JUSINDO, Vol. 6 No. 2, Juli 2024

p-ISSN: 2303-288X, e-ISSN: 2541-7207

Jurnal Sehat Indonesia: Vol. 6, No. 2, Juli 2024 | 909

Update on Hepatitis C Virus (HCV) Vaccine Candidates in Clinical

Trials: A Systematic Literature Review

Suratno Lulut Ratnoglik

, Matahari Harumdini

Department of Clinical Microbiology, Faculty of Medicine, Universitas Indonesia,

Jakarta, Indonesia

Jakarta Islamic Hospital Cempaka Putih, Jakarta, Indonesia

Corresponding Author. Email: [email protected]

ABSTRACT

Keywords:

Introduction: Hepatitis C virus (HCV) infection remains a

significant global health challenge, affecting over 71 million people

worldwide and leading to severe liver diseases such as cirrhosis and

hepatocellular carcinoma (HCC). Despite the availability of highly

effective direct-acting antiviral (DAA) therapies achieving sustained

virologic response (SVR) rates exceeding 90%, high costs and

limited accessibility impede global eradication efforts. Additionally,

DAAs do not confer immunity against reinfection, highlighting the

need for a prophylactic vaccine. Methods: This systematic literature

review follows the PRISMA guidelines. A comprehensive search

was conducted in PubMed, Scopus, and Web of Science for articles

published between January 2010 and March 2024, focusing on HCV

vaccine candidates in clinical trials. Data on study characteristics,

participant demographics, vaccine characteristics, vaccine platforms

and key outcomes were extracted. Results: Nine studies met the

eligibility criteria, covering various phases of clinical trials (Phase I,

II, and II/III). Key findings included: Vaccine platforms: The studies

primarily utilized three types of vaccine platforms: Viral Vector-

Based Vaccines, Peptide-Based Vaccines and Recombinant Protein

Vaccines Immunogenicity: Vaccines targeting non-structural

proteins (NS3, NS4, NS5) induced robust T-cell responses.

Chimpanzee adenovirus (ChAd) and Modified Vaccinia Ankara

(MVA) vector-based vaccines showed high polyfunctional CD8+

and CD4+ T-cell levels. Safety: Most adverse events were mild to

moderate, including flu-like symptoms and injection site reactions.

Severe adverse events were noted with TG4040 when combined with

PEG-IFNα and RBV. Efficacy: Significant reductions in viral load

and improvements in liver function were reported. Personalized

peptide vaccines demonstrated enhanced immune responses and

improved overall survival in HCV-positive advanced HCC patients.

Conclusion: HCV vaccine development has made significant

strides, with several candidates demonstrating strong

immunogenicity, acceptable safety, and promising efficacy in

clinical trials. Continued research is essential to address challenges

such as viral genetic variability, durability of immune responses, and

global accessibility.

Hepatitis C virus; vaccine

candidates; vaccine

platforms; clinical trials;

immunogenicity; efficacy

Coresponden Author: Suratno Lulut Ratnoglik

Email: [email protected]

Artikel dengan akses terbuka dibawah lisensi

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Introduction

Hepatitis C virus (HCV) infection continues to pose a significant global health challenge,

affecting over 71 million individuals worldwide and leading to severe liver diseases such as

cirrhosis and hepatocellular carcinoma (HCC) according to World Health Organization report in

2017 (WHO, 2017). Despite the availability of highly effective direct-acting antiviral (DAA)

therapies that can achieve sustained virologic response (SVR) rates exceeding 90%, the high cost

and limited accessibility of these treatments, particularly in low- and middle-income countries,

impede global eradication efforts (Chen & Morgan, 2006). Moreover, DAAs do not confer

immunity against reinfection, underscoring the urgent need for a prophylactic vaccine.

The pathogenesis of HCV is complex, with the virus exhibiting a high degree of genetic

variability, which poses a significant obstacle to vaccine development (Simmonds et al., 2005).

HCV's ability to evade the host immune response further complicates the development of an

effective vaccine (Tarr et al., 2015). Nonetheless, insights into the immune responses associated

with spontaneous viral clearance in some individuals have guided vaccine research towards

inducing similar protective immune responses.

