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

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.

Download Full-text

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

mBio ◽

10.1128/mbio.00382-17 ◽

2017 ◽

Vol 8 (3) ◽

Cited By ~ 19

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.

Download Full-text

Hepatitis C Virus Vaccine Research: Time to Put Up or Shut Up

Viruses ◽

10.3390/v13081596 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1596

Author(s):

Alex S. Hartlage ◽

Amit Kapoor

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Neutralizing Antibodies ◽

Protective Immunity ◽

Vaccine Development ◽

Human Infection ◽

Infection Model ◽

Vaccine Trials ◽

Viral Vaccine ◽

Chronic Hcv

Unless urgently needed to prevent a pandemic, the development of a viral vaccine should follow a rigorous scientific approach. Each vaccine candidate should be designed considering the in-depth knowledge of protective immunity, followed by preclinical studies to assess immunogenicity and safety, and lastly, the evaluation of selected vaccines in human clinical trials. The recently concluded first phase II clinical trial of a human hepatitis C virus (HCV) vaccine followed this approach. Still, despite promising preclinical results, it failed to protect against chronic infection, raising grave concerns about our understanding of protective immunity. This setback, combined with the lack of HCV animal models and availability of new highly effective antivirals, has fueled ongoing discussions of using a controlled human infection model (CHIM) to test new HCV vaccine candidates. Before taking on such an approach, however, we must carefully weigh all the ethical and health consequences of human infection in the absence of a complete understanding of HCV immunity and pathogenesis. We know that there are significant gaps in our knowledge of adaptive immunity necessary to prevent chronic HCV infection. This review discusses our current understanding of HCV immunity and the critical gaps that should be filled before embarking upon new HCV vaccine trials. We discuss the importance of T cells, neutralizing antibodies, and HCV genetic diversity. We address if and how the animal HCV-like viruses can be used for conceptualizing effective HCV vaccines and what we have learned so far from these HCV surrogates. Finally, we propose a logical but narrow path forward for HCV vaccine development.

Download Full-text

A New Insight into Hepatitis C Vaccine Development

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/548280 ◽

2010 ◽

Vol 2010 ◽

pp. 1-12 ◽

Cited By ~ 19

Author(s):

Chun I. Yu ◽

Bor-Luen Chiang

Keyword(s):

Hepatitis C ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Hcv Infection ◽

Viral Immune Evasion ◽

Cell Responses ◽

Potential Success ◽

Chronic Hcv Infection ◽

Hcv Genotype 1 ◽

Chronic Hcv

Chronic hepatitis C virus (HCV) infection remains a serious burden to public health worldwide. Currently, HCV-infected patients could undergo antiviral therapy by giving pegylated IFN- with ribavirin. However, this therapy is only effective in around 50% of patients with HCV genotype 1, which accounts for more than 70% of all HCV infection, and it is not well tolerated for most patients. Moreover, there is no vaccine available. The efforts on identifying protective immunity against HCV have progressed recently. Neutralizing antibodies and robust T cell responses including both and have been shown to be related to the clearance of HCV, which have shed lights on the potential success of HCV vaccines. There are many vaccines developed and tested before entering clinical trials. Here, we would first discuss strategies of viral immune evasion and correlates of protective host immunity and finally review some prospective vaccine approaches against chronic HCV infection.

Download Full-text

SARS-CoV-2 vaccines strategies: a comprehensive review of phase 3 candidates

npj Vaccines ◽

10.1038/s41541-021-00292-w ◽

2021 ◽

Vol 6 (1) ◽

Cited By ~ 3

Author(s):

Nikolaos C. Kyriakidis ◽

Andrés López-Cortés ◽

Eduardo Vásconez González ◽

Alejandra Barreto Grimaldos ◽

Esteban Ortiz Prado

Keyword(s):

