Antibody Responses to Immunization With HCV Envelope Glycoproteins as a Baseline for B-Cell–Based Vaccine Development

Chen, Fang; Nagy, Kenna; Chavez, Deborah J.; Willis, Shelby; McBride, Ryan; Giang, Erick; Honda, Andrew; Bukh, Jens; Ordoukhanian, Phillip; Zhu, Jiang; Frey, Sharon E.; Lanford, Robert E.; Law, Mansun

doi:10.1053/j.gastro.2019.11.282

Cited by 37 publications

(56 citation statements)

References 65 publications

(71 reference statements)

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“…These results are in line with those reported by others that show that mice do not elicit HCV neutralizing antibodies [ 89 , 90 ]. In contrast, several studies have demonstrated that mice and other small mammals can induce neutralizing antibodies [ 55 , 62 , 91 , 92 ]. The experimental conditions between the studies that reported induction of NAbs and ours differed widely so it is therefore difficult to explain this discrepancy.…”

Section: Discussionmentioning

confidence: 99%

Optimized Hepatitis C Virus (HCV) E2 Glycoproteins and their Immunogenicity in Combination with MVA-HCV

et al. 2020

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Hepatitis C virus (HCV) represents a major global health challenge and an efficient vaccine is urgently needed. Many HCV vaccination strategies employ recombinant versions of the viral E2 glycoprotein. However, recombinant E2 readily forms disulfide-bonded aggregates that might not be optimally suited for vaccines. Therefore, we have designed an E2 protein in which we strategically changed eight cysteines to alanines (E2.C8A). E2.C8A formed predominantly monomers and virtually no aggregates. Furthermore, E2.C8A also interacted more efficiently with broadly neutralizing antibodies than conventional E2. We used mice to evaluate different prime/boost immunization strategies involving a modified vaccinia virus Ankara (MVA) expressing the nearly full-length genome of HCV (MVA-HCV) in combination with either the E2 aggregates or the E2.C8A monomers. The combined MVA-HCV/E2 aggregates prime/boost strategy markedly enhanced HCV-specific effector memory CD4+ T cell responses and antibody levels compared to MVA-HCV/MVA-HCV. Moreover, the aggregated form of E2 induced higher levels of anti-E2 antibodies in vaccinated mice than E2.C8A monomers. These antibodies were cross-reactive and mainly of the IgG1 isotype. Our findings revealed how two E2 viral proteins that differ in their capacity to form aggregates are able to enhance to different extent the HCV-specific cellular and humoral immune responses, either alone or in combination with MVA-HCV. These combined protocols of MVA-HCV/E2 could serve as a basis for the development of a more effective HCV vaccine.

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Section: Discussionmentioning

confidence: 99%

Optimized Hepatitis C Virus (HCV) E2 Glycoproteins and their Immunogenicity in Combination with MVA-HCV

et al. 2020

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“…The exact binding epitopes of many bnAbs were identified by global alanine scanning of the E1E2 protein, followed by antibody binding assays [28,29]. The immunodominance of bnAbs were analyzed very recently in natural acute infection [30], as well as in samples from a (historic) E1E2 vaccination study in healthy volunteers [31].…”

Section: Antibody Responsementioning

confidence: 99%

Adaptive Immune Response against Hepatitis C Virus

Kemming

Thimme

2020

IJMS

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A functional adaptive immune response is the major determinant for clearance of hepatitis C virus (HCV) infection. However, in the majority of patients, this response fails and persistent infection evolves. Here, we dissect the HCV-specific key players of adaptive immunity, namely B cells and T cells, and describe factors that affect infection outcome. Once chronic infection is established, continuous exposure to HCV antigens affects functionality, phenotype, transcriptional program, metabolism, and the epigenetics of the adaptive immune cells. In addition, viral escape mutations contribute to the failure of adaptive antiviral immunity. Direct-acting antivirals (DAA) can mediate HCV clearance in almost all patients with chronic HCV infection, however, defects in adaptive immune cell populations remain, only limited functional memory is obtained and reinfection of cured individuals is possible. Thus, to avoid potential reinfection and achieve global elimination of HCV infections, a prophylactic vaccine is needed. Recent vaccine trials could induce HCV-specific immunity but failed to protect from persistent infection. Thus, lessons from natural protection from persistent infection, DAA-mediated cure, and non-protective vaccination trials might lead the way to successful vaccination strategies in the future.

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“…We hypothesize that the infectious nature of sera from early phase infected patients re ects the presence of non-neutralized virions, whereas in chronic infection virus particles circulate as noninfectious immune-complexed forms (42,43). These results, together with reports that HCV infection of chimeric liver mouse models can be neutralized by the passive transfer of monoclonal antibodies targeting conserved epitopes within the HCV-E2 glycoprotein, provides optimism on the feasibility to develop effective HCV vaccines (16,18,53,54 variants, may provide a biomarker of the presence of HCV transmitting B cells rather than being itself the mediator of transmission. A potential role for B cells in chronic HCV infection warrants further research to understand the etiology of B cell lymphoproliferative disorders and viral persistence.…”

Section: Discussionmentioning

confidence: 99%

A role for B cells to transmit hepatitis C virus infection

Desombere

Houtte

Farhoudi

et al. 2020

Preprint

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Hepatitis C virus (HCV) is highly variable and transmits through infected blood to establish a chronic liver infection in the majority of patients. Our knowledge of the infectivity of clinical HCV strains is hampered by the lack of in vitro cell culture systems that support efficient viral replication. We previously reported that laboratory strains of HCV associated with non-permissive B cells could trans-infect hepatocytes and thereby evade host neutralizing antibody responses, suggesting a role for B cells in HCV transmission. To evaluate this hypothesis, we assessed the ability of B cells and sera from recent (<2 years) or chronic (≥ 2 years) infections to infect humanized liver chimeric mice. HCV was efficiently transmitted by B cells from chronically infected patients whereas the sera were non-infectious. In contrast, we noted that B cells from recently infected patients failed to transmit HCV to the mice, whereas all serum samples were infectious. Only patients with circulating anti-glycoprotein antibodies harbored genomic HCV-RNA in B cells. Taken together, our studies provide direct in vivo evidence for HCV transmission by B cells and these findings may have clinical implications for prophylactic and therapeutic antibody-based vaccine design.

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Antibody Responses to Immunization With HCV Envelope Glycoproteins as a Baseline for B-Cell–Based Vaccine Development

Cited by 37 publications

References 65 publications

Optimized Hepatitis C Virus (HCV) E2 Glycoproteins and their Immunogenicity in Combination with MVA-HCV

Optimized Hepatitis C Virus (HCV) E2 Glycoproteins and their Immunogenicity in Combination with MVA-HCV

Adaptive Immune Response against Hepatitis C Virus

A role for B cells to transmit hepatitis C virus infection

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