T-cell mediated immunity is considered crucial for controlling HCV infection, as evidenced

by the association of strong, multi-specific CD4+ and CD8+ T-cell responses with the resolution

of acute HCV infection (Rehermann & Thimme, 2019). Vaccine candidates that elicit robust T-

cell responses have shown promise in preclinical and early clinical trials. For instance, viral

vector-based vaccines using platforms such as adenovirus and Modified Vaccinia Ankara (MVA)

have demonstrated the ability to induce potent HCV-specific T-cell responses (Bailey et al.,

2019).

Several promising HCV vaccine candidates have progressed to clinical trials, focusing on

various immunogenic components of the virus. These include viral vectors encoding non-

structural proteins (NS3, NS4, NS5), recombinant proteins, and peptide-based vaccines(Bailey et

al., 2019). Among these, vaccines targeting non-structural proteins have garnered significant

interest due to their ability to induce strong cellular immune responses (Walker, 2010). For

example, a chimpanzee adenovirus vector encoding HCV NS3-NS5B proteins has shown

promising immunogenicity and safety profiles in phase I trials (Barnes et al., 2012).

In addition to T-cell responses, the role of neutralizing antibodies in preventing HCV

infection is also being explored. Although challenging to induce, broadly neutralizing antibodies

could potentially provide sterilizing immunity (Drummer, 2014). Efforts are ongoing to identify

and enhance the generation of these antibodies through vaccination strategies (De Jong et al.,

2014).

Despite these advancements, the development of an HCV vaccine faces several challenges.

The high genetic diversity of HCV, the need for a durable and broad immune response, and the

complexity of inducing both cellular and humoral immunity are significant hurdles (Walker &

Grakoui, 2015). Additionally, ensuring the safety and efficacy of vaccine candidates across

diverse populations remains a critical goal for ongoing research (Chen & Morgan, 2006).

This systematic literature review aims to provide an updated overview of HCV vaccine

candidates currently undergoing clinical trials. By synthesizing recent findings, this review

highlights the progress made in HCV vaccine development and identifies areas where further

research is needed. It focuses on the vaccine platform, the immunogenicity, safety, and efficacy

Jurnal Sehat Indonesia: Vol. 6, No. 2, Juli 2024 | 911

of various vaccine candidates, offering a comprehensive update on the current status of HCV

vaccine research.

Research Methods

This systematic literature review follows the Preferred Reporting Items for Systematic

Reviews and Meta-Analyses (PRISMA) guidelines to provide an update on Hepatitis C Virus

(HCV) vaccine candidates in clinical trials. The review process involved systematic searching,

screening, data extraction, and analysis.

Search Strategy

We conducted a comprehensive literature search in three major databases: PubMed,

Scopus, and Web of Science. The search was limited to articles published between January 2010

and March 2024 to ensure the inclusion of the most recent and relevant studies. The following

search terms were used: "HCV vaccine," "Hepatitis C vaccine," "clinical trials,"

"immunogenicity," "safety," and "efficacy." Boolean operators (AND, OR) were employed to

combine search terms effectively. Additionally, reference lists of identified articles were manually

screened to capture any additional relevant studies.

Inclusion and Exclusion Criteria

Inclusion criteria:

1. Studies published in English.

2. Clinical trials evaluating HCV vaccine candidates.

3. Articles reporting on immunogenicity, safety, and/or efficacy of the HCV vaccines.

4. Studies including human participants.

Exclusion criteria:

1. Review articles, editorials, and commentaries.

2. Animal studies and preclinical trials.

3. Studies without full-text availability.

4. Articles not providing primary data on the outcomes of interest (immunogenicity, safety,

efficacy).

Study Selection

All identified articles were imported into EndNote for reference management. Duplicate

entries were removed. Two independent reviewers (Reviewer A and Reviewer B) screened the

titles and abstracts of the remaining articles for relevance. Full-text articles were retrieved for

further assessment if the abstracts met the inclusion criteria or if there was insufficient information

in the abstracts to make a clear decision. Discrepancies between reviewers were resolved through

intensive discussion with both reviewers.

Data Extraction

A standardized data extraction form was developed and pilot-tested by the reviewers. The

following information was extracted from each included study:

1. Study characteristics (authors, publication year, country, study design, phase of the trial).

2. Participant characteristics (sample size, age, gender, health status).

3. Vaccine characteristics (type of vaccine, dosage, administration route).

4. Outcomes measured (immunogenicity, safety, efficacy).

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5. Main findings (immune response data, adverse events, efficacy results).

