To Include or Occlude: Rational Engineering of HCV Vaccines for Humoral Immunity

Schlotthauer, Felicia; McGregor, Joey; Drummer, Heidi E

doi:10.3390/v13050805

Cited by 5 publications

(3 citation statements)

References 166 publications

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“…The epitopes targeted by many bNAbs have been reported in the literature. Most of these epitopes lie on the neutralizing face of the E2 molecule [ 31 , 32 ]. Three important regions each bound by several bNAbs are Domain E (E2 aa412-423), Domain D (E2 aa 420-428, 441-443, 616) and Domain B (E2 aa 431-439, 529-535).…”

Section: Resultsmentioning

confidence: 99%

The Neutralizing Antibody Responses of Individuals That Spontaneously Resolve Hepatitis C Virus Infection

Cowton

Dunlop

Cole

et al. 2022

Viruses

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Hepatitis C virus (HCV) infection is a major global health problem. In the majority of cases the virus is not cleared by the host immune response and progresses to chronic infection. Studies of the neutralizing antibody responses in individuals that naturally clear infection are limited. Understanding what constitutes a successful antibody response versus one that has ‘failed’ and resulted in chronic infection is important to understand what type of antibody response would need to be elicited by a protective vaccine. Samples from spontaneous clearers are difficult to obtain therefore studies are often limited. In our study through HCV Research UK, we had access to a cohort of over 200 samples. We identified the samples that contained HCV neutralizing antibodies using ELISA and HCV pseudoparticle (HCVpp) assays. We then utilised mutagenesis and cross-competition analysis to determine the profile of the neutralizing antibody responses. In addition, we analysed a cohort of samples from chronic infection using the same techniques to enable direct comparison of the antibody profiles observed in both cohorts. We conclude that similar profiles are present in both cohorts indicating that it is not the neutralizing antibody response per se that determines the outcome of infection. These data will provide useful information for future HCV vaccine design.

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Section: Resultsmentioning

confidence: 99%

The Neutralizing Antibody Responses of Individuals That Spontaneously Resolve Hepatitis C Virus Infection

Cowton

Dunlop

Cole

et al. 2022

Viruses

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show abstract

“…Together, studies of the recombinant HCV-1 E1E2 vaccines provide a solid basis for the pursuit of an antibody vaccine, while highlighting the need for optimization to better elicit robust neutralizing responses against conserved regions of the envelope glycoprotein. As such, significant effort has been made to engineer a rational antibody vaccine for HCV, as recently reviewed in detail by several groups [ 93 , 94 , 95 ]. These efforts follow insights gained from crystal structures of antibody-bound constructs of truncated E2, improved modeling of the E1E2 heterodimer, and expanded mapping of neutralizing and non-neutralizing antibody binding sites on E1E2.…”

Section: Harnessing Neutralizing Antibody Responses In New Vaccinesmentioning

confidence: 99%

Where to Next? Research Directions after the First Hepatitis C Vaccine Efficacy Trial

Phelps

Walker

Honegger

2021

Viruses

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Thirty years after its discovery, the hepatitis C virus (HCV) remains a leading cause of liver disease worldwide. Given that many countries continue to experience high rates of transmission despite the availability of potent antiviral therapies, an effective vaccine is seen as critical for the elimination of HCV. The recent failure of the first vaccine efficacy trial for the prevention of chronic HCV confirmed suspicions that this virus will be a challenging vaccine target. Here, we examine the published data from this first efficacy trial along with the earlier clinical and pre-clinical studies of the vaccine candidate and then discuss three key research directions expected to be important in ongoing and future HCV vaccine development. These include the following: 1. design of novel immunogens that generate immune responses to genetically diverse HCV genotypes and subtypes, 2. strategies to elicit broadly neutralizing antibodies against envelope glycoproteins in addition to cytotoxic and helper T cell responses, and 3. consideration of the unique immunological status of individuals most at risk for HCV infection, including those who inject drugs, in vaccine platform development and early immunogenicity trials.

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“…Additionally, it was recently found that cross-genotype-reactive broadly NAbs (bNAbs) were associated with viral clearance 14 . While efforts to use E1/E2 complexes as vaccine antigens are ongoing [15][16][17] , most antibody-based vaccine research has focused on transmembrane truncated, soluble, E2 (sE2), which recapitulates many important bNAb epitopes 18,19 . The relevance of basing HCV vaccines on E2 was further supported by our recent finding that it was challenging for HCV to evade antibodies targeting the E2 antigenic region 3 (AR3) 20 .…”

Section: Introductionmentioning

confidence: 99%

Two-component vaccine consisting of virus-like particles displaying hepatitis C virus envelope protein 2 oligomers

et al. 2022

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Development of B-cell-based hepatitis C virus (HCV) vaccines that induce broadly neutralizing antibodies (bNAbs) is hindered by extensive sequence diversity and low immunogenicity of envelope glycoprotein vaccine candidates, most notably soluble E2 (sE2). To overcome this, we employed two-component approaches using self-assembling virus-like particles (cVLPs; component 1), displaying monomeric or oligomeric forms of HCV sE2 (sE2mono or sE2oligo; component 2). Immunization studies were performed in BALB/c mice and the neutralizing capacity of vaccine-induced antibodies was tested in cultured-virus-neutralizations, using HCV of genotypes 1–6. sE2-cVLP vaccines induced significantly higher levels of NAbs (p = 0.0065) compared to corresponding sE2 vaccines. Additionally, sE2oligo-cVLP was superior to sE2mono-cVLP in inducing bNAbs. Interestingly, human monoclonal antibody AR2A had reduced binding in ELISA to sE2oligo-cVLP compared with sE2mono-cVLP and competition ELISA using mouse sera from vaccinated animals indicated that sE2oligo-cVLP induced significantly less non-bNAbs AR2A (p = 0.0043) and AR1B (p = 0.017). Thus, cVLP-displayed oligomeric sE2 shows promise as an HCV vaccine candidate.

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To Include or Occlude: Rational Engineering of HCV Vaccines for Humoral Immunity

Cited by 5 publications

References 166 publications

The Neutralizing Antibody Responses of Individuals That Spontaneously Resolve Hepatitis C Virus Infection

The Neutralizing Antibody Responses of Individuals That Spontaneously Resolve Hepatitis C Virus Infection

Where to Next? Research Directions after the First Hepatitis C Vaccine Efficacy Trial

Two-component vaccine consisting of virus-like particles displaying hepatitis C virus envelope protein 2 oligomers

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