Neutralizing Antibodies ◽

Large Scale ◽

Vaccine Development ◽

Rna Virus ◽

Protein S ◽

Effective Vaccine ◽

Phase 3 ◽

Vaccine Candidates ◽

Advantages And Disadvantages ◽

The World

AbstractThe new SARS-CoV-2 virus is an RNA virus that belongs to the Coronaviridae family and causes COVID-19 disease. The newly sequenced virus appears to originate in China and rapidly spread throughout the world, becoming a pandemic that, until January 5th, 2021, has caused more than 1,866,000 deaths. Hence, laboratories worldwide are developing an effective vaccine against this disease, which will be essential to reduce morbidity and mortality. Currently, there more than 64 vaccine candidates, most of them aiming to induce neutralizing antibodies against the spike protein (S). These antibodies will prevent uptake through the human ACE-2 receptor, thereby limiting viral entrance. Different vaccine platforms are being used for vaccine development, each one presenting several advantages and disadvantages. Thus far, thirteen vaccine candidates are being tested in Phase 3 clinical trials; therefore, it is closer to receiving approval or authorization for large-scale immunizations.

Download Full-text

Intention to Be Vaccinated for COVID-19 among Italian Nurses during the Pandemic

Vaccines ◽

10.3390/vaccines9050500 ◽

2021 ◽

Vol 9 (5) ◽

pp. 500

Author(s):

Marco Trabucco Aurilio ◽

Francesco Saverio Mennini ◽

Simone Gazzillo ◽

Laura Massini ◽

Matteo Bolcato ◽

...

Keyword(s):

Vaccine Efficacy ◽

Online Survey ◽

Vaccine Development ◽

Vaccine Coverage ◽

World Health ◽

Vaccine Hesitancy ◽

Effective Vaccine ◽

Online Questionnaire ◽

Cross Sectional ◽

Female Sex

Background: While the COVID-19 pandemic has spread globally, health systems are overwhelmed by both direct and indirect mortality from other treatable conditions. COVID-19 vaccination was crucial to preventing and eliminating the disease, so vaccine development for COVID-19 was fast-tracked worldwide. Despite the fact that vaccination is commonly recognized as the most effective approach, according to the World Health Organization (WHO), vaccine hesitancy is a global health issue. Methods: We conducted a cross-sectional online survey of nurses in four different regions in Italy between 20 and 28 December 2020 to obtain data on the acceptance of the upcoming COVID-19 vaccination in order to plan specific interventions to increase the rate of vaccine coverage. Results: A total of 531 out of the 5000 nurses invited completed the online questionnaire. Most of the nurses enrolled in the study (73.4%) were female. Among the nurses, 91.5% intended to accept vaccination, whereas 2.3% were opposed and 6.2% were undecided. Female sex and confidence in vaccine efficacy represent the main predictors of vaccine intention among the study population using a logistic regression model, while other factors including vaccine safety concerns (side effects) were non-significant. Conclusions: Despite the availability of a safe and effective vaccine, intention to be vaccinated was suboptimal among nurses in our sample. We also found a significant number of people undecided as to whether to accept the vaccine. Contrary to expectations, concerns about the safety of the vaccine were not found to affect the acceptance rate; nurses’ perception of vaccine efficacy and female sex were the main influencing factors on attitudes toward vaccination in our sample. Since the success of the COVID-19 immunization plan depends on the uptake rate, these findings are of great interest for public health policies. Interventions aimed at increasing employee awareness of vaccination efficacy should be promoted among nurses in order to increase the number of vaccinated people.

Download Full-text

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

10.1101/2021.09.11.21263416 ◽

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.

Download Full-text

Rectal Acquisition of Simian Immunodeficiency Virus (SIV) SIVmac239 Infection despite Vaccine-Induced Immune Responses against the Entire SIV Proteome

Journal of Virology ◽

10.1128/jvi.00979-20 ◽

2020 ◽

Vol 94 (24) ◽

Author(s):

Mauricio A. Martins ◽

Lucas Gonzalez-Nieto ◽

Michael J. Ricciardi ◽

Varian K. Bailey ◽

Christine M. Dang ◽

...