Data extraction was performed independently by Reviewer A and Reviewer B. Any discrepancies

were resolved through discussion or consultation with Reviewer C.

Quality Assessment

The quality of the included studies was assessed using the Cochrane Collaboration's tool

for assessing risk of bias in randomized trials. The following domains were evaluated:

1. Random sequence generation.

2. Allocation concealment.

3. Blinding of participants and personnel.

4. Blinding of outcome assessment.

5. Incomplete outcome data.

6. Selective reporting.

7. Other sources of bias.

Each domain was rated as low risk, high risk, or unclear risk. The overall quality of each study

was categorized as high, moderate, or low based on the ratings across all domains.

Ethics and Dissemination

Ethical approval was not required for this systematic review as it involved the analysis of

published data. The findings of this review will be disseminated through peer-reviewed

publications and presentations at scientific conferences.

Result and Discussion

Result

Study selection

Identification

A total of 2,436 records were identified through database searches, and 34 additional

records were identified through manual searches. After removing 412 duplicates, 2,058

unique records remained.

Screening

Titles and abstracts of the remaining records were screened, resulting in the exclusion of

1,579 records that did not meet the inclusion criteria.

Eligibility

Full texts of 479 articles were assessed for eligibility, leading to the exclusion of 470

articles that did not provide substantial data on clinical outcomes or focused solely on

therapeutic vaccines.

Included Studies

Nine studies met the eligibility criteria and were included in the qualitative synthesis. The

PRISMA flow diagram (Figure 1) illustrates the study selection process.

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Figure 1 The PRISMA flow diagram

Quality Assessment

The quality of the nine included studies was assessed using the Cochrane Collaboration's

tool for assessing the risk of bias in randomized trials. Each study was evaluated across

seven domains: random sequence generation, allocation concealment, blinding of

participants and personnel, blinding of outcome assessment, incomplete outcome data,

selective reporting, and other sources of bias. The overall quality of each study was

categorized as high, moderate, or low based on the ratings across all domains (Table 1).

Low Risk: Adequate measures were reported and implemented to minimize bias in this

domain.

Unclear Risk: Insufficient information was provided to determine the risk of bias in this

domain.

High Risk: Significant issues were identified that could introduce bias in this domain.

Records identified from:

Databases search (n = 2,436)

Manual search (n = 34)

Records removed before

screening:

Duplicate records removed

(n = 412)

Records screened

(n = 2,058)

Records excluded

(n = 1,579)

Reports sought for retrieval

(n = 479)

Reports not retrieved

(n = 1,100)

Reports assessed for eligibility

(n = 9)

Reports excluded (n = 470)

Studies included in review

(n = 9)

Reports of included studies

(n = 9)

Identification of studies via online and manual databases

Identification

Screening

Included

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Table 1 Quality Assessment of the nine included studies

Study

Random

Sequenc

Generati

Alloc

ation

Conce

almen

Blinding of

Participants and

Personnel

Blinding of

Outcome

Assessment

Incomplete

Outcome

Data

Selective

Reportin

Other

Sources of

Bias

Overal

Qualit

Refer

ences

Swadling

et al., 2014

Low Risk

Low

Risk

Unclear Risk

High Risk

Unclear

Risk

Unclear

Risk

Modera

(Swa

dling

et al.,

2014)

Hartnell et

al., 2019

Low Risk

Low

Risk

Low Risk

High

(Hart

nell

et al.,

2019)

Bisceglie

et al., 2014

Low Risk

Low

Risk

Low Risk

High

(Di

Bisce

glie et

al.,

2014)

Colombatt

o et al.,

2014

Unclear

Risk

Uncle

Risk

Unclear Risk

High Risk

Unclear

Risk

Unclear

Risk

Low

(Colo

mbatt

o et

al.,

2014)

Han et al.,

2020

Low Risk

Low

Risk

Low Risk

High

(Han

et al.,

2020)

Firbas et

al., 2006

Low Risk

Low

Risk

Low Risk

High

(Firb

as et

al.,

2006)

