV incidence rate in women (41.62 and 36.83 PYO, respectively), we found no sex differences attributed to these risk factors. Conclusions:Our findings indicate that women who inject drugs may be at greater risk of HCV acquisition than men, independent of demographic characteristics and risk behaviors. Multiple factors, including biological (hormonal), social network, and differential access to prevention services, may contribute to increased HCV susceptibility in women who inject drugs.

BackgroundWe determined temporal trends (1985-2011) in hepatitis C virus (HCV) incidence and associated behavioral exposures for people who inject drugs (PWID) from the United States (Boston, Baltimore, and San Francisco), Canada (Montreal), the Netherlands (Amsterdam), and Australia (Sydney and Melbourne).MethodsUsing population-based cohort data from HCV-negative PWID, we calculated overall and within-city HCV incidence trends, HCV rates by study enrollment period (1985-2011), and temporal trends in exposure behaviors. Poisson regression models estimated trends in HCV incidence over calendar-time. Survival models identified risk factors for HCV incidence across cities and estimated independent effects of city and calendar period on HCV infection risk.ResultsAmong 1391 initially HCV-negative participants followed prospectively (1644.5 person-years of observation [PYO]), 371 HCV incident infections resulted in an overall incidence of 22.6 per 100 PYO (95% confidence interval [CI], 20.4-25.0). Incidence was highest and remained elevated in Baltimore (32.6/100 PYO), San Francisco (24.7/100 PYO), and Montreal (23.5/100 PYO), lowest in Melbourne and Amsterdam (7.5/100 PYO and 13.1/100 PYO, respectively), and moderate (21.4/100 PYO) in Sydney. Higher rates of syringe and equipment sharing and lower prevalence of opioid agonist therapy were associated with HCV incidence in cities with the highest incidence. Risk for infection dropped by 18% for every 3-year increase in calendar-time (adjusted hazard ratio, 0.8 [95% CI, .8-.9]) in the multivariable model.ConclusionsDifferences in prevention strategies and injecting contexts may explain the ongoing high HCV incidence in these North American cities and emphasize the need for scale-up of opioid agonist therapy and increased coverage of needle and syringe programs in North America.

Long Covid is defined by a wide range of symptoms that persist after the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Commonly reported symptoms include fatigue, weakness, postexertional malaise, and cognitive dysfunction, with many other symptoms reported. Symptom range, duration, and severity are highly variable and partially overlap with symptoms of myalgic encephalomyelitis/chronic fatigue syndrome and other post-acute infectious syndromes, highlighting opportunities to define shared mechanisms of pathogenesis. Potential mechanisms of Long Covid are diverse, including persistence of viral reservoirs, dysregulated immune responses, direct viral damage of tissues targeted by SARS-CoV-2, inflammation driven by reactivation of latent viral infections, vascular endothelium activation or dysfunction, and subsequent thromboinflammation, autoimmunity, metabolic derangements, microglial activation, and microbiota dysbiosis. The heterogeneity of symptoms and baseline characteristics of people with Long Covid, as well as the varying states of immunity and therapies given at the time of acute infection, have made etiologies of Long Covid difficult to determine. Here, we examine progress on preclinical models for Long Covid and review progress being made in clinical trials, highlighting the need for large human studies and further development of models to better understand Long Covid. Such studies will inform clinical trials that will define treatments to benefit those living with this condition. [ABSTRACT FROM AUTHOR]

Durability of variant neutralization in solid organ transplant recipients following Omicron-containing boosters is unknown. We report wane in XBB.1.5 neutralization by 3 months following a first bivalent booster, improved by a second booster; hybrid immunity improved peak, and duration of neutralization. Boosting at 3 to 6 months appears necessary to maintain neutralization. [ABSTRACT FROM AUTHOR]

BackgroundApproximately one quarter of persons exposed to hepatitis C virus (HCV) will spontaneously clear infection. We undertook this study to investigate the impact of alcohol on likelihood of HCV spontaneous viral clearance stratified by sex groups.MethodsPooled data from an international collaboration of prospective observational studies of incident HIV and HCV infection in high-risk cohorts (the InC3 Study) was restricted to 411 persons (or 560.7 person-years of observation) with documented acute HCV infection and data regarding alcohol use. The predictor of interest was self-reported alcohol use at or after estimated date of incident HCV infection and the outcome was HCV spontaneous clearance. Sex stratified Cox proportional hazards models were used to evaluate the association between alcohol and spontaneous clearance, adjusting for age, race/ethnicity, and IFNL4 genotype.ResultsThe median age was 28.5 years, 30.4% were women, 87.2% were white, and 71.8% reported alcohol use at or after incident infection. There were 89 (21.6%) cases of spontaneous clearance observed, 39 (31.2%) among women and 50 (17.5%) in men (p