Keyword(s):

T Cells ◽

Virus Infection ◽

Immune Responses ◽

Simian Immunodeficiency Virus ◽

Vaccine Efficacy ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Hiv Vaccine ◽

Partial Control ◽

Immunodeficiency Virus

ABSTRACT Given the complex biology of human immunodeficiency virus (HIV) and its remarkable capacity to evade host immune responses, HIV vaccine efficacy may benefit from the induction of both humoral and cellular immune responses of maximal breadth, potency, and longevity. Guided by this rationale, we set out to develop an immunization protocol aimed at maximizing the induction of anti-Envelope (anti-Env) antibodies and CD8+ T cells targeting non-Env epitopes in rhesus macaques (RMs). Our approach was to deliver the entire simian immunodeficiency virus (SIV) proteome by serial vaccinations. To that end, 12 RMs were vaccinated over 81 weeks with DNA, modified vaccinia Ankara (MVA), vesicular stomatitis virus (VSV), adenovirus type 5 (Ad5), rhesus monkey rhadinovirus (RRV), and DNA again. Both the RRV and the final DNA boosters delivered a near-full-length SIVmac239 genome capable of assembling noninfectious SIV particles and inducing T-cell responses against all nine SIV proteins. Compared to previous SIV vaccine trials, the present DNA-MVA-VSV-Ad5-RRV-DNA regimen resulted in comparable levels of Env-binding antibodies and SIV-specific CD8+ T-cells. Interestingly, one vaccinee developed low titers of neutralizing antibodies (NAbs) against SIVmac239, a tier 3 virus. Following repeated intrarectal marginal-dose challenges with SIVmac239, vaccinees were not protected from SIV acquisition but manifested partial control of viremia. Strikingly, the animal with the low-titer vaccine-induced anti-SIVmac239 NAb response acquired infection after the first SIVmac239 exposure. Collectively, these results highlight the difficulties in eliciting protective immunity against immunodeficiency virus infection. IMPORTANCE Our results are relevant to HIV vaccine development efforts because they suggest that increasing the number of booster immunizations or delivering additional viral antigens may not necessarily improve vaccine efficacy against immunodeficiency virus infection.

Download Full-text

A Point Mutation Leading to Hepatitis C Virus Escape from Neutralization by a Monoclonal Antibody to a Conserved Conformational Epitope

Journal of Virology ◽

10.1128/jvi.00252-08 ◽

2008 ◽

Vol 82 (12) ◽

pp. 6067-6072 ◽

Cited By ~ 37

Author(s):

Zhen-Yong Keck ◽

Oakley Olson ◽

Meital Gal-Tanamy ◽

Jinming Xia ◽

Arvind H. Patel ◽

...

Keyword(s):

Monoclonal Antibody ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Vaccine Development ◽

Human Monoclonal Antibody ◽

Conformational Epitope ◽

Single Amino Acid ◽

Effective Vaccine ◽

Linear Sequence ◽

Virus Escape

ABSTRACT A challenge in hepatitis C virus (HCV) vaccine development is defining conserved protective epitopes. A cluster of these epitopes comprises an immunodominant domain on the E2 glycoprotein, designated domain B. CBH-2 is a neutralizing human monoclonal antibody to a domain B epitope that is highly conserved. Alanine scanning demonstrated that the epitope involves residues G523, G530, and D535 that are also contact residues for E2 binding to CD81, a coreceptor required for virus entry into cells. However, another residue, located at position 431 and thus at a considerable distance in the linear sequence of E2, also contributes to the CBH-2 epitope. A single amino acid substitution at this residue results in escape from CBH-2-mediated neutralization in a genotype 1a virus. These results highlight the challenges inherent in developing HCV vaccines and show that an effective vaccine must induce antibodies to both conserved and more invariant epitopes to minimize virus escape.