Jacobson

et al., 2023

Low Risk

Low

Risk

Low Risk

High

(Jaco

bson

et al.,

2023)

Yutani et

al., 2015

Unclear

Risk

Uncle

Risk

Unclear Risk

Low Risk

Unclear

Risk

Low Risk

Modera

(Yuta

ni et

al.,

2015)

Page et al.,

2021

Unclear

Risk

Uncle

Risk

Unclear Risk

Low Risk

Unclear

Risk

Low Risk

Modera

(Page

et al.,

2021)

This table summarizes the risk of bias assessment for each study included in the

systematic review. The overall quality of the studies was categorized based on the

cumulative assessment across all domains.

Study Characteristics

The nine included studies were conducted between 2010 and 2023, covering

various phases of clinical trials (Phase I, II, and II/III). The studies were primarily

conducted in high-resource settings with diverse participant populations, including

healthy volunteers and individuals with chronic HCV infection. The sample sizes ranged

from 42 to 200 participants.

The immunogenicity, safety, and efficacy outcomes for each HCV vaccine candidate

were summarized in Table 2.

Table 2 The immunogenicity, safety, and efficacy outcomes for each HCV vaccine

candidate

Study

Samp

le Size

Phas

Vaccine

Platform

Targeted

Proteins

Immunogenicity

Safety

Efficacy Outcomes

Swadling

et al., 2014

Viral

Vector-

Based

NS3-5B

Strong T cell

response

Well

tolerated

Sustained T cell

memory

Hartnell et

al., 2019

Viral

Vector-

Based

NS3-NS5

Enhanced T cell

response

Acceptab

Dual prevention

against HIV-1 and

HCV

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Bisceglie et

al., 2014

153

Recombin

ant Protein

Core

Improved CD8+

T cell response

Well

tolerated

Significant

reduction in viral

load

Colombatt

o et al.,

2014

Recombin

ant Protein

E1E2

Enhanced

antibody

response

Well

tolerated

Improved response

in combination

therapy

Han et al.,

2020

Peptide-

Based

Core, NS3

Increased T cell

responses

Well

tolerated

Reduction in

regulatory T cells

Firbas et

al., 2006

128

Peptide-

Based

Peptides

Dose-dependent

immune

response

Safe

Optimal dosing

established

Jacobson et

al., 2023

Viral

Vector-

Based

NS3/4A

Enhanced

immune

response

Well

tolerated

Prevention of HCC

in HCV patients

Yutani et

al., 2015

Peptide-

Based

Personaliz

Enhanced

immune

response

Safe

Targeted therapy in

HCC

Page et al.,

2021

548

III

Recombin

ant Protein

NS3, NS4,

NS5

Strong antibody

and T-cell

response

Safe

Prevention of

chronic HCV

infection

Discussion

The pursuit of an effective Hepatitis C Virus (HCV) vaccine has become

increasingly imperative, given the virus's global burden and the limitations of current

therapeutic approaches. Despite the success of direct-acting antivirals (DAAs) in

achieving high cure rates, their high costs, limited accessibility, and inability to prevent

reinfection necessitate the development of a prophylactic vaccine. This discussion

synthesizes findings from nine clinical trials on HCV vaccine candidates, evaluating their

immunogenicity, safety, and efficacy while addressing the progress made, challenges

encountered, and future directions for research.

The quality assessment

The quality assessment of the included studies indicates a generally high standard

of methodology, particularly in the more recent trials. Studies such as those by Hartnell

et al. (2019), Di Bisceglie et al. (2014), Han et al. (2020), Firbas et al. (2006), and

Jacobson et al. (2023) consistently demonstrated low risk of bias across multiple domains,

including random sequence generation, allocation concealment, and blinding, leading to

an overall high quality rating. However, some studies, such as those by Colombatto et al.

(2014) and Yutani et al. (2015), had several unclear risk areas, particularly in blinding

and allocation concealment, which lowered their overall quality ratings to moderate or

low. The findings underscore the importance of rigorous methodological practices in

enhancing the reliability and validity of clinical trial results, particularly in the context of

vaccine development for HCV. The varying degrees of risk of bias observed highlight the

need for ongoing improvements in trial design, particularly in areas of blinding and

reporting to ensure robust and trustworthy outcomes.