Background.  We assessed immune activation after antiretroviral therapy (ART) initiation to understand clinical failure in diverse settings. Methods.  We performed a case-control study in ACTG Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS). Cases were defined as incident World Health Organization Stage 3 or 4 human immunodeficiency virus (HIV) disease or death, analyzed from ART weeks 24 (ART24) to 96. Controls were randomly selected. Interleukin (IL)-6, interferon (IFN)-γ-inducible protein-10, IL-18, tumor necrosis factor-α, IFN-γ, and soluble CD14 (sCD14) were measured pre-ART and at ART24 in plasma. Continued elevation was defined by thresholds set by highest pre-ART quartiles (>Q3). Incident risk ratios (IRRs) for clinical progression were estimated by Poisson regression, adjusting for age, sex, treatment, country, time-updated CD4+ T-cell count, HIV ribonucleic acid (RNA), and prevalent tuberculosis. Results.  Among 99 cases and 234 controls, median baseline CD4+ T-cell count was 181 cells/µL, and HIV RNA was 5.05 log10 cp/mL. Clinical failure was independently associated with continued elevations of IL-18 (IRR, 3.03; 95% confidence interval [CI], 1.27-7.20), sCD14 (IRR, 2.17; 95% CI, 1.02-4.62), and IFN-γ (IRR, 0.08; 95% CI, 0.01-0.61). Among 276 of 333 (83%) who were virologically suppressed at ART24, IFN-γ was associated with protection from failure, but the association with sCD14 was attenuated. Conclusions.  Continued IL-18 and sCD14 elevations were associated with clinical ART failure. Interferon-γ levels may reflect preserved immune function.

Symptomatic acute HCV infection and interferon lambda 4 (IFNL4) genotypes are important predictors of spontaneous viral clearance. Using data from a multicohort database (Injecting Cohorts [InC3] Collaborative), we establish an independent association between host IFNL4 genotype and symptoms of acute hepatitis C virus infection. This association potentially explains the higher spontaneous clearance observed in some patients with symptomatic disease.

Background and objectivesHepatitis C virus (HCV) RNA level in acute HCV infection is predictive of spontaneous clearance. This study assessed factors associated with HCV RNA levels during early acute infection among people who inject drugs with well-defined acute HCV infection.Study designData were from International Collaboration of Incident HIV and Hepatitis C in Injecting Cohorts (InC(3)) Study, an international collaboration of nine prospective cohorts studying acute HCV infection. Individuals with available HCV RNA levels during early acute infection (first two months following infection) were included. The distribution of HCV RNA levels during early acute infection were compared by selected host and virological factors.ResultsA total of 195 individuals were included. Median HCV RNA levels were significantly higher among individuals with interferon lambda 3 (IFNL3, formerly called IL28B) CC genotype compared to those with TT/CT genotype (6.28 vs. 5.39logIU/mL, respectively; P=0.01). IFNL3 CC genotype was also associated with top tertile HCV RNA levels (≥6.3log IU/mL; vs. TT/CT genotype; adjusted Odds Ratio: 4.28; 95%CI: 2.01, 9.10; P

Background Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory condition caused by recent infection with severe acute respiratory syndrome coronavirus 2, but the underlying immunological mechanisms driving this distinct syndrome are unknown. Methods We utilized high-dimensional flow cytometry, cell-free (cf) DNA, and cytokine and chemokine profiling to identify mechanisms of critical illness distinguishing MIS-C from severe acute coronavirus disease 2019 (SAC). Results Compared to SAC, MIS-C patients demonstrated profound innate immune cell death and features of emergency myelopoiesis (EM), an understudied phenomenon observed in severe inflammation. EM signatures were characterized by fewer mature myeloid cells in the periphery and decreased expression of HLA-DR and CD86 on antigen-presenting cells. Interleukin 27 (IL-27), a cytokine known to drive hematopoietic stem cells toward EM, was increased in MIS-C, and correlated with immature cell signatures in MIS-C. Upon recovery, EM signatures decreased and IL-27 plasma levels returned to normal levels. Despite profound lymphopenia, we report a lack of cfDNA released by adaptive immune cells and increased CCR7 expression on T cells indicative of egress out of peripheral blood. Conclusions Immune cell signatures of EM combined with elevated innate immune cell-derived cfDNA levels distinguish MIS-C from SAC in children and provide mechanistic insight into dysregulated immunity contributing toward MIS-C, offering potential diagnostic and therapeutic targets. [ABSTRACT FROM AUTHOR]

Introduction An estimated 71 million people are infected with hepatitis C virus (HCV) worldwide (1). Given the largely asymptomatic nature of this disease, only a fraction of the HCV-infected population [...], A prophylactic hepatitis C virus (HCV) vaccine that elicits neutralizing antibodies could be key to HCV eradication. However, the genetic and antigenic properties of HCV envelope (E1E2) proteins capable of inducing anti-HCV broadly neutralizing antibodies (bNAbs) in humans have not been defined. Here, we investigated the development of bNAbs in longitudinal plasma of HCV-infected persons with persistent infection or spontaneous clearance of multiple reinfections. By measuring plasma antibody neutralization of a heterologous virus panel, we found that the breadth and potency of the antibody response increased upon exposure to multiple genetically distinct infections and with longer duration of viremia. Greater genetic divergence between infecting strains was not associated with enhanced neutralizing breadth. Rather, repeated exposure to antigenically related, antibody-sensitive E1E2s was associated with potent bNAb induction. These data reveal that a prime-boost vaccine strategy with genetically distinct, antibody-sensitive viruses is a promising approach to inducing potent bNAbs in humans.

Introduction A vaccine to prevent hepatitis C virus (HCV) infection is urgently needed. Although recently developed direct-acting antivirals are highly effective for HCV treatment, most individuals are unaware of their [...], 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.