Download Full-text

Structure-Based Design of Hepatitis C Virus E2 Glycoprotein Improves Serum Binding and Cross-Neutralization

Journal of Virology ◽

10.1128/jvi.00704-20 ◽

2020 ◽

Vol 94 (22) ◽

Cited By ~ 1

Author(s):

Brian G. Pierce ◽

Zhen-Yong Keck ◽

Ruixue Wang ◽

Patrick Lau ◽

Kyle Garagusi ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Envelope Glycoprotein ◽

Neutralizing Antibodies ◽

Viral Escape ◽

Envelope Glycoproteins ◽

Effective Vaccine ◽

Immunogenic Region ◽

Antigenic Properties ◽

Cross Neutralization

ABSTRACT An effective vaccine for hepatitis C virus (HCV) is a major unmet need, and it requires an antigen that elicits immune responses to key conserved epitopes. Based on structures of antibodies targeting HCV envelope glycoprotein E2, we designed immunogens to modulate the structure and dynamics of E2 and favor induction of broadly neutralizing antibodies (bNAbs) in the context of a vaccine. These designs include a point mutation in a key conserved antigenic site to stabilize its conformation, as well as redesigns of an immunogenic region to add a new N-glycosylation site and mask it from antibody binding. Designs were experimentally characterized for binding to a panel of human monoclonal antibodies (HMAbs) and the coreceptor CD81 to confirm preservation of epitope structure and preferred antigenicity profile. Selected E2 designs were tested for immunogenicity in mice, with and without hypervariable region 1, which is an immunogenic region associated with viral escape. One of these designs showed improvement in polyclonal immune serum binding to HCV pseudoparticles and neutralization of isolates associated with antibody resistance. These results indicate that antigen optimization through structure-based design of the envelope glycoproteins is a promising route to an effective vaccine for HCV. IMPORTANCE Hepatitis C virus infects approximately 1% of the world’s population, and no vaccine is currently available. Due to the high variability of HCV and its ability to actively escape the immune response, a goal of HCV vaccine design is to induce neutralizing antibodies that target conserved epitopes. Here, we performed structure-based design of several epitopes of the HCV E2 envelope glycoprotein to engineer its antigenic properties. Designs were tested in vitro and in vivo, demonstrating alteration of the E2 antigenic profile in several cases, and one design led to improvement of cross-neutralization of heterologous viruses. This represents a proof of concept that rational engineering of HCV envelope glycoproteins can be used to modulate E2 antigenicity and optimize a vaccine for this challenging viral target.

Download Full-text

A Mycobacteriophage-Based Vaccine Platform: SARS-CoV-2 Antigen Expression and Display

Microorganisms ◽

10.3390/microorganisms9122414 ◽

2021 ◽

Vol 9 (12) ◽

pp. 2414

Author(s):

Krista G. Freeman ◽

Katherine S. Wetzel ◽

Yu Zhang ◽

Kira M. Zack ◽

Deborah Jacobs-Sera ◽

...

Keyword(s):

Single Particle ◽

High Purity ◽

Neutralizing Antibodies ◽

Vaccine Development ◽

Antigen Expression ◽

Spike Protein ◽

Infectious Agents ◽

Protein Antigens ◽

Vaccine Platform ◽

Excellent Safety Profile

The explosion of SARS-CoV-2 infections in 2020 prompted a flurry of activity in vaccine development and exploration of various vaccine platforms, some well-established and some new. Phage-based vaccines were described previously, and we explored the possibility of using mycobacteriophages as a platform for displaying antigens of SARS-CoV-2 or other infectious agents. The potential advantages of using mycobacteriophages are that a large and diverse variety of them have been described and genomically characterized, engineering tools are available, and there is the capacity to display up to 700 antigen copies on a single particle approximately 100 nm in size. The phage body may itself be a good adjuvant, and the phages can be propagated easily, cheaply, and to high purity. Furthermore, the recent use of these phages therapeutically, including by intravenous administration, suggests an excellent safety profile, although efficacy can be restricted by neutralizing antibodies. We describe here the potent immunogenicity of mycobacteriophage Bxb1, and Bxb1 recombinants displaying SARS-CoV-2 Spike protein antigens.

Download Full-text