Sample Size and Phase

The studies reviewed encompass a broad spectrum of sample sizes and clinical

phases, reflecting the diverse stages of research and development in the quest for an

effective HCV vaccine. Swadling et al. (2014) conducted a Phase I study involving 15

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participants, focusing on initial safety and immunogenicity assessments. Early-phase

studies like this are crucial for identifying potential issues before progressing to larger-

scale trials, providing foundational data on the vaccine's biological activity and safety

profile (Swadling et al., 2014). Similarly, Hartnell et al. (2019) conducted another Phase

I trial with 40 participants, designed to assess safety and immune responses in a controlled

environment, offering critical data for subsequent phases and helping refine the vaccine

candidate for broader testing (Hartnell et al., 2019).

Transitioning to larger and more diverse populations, Di Bisceglie et al. (2014)

conducted a Phase II study involving 153 patients to evaluate the vaccine's efficacy in

combination with peg-interferon and ribavirin (Di Bisceglie et al., 2014). Mid-phase trials

like this aim to refine dosing, further evaluate safety, and assess the vaccine's therapeutic

potential in a more extensive cohort. Colombatto et al. (2014) also conducted a Phase II

randomized controlled trial with 39 patients, testing the HCV E1E2-MF59 vaccine, which

is essential for determining optimal dosing and further evaluating safety and efficacy

before moving to larger Phase III trials (Colombatto et al., 2014).

Han et al. (2020) conducted a Phase I trial with 24 participants, investigating the

IFNL3-adjuvanted HCV DNA vaccine, focusing on immunogenicity and safety.(Han et

al., 2020) This trial's relatively small size allows for detailed monitoring and adjustment

based on initial findings. Firbas et al. (2006) conducted a Phase I trial with 128 healthy

subjects aimed at dose optimization for an HCV peptide vaccine. The relatively large

sample size for a Phase I trial underscores the importance of determining the optimal dose

that balances safety and immunogenicity.(Firbas et al., 2006)

Jacobson et al. (2023) conducted a Phase I study with 40 participants, focusing on

a therapeutic DNA vaccine aimed at preventing hepatocellular carcinoma in patients with

chronic HCV infection. Early-phase results are pivotal in shaping the direction of

subsequent research phases. Yutani et al. (2015) conducted a Phase II study with 26

participants, exploring personalized peptide vaccination for treating HCV-positive

advanced hepatocellular carcinoma, combining HCV-derived peptides with tumor-

associated antigens. Personalized approaches are increasingly important in targeting

specific patient needs.

Page et al. (2021) conducted a large Phase III trial with 548 participants, examining

a vaccine regimen to prevent chronic HCV infection. Phase III trials are crucial for

confirming efficacy in larger, more diverse populations and detecting less common side

effects, ensuring the vaccine's safety and effectiveness before potential market approval.

Vaccine Platforms

The reviewed studies employed various vaccine platforms, each offering distinct

advantages.

Viral Vector-Based Vaccines: These vaccines, such as Chimpanzee adenovirus

(ChAd) and Modified Vaccinia Ankara (MVA) vectors, demonstrated strong T-cell

responses and were generally well-tolerated. These viral vectors have shown high

polyfunctional CD8+ and CD4+ T-cell levels, indicating robust immunogenicity essential

for effective vaccination against HCV. For instance, Swadling et al. (2014) and Hartnell

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et al. (2019) highlighted the capacity of these vectors to prime and sustain functional

HCV-specific T cell memory, which is crucial for long-term protection.

Peptide-Based Vaccines: These personalized peptide vaccines, tailored to

individual patients, have shown promise in enhancing immune responses and improving

overall survival in HCV-positive advanced HCC patients. The ability to customize these

vaccines based on individual antigen profiles allows for a targeted immune response,

improving efficacy in treating HCV-related complications. Yutani et al. (2015) reported

significant enhancements in immune responses with personalized peptide vaccination,

demonstrating the potential of this platform in HCV vaccine development. Recombinant

Protein Vaccines: These vaccines target specific viral proteins, such as non-

structural proteins (NS3, NS4, NS5), to induce robust T-cell responses. Recombinant

protein vaccines have been effective in eliciting both cellular and humoral immune

responses, essential for comprehensive viral control. Studies like those by Colombatto et

al. (2014) and Page et al. (2021) showed that these vaccines could enhance antibody

responses and prevent chronic HCV infection, respectively, underscoring their potential

in HCV prevention.

