Current and future prophylactic vaccines for hepatitis C virus

Dunlop, James I.; Owsianka, Anna M.; Cowton, Vanessa M.; Patel, Arvind H.

doi:10.2147/vdt.s48437

Cited by 7 publications

(2 citation statements)

References 136 publications

(154 reference statements)

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“…These include the genetic diversity of HCV of at least seven HCV genotypes that differ up to 30% in nucleotide sequence (which can be further subdivided into over 90 subtypes), flexibility of the conformational regions, glycan shielding of neutralizing epitopes, the presence of immunodominant non-neutralizing "decoy" epitopes, and the tendency for membrane-solubilized E1E2 antigen preparations to form aggregates [21,[24][25][26][27][28][29]. Moreover, direct cell-to-cell transmission of the virus, systemic circulation of virions associate with lipoproteins, and the downregulation of major histocompatibility complex (MHC) expression are other mechanisms for the virus to escape protective immunity [26,[30][31][32]. Although immune correlates of protection have yet to be defined for HCV, there is broad agreement that both B and T cell immunity contribute to the control of acute HCV infection [22,33,34].…”

Section: Additionally the Diagnosis Of Hcv Infectionmentioning

confidence: 99%

Hepatitis C Virus E1E2 Structure, Diversity, and Implications for Vaccine Development

Pierce,

Felbinger,

Metcalf

et al. 2024

Viruses

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Hepatitis C virus (HCV) is a major medical health burden and the leading cause of chronic liver disease and cancer worldwide. More than 58 million people are chronically infected with HCV, with 1.5 million new infections occurring each year. An effective HCV vaccine is a major public health and medical need as recognized by the World Health Organization. However, due to the high variability of the virus and its ability to escape the immune response, HCV rapidly accumulates mutations, making vaccine development a formidable challenge. An effective vaccine must elicit broadly neutralizing antibodies (bnAbs) in a consistent fashion. After decades of studies from basic research through clinical development, the antigen of choice is considered the E1E2 envelope glycoprotein due to conserved, broadly neutralizing antigenic domains located in the constituent subunits of E1, E2, and the E1E2 heterodimeric complex itself. The challenge has been elicitation of robust humoral and cellular responses leading to broad virus neutralization due to the relatively low immunogenicity of this antigen. In view of this challenge, structure-based vaccine design approaches to stabilize key antigenic domains have been hampered due to the lack of E1E2 atomic-level resolution structures to guide them. Another challenge has been the development of a delivery platform in which a multivalent form of the antigen can be presented in order to elicit a more robust anti-HCV immune response. Recent nanoparticle vaccines are gaining prominence in the field due to their ability to facilitate a controlled multivalent presentation and trafficking to lymph nodes, where they can interact with both the cellular and humoral components of the immune system. This review focuses on recent advances in understanding the E1E2 heterodimeric structure to facilitate a rational design approach and the potential for development of a multivalent nanoparticle-based HCV E1E2 vaccine. Both aspects are considered important in the development of an effective HCV vaccine that can effectively address viral diversity and escape.

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Section: Additionally the Diagnosis Of Hcv Infectionmentioning

confidence: 99%

Hepatitis C Virus E1E2 Structure, Diversity, and Implications for Vaccine Development

Pierce,

Felbinger,

Metcalf

et al. 2024

Viruses

View full text Add to dashboard Cite

show abstract

“…These include the genetic diversity of HCV of at least seven HCV genotypes that differ up to 30% in nucleotide sequence, which can be further subdivided into over 90 subtypes, flexibility of the conformational regions, glycan shielding of neutralizing epitopes, the presence of immunodominant non-neutralizing "decoy" epitopes, and the tendency for membrane solubilized E1E2 antigen preparations to form aggregates [25,[28][29][30][31][32][33]. Moreover, direct cell-to-cell transmission of the virus, systemic circulation of virions associate with lipoproteins, and downregulation of major histocompatibility complex (MHC) expression are other mechanisms for the virus to escape protective immunity [30,[34][35][36]. Although immune correlates of protection have yet to be defined for HCV, there is broad agreement that both B and T cell immunity contribute to the control of acute HCV infection [26,37,38].…”

Section: Introductionmentioning

confidence: 99%

Hepatitis C Virus E1E2 Structure, Diversity, and Implications for Vaccine Development

Pierce,

Felbinger,

Metcalf

et al. 2024

Preprint

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Hepatitis C virus (HCV) is a major medical health burden and leading cause of chronic liver disease and cancer worldwide. More than 58 million people are chronically infected with HCV, with 1.5 million new infections occurring each year. An effective HCV vaccine is a major public health and medical need as recognized by the World Health Organization. However, due to the high variability of the virus and its ability to escape the immune response, HCV rapidly accumulates mutations making a vaccine a formidable challenge. An effective vaccine must elicit broadly neutralizing antibodies (bnAbs) in a consistent fashion. After decades of studies from basic research through clinical development, the antigen of choice is considered to be the E1E2 envelope glycoprotein due to conserved, broadly neutralizing antigenic domains located in the constituent subunits of E1, E2, and the E1E2 heterodimeric complex itself. The challenge has been elicitation of robust humoral and cellular responses leading to broad virus neutralization due to the relatively low immunogenicity of this antigen. In view of this challenge, structure-based vaccine design approaches to stabilize key antigenic domains have been hampered due to the lack of E1E2 atomic-level resolution structures to guide them. Another challenge has been development of a delivery platform in which a multivalent form of the antigen can be presented in order to elicit a more robust anti-HCV immune response. Recent nanoparticle vaccines are gaining prominence in the field due to their ability to facilitate a controlled multivalent presentation and trafficking to lymph nodes, where they can interact with both the cellular and humoral components of the immune system. This review focuses on recent advances in understanding the E1E2 heterodimeric structure to facilitate a rational design approach and the potential for development of a multivalent nanoparticle-based HCV E1E2 vaccine. Both aspects are considered important in the development of an effective HCV vaccine that can effectively address viral diversity and escape.

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