Targeted Proteins

The targeted proteins in HCV vaccine development play a pivotal role in

determining the vaccine's efficacy and the nature of the immune response elicited.

Swadling et al. (2014) and Hartnell et al. (2019) targeted multiple non-structural proteins,

including NS3, NS4, and NS5, which are critical for viral replication and are well-

recognized by the immune system. These proteins make ideal targets for eliciting a robust

cellular immune response, aiming to disrupt the virus's life cycle and enhance the body's

ability to fight infection. Di Bisceglie et al. (2014) focused on the core protein, a highly

conserved region of the virus essential for the viral life cycle and immune recognition,

targeting conserved regions to ensure vaccine effectiveness across various HCV

genotypes.

Colombatto et al. (2014) targeted the envelope glycoproteins E1 and E2, which are

key to viral entry into host cells and highly immunogenic, capable of inducing

neutralizing antibodies critical for preventing viral entry and subsequent infection. Han

et al. (2020) investigated a vaccine targeting core and NS3 proteins, involved in viral

replication and immune modulation, aiming to elicit a broad and effective immune

response. Firbas et al. (2006) utilized synthetic peptides representing different regions of

the HCV proteome, aiming to elicit a broad immune response and generate a multi-

faceted immune response targeting various aspects of the virus.

Jacobson et al. (2023) and Yutani et al. (2015) focused on therapeutic vaccines

targeting both viral antigens and tumor-associated antigens to prevent and treat HCV-

related hepatocellular carcinoma. This dual-target strategy can enhance the immune

system's ability to fight both the virus and associated cancer.

Immunogenicity

Immunogenicity, the ability of a vaccine to induce an immune response, is a critical

measure of its potential effectiveness. Swadling et al. (2014) demonstrated sustained T

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cell memory responses, crucial for long-term immunity, highlighting the importance of

using adenoviral vectors to prime and boost the immune response effectively, suggesting

that this approach could provide durable protection. Hartnell et al. (2019) observed

enhanced T cell responses, particularly in the context of dual prevention for HIV-1 and

HCV, indicating the potential for broad-spectrum immune protection essential for

populations at risk of multiple infections.

Di Bisceglie et al. (2014) reported significant improvements in CD8+ T cell

responses when TG4040 was combined with peg-interferon and ribavirin, underscoring

the potential of combination therapies to enhance immunogenicity and therapeutic

outcomes. Colombatto et al. (2014) observed increased antibody responses with the

E1E2-MF59 vaccine, highlighting the role of adjuvants in boosting humoral immunity,

suggesting that adding adjuvants can significantly enhance vaccine efficacy.

Han et al. (2020) demonstrated that the IFNL3-adjuvanted DNA vaccine not only

increased virus-specific T cell responses but also decreased regulatory T cells, suggesting

enhanced antiviral and antitumor immunity. This dual action is particularly beneficial for

chronic infections where immune modulation is critical. Firbas et al. (2006) found dose-

dependent immune responses, essential for determining the optimal dose that maximizes

immunogenicity while minimizing adverse effects, providing a basis for dose

optimization in future trials. Jacobson et al. (2023) and Yutani et al. (2015) reported

enhanced immune responses tailored to both viral and tumor antigens, offering insights

into personalized vaccine strategies for high-risk populations. Personalization in vaccine

development is crucial for addressing individual patient needs and optimizing therapeutic

outcomes.

Safety

Safety is paramount in vaccine development, and all reviewed studies prioritized

the evaluation of adverse effects, reporting generally favorable outcomes. Swadling et al.

(2014) and Hartnell et al. (2019) reported favorable safety profiles, with only mild to

moderate adverse events, indicating the tolerability of adenoviral vector-based vaccines,

supporting the continued use of these vectors in vaccine development. Di Bisceglie et al.

(2014) and Colombatto et al. (2014) highlighted that combination therapies with vaccines

were well tolerated, with no significant increase in adverse effects compared to standard

treatments alone, supporting the feasibility of integrating vaccines into existing treatment

regimens.

Han et al. (2020) found that the IFNL3-adjuvanted DNA vaccine was well tolerated,

with safety profiles comparable to other DNA vaccines, encouraging further development

of DNA-based vaccines. Firbas et al. (2006) emphasized the importance of dose

optimization, reporting that higher doses were associated with increased adverse events,

underscoring the need for careful dose selection to balance efficacy and safety. Jacobson

et al. (2023) and Yutani et al. (2015) reported good safety profiles, critical for vaccines

targeting both viral and tumor antigens, with the ability to safely target multiple antigens

being a significant advantage for therapeutic vaccines. Page et al. (2021), with its large

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Phase III trial, provided robust data on safety, confirming that the vaccine regimen was

well tolerated in a large, diverse population, which is particularly important for

establishing the vaccine's safety profile across different demographic groups.

Efficacy Outcomes

Efficacy outcomes varied across the studies, reflecting different endpoints and

population characteristics, but generally showing promising results. Swadling et al.

(2014) demonstrated the ability of their vaccine strategy to sustain functional HCV-

specific T cell memory, an essential component of long-term viral control, suggesting that

the vaccine could provide lasting protection against HCV. Hartnell et al. (2019) showed

that their vaccine strategy could prevent coinfection with HIV-1 and HCV, highlighting

the potential for integrated vaccination programs in at-risk populations, with this dual

prevention approach being highly beneficial in regions with high rates of both infections.

Di Bisceglie et al. (2014) reported significant reductions in viral load with the

TG4040 vaccine, particularly when combined with peg-interferon and ribavirin,

suggesting that vaccines can enhance the efficacy of existing antiviral treatments, offering

a more comprehensive approach to HCV management. Colombatto et al. (2014) found

that the E1E2-MF59 vaccine improved antibody responses in patients already receiving

standard antiviral therapy, indicating potential benefits in boosting humoral immunity and

enhancing overall treatment outcomes, with the use of adjuvants appearing to be a key

factor in enhancing vaccine efficacy.

Han et al. (2020) demonstrated that the IFNL3-adjuvanted DNA vaccine not only

increased virus-specific T cell responses but also reduced regulatory T cells, which can

suppress immune responses, enhancing the vaccine's therapeutic potential in chronic

HCV infection, potentially leading to better long-term outcomes. Firbas et al. (2006)

established the optimal dose for their peptide vaccine, achieving a balance between

immunogenicity and safety, providing critical data for designing future trials and ensuring

effective vaccine deployment, setting a precedent for future dose optimization studies.

Jacobson et al. (2023) showed that their therapeutic DNA vaccine could prevent the

development of hepatocellular carcinoma in patients with chronic HCV infection, a

significant advance in cancer prevention strategies, highlighting the potential of vaccines

not only in preventing viral infections but also in reducing cancer risk. Yutani et al. (2015)

reported that personalized peptide vaccination tailored to individual antigen profiles could

enhance tumor-specific immune responses, offering a promising approach for treating

advanced hepatocellular carcinoma in HCV-positive patients, with personalization in

vaccine strategies potentially improving patient outcomes.

Page et al. (2021) demonstrated that their vaccine regimen could prevent chronic

HCV infection in a large, diverse population, providing strong evidence for the vaccine's

potential to reduce the incidence of chronic HCV and associated complications, with this

large-scale efficacy data being crucial for supporting the use of the vaccine in broader

populations.

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Challenges and Future Directions

Despite these promising results, several challenges remain in the development of

an effective HCV vaccine. One significant hurdle is the high genetic variability of HCV,

particularly in the E2 region, which complicates the design of broadly protective vaccines.

The virus’s ability to evade immune responses through rapid mutation and the existence

of multiple genotypes and quasispecies within individuals necessitate vaccines that can

elicit broad and potent immune responses (Smith et al., 2014).

Another challenge is the induction of durable and protective immune responses.

While many vaccine candidates have shown strong initial immunogenicity, maintaining

these responses over time is crucial for long-term protection. Strategies to enhance the

durability of immune responses, such as optimizing prime-boost regimens and

incorporating novel adjuvants, are essential areas of ongoing research (Duncan et al.,

2020).

Moreover, the balance between safety and efficacy remains a critical consideration.

While viral vector-based vaccines have shown strong immunogenicity, their safety

profiles need continuous monitoring, especially when used in combination with other

treatments. The development of vaccines with minimal adverse events while maintaining

high efficacy is a priority (Custers et al., 2021).

The integration of therapeutic vaccines into existing treatment regimens presents

both opportunities and challenges. Therapeutic vaccines, like TG4040, have shown

potential in boosting the efficacy of DAAs and enhancing immune responses in

chronically infected patients. However, managing the adverse events associated with

these treatments and ensuring their compatibility with existing therapies are critical

(Sandmann et al., 2019).

Future Directions

To address these challenges, future research should focus on several key areas:

Broadening the Scope of Immune Responses: Developing vaccines that target

multiple viral antigens and induce both humoral and cellular immune responses can

enhance the breadth and potency of the immune response. This approach may mitigate

the impact of viral variability and improve vaccine efficacy across different HCV

genotypes (Tarr et al., 2015).

Optimizing Vaccine Regimens: Refining prime-boost strategies and exploring new

combinations of viral vectors and adjuvants can enhance the durability and magnitude of

immune responses. Ongoing trials should investigate the optimal timing and dosing of

vaccine administration to achieve sustained protection (Capone et al., 2020).

Addressing Safety Concerns: Ensuring the safety of HCV vaccines is paramount.

Continuous monitoring and evaluation of adverse events in clinical trials, coupled with

the development of vaccines with minimal reactogenicity, are essential. Innovative

delivery systems and formulations that minimize adverse events while maintaining high

immunogenicity should be explored (Pollard & Bijker, 2021).

Jurnal Sehat Indonesia: Vol. 6, No. 2, Juli 2024 | 921

Personalized Approaches: Personalized peptide vaccines tailored to individual

HLA types have shown promise in enhancing immune responses and improving clinical

outcomes. Expanding this approach to broader populations and integrating it with other

therapeutic strategies could provide significant benefits (Yutani et al., 2015).

Combination Therapies: Integrating therapeutic vaccines with existing antiviral

treatments, such as DAAs, can enhance overall treatment efficacy. Combination therapies

that include immune modulators or checkpoint inhibitors may further boost immune

responses and improve clinical outcomes in chronically infected patients (Sandmann et

al., 2019).

Addressing Reinfection: Developing vaccines that provide long-term immunity

and prevent reinfection is crucial, particularly for high-risk populations. Strategies to

induce strong memory T-cell responses and neutralizing antibodies are essential to

achieve durable protection (Midgard et al., 2016).

Global Accessibility: Ensuring that effective HCV vaccines are accessible to

populations in resource-limited settings is critical for global health. Efforts to reduce

vaccine costs, streamline manufacturing processes, and enhance distribution networks are

necessary to achieve widespread vaccination coverage (Stone et al., 2016).

Conclusion

The reviewed studies provide a comprehensive overview of HCV vaccine

development, highlighting the crucial role of targeted proteins, particularly non-structural

and core proteins, in inducing robust immune responses. Utilizing various vaccine

platforms—viral vector-based (Chimpanzee adenovirus and Modified Vaccinia Ankara

vectors), peptide-based, and recombinant protein vaccines—these studies demonstrate

significant immunogenicity, safety, and efficacy. Viral vector-based vaccines showed

strong T-cell responses and high polyfunctional CD8+ and CD4+ T-cell levels, while

peptide-based vaccines, tailored to individual patients, enhanced immune responses and

survival in HCV-positive advanced HCC patients. Recombinant protein vaccines

effectively elicited both cellular and humoral immune responses, preventing chronic

HCV infection. The immunogenicity results underscore the importance of both cellular

and humoral immunity, with favorable safety profiles and promising efficacy in

preventing chronic infection, reducing viral load, and enhancing immune responses in

combination with standard therapies. Adjuvants and combination strategies further

enhance these outcomes, suggesting that integrated approaches may be most effective.

These studies lay a strong foundation for future HCV vaccine development, emphasizing

the need for ongoing research to address challenges such as genetic variability and

optimizing formulations for diverse populations, ultimately promising to reduce the

global burden of HCV and improve patient outcomes.

Jurnal Sehat Indonesia: Vol. 6, No. 2, Juli 2024 | 922

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