Hepatitis C Vaccination: Where We Are and Where We Need to Be

In many parts of the world, the hepatitis C virus (HCV) is a frequent cause of chronic liver disease and liver cancer. The frequency of new infections is not declining at the predicted rate to meet the World Health Organization (WHO) aim for the eradication of HCV by 2030, despite advancements in curative medicines for the disease. In fact, there are currently more new cases of infection than there are cures, both in the United States and globally. Poor access to care and the opioid crisis are two factors contributing to the increase in new cases. To completely eradicate the virus, a multimodal strategy is necessary due to the clinical burden of HCV. The use of vaccines would be a great way to stop the spread of new illnesses;Making a widely reactive vaccination is challenging, nevertheless, due to the genetic variety of HCV and its capacity to create quasispecies within an infected host. Despite the fact that various vaccine candidates have been found, no target has yet produced a widely reactive vaccination, even if several of the possibilities show promise. Additionally, it is difficult to cultivate the virus and it is unethical to test potential candidates on people or chimpanzees. Vaccination still stands as a crucial weapon in the war against HCV despite the numerous obstacles to its development.

The hepatitis C virus (HCV) is a systemic infection that has an impact on a variety of organ systems as well as quality of life. It is one of the most prevalent causes of chronic liver disease, cirrhosis, liver transplantation, and liver cancer globally. Up to 75% of individuals who have an acute HCV infection go on to develop a chronic infection, which frequently results in liver disease-related morbidity and death. Since the 1980s, certain countries have seen a fall in the prevalence of new HCV infections, while other nations have seen an increase in incidence, which has blunted the decline in prevalence. The treatment and cure of chronic HCV have considerably improved with the introduction of direct-acting antiviral (DAAs) medications.

At an annual incidence of 3–4 million/year, around 100 million individuals worldwide have HCV infection (i.e., are anti-HCV positive), while an estimated 71 million people are believed to have CHC (i.e., HCV RNA positive). With the eastern Mediterranean area having the greatest prevalence of HCV at 2.3% and the western Pacific region having the lowest prevalence at 0.5%, there is a significant regional variation in HCV prevalence. Countries with limited resources to HCV screening are at higher risk of sequelae from undiagnosed CHC due to the delays in diagnosis and receiving care, in contrast to the United States Preventive Services Task Force (USPSTF) recommendations for universal HCV screening of all asymptomatic adults aged 18 to 79 years.

Furthermore, data from the Centers for Disease Control and Prevention (CDC), which has tracked the incidence of acute HCV in the US since 1982, reveal that while acute infections in the country have decreased from their peak in 1989 to their lowest point in 2010, there has been a troubling trend of increasing cases since 2010. For instance, according to the CDC, the number of infections increased four times between 2010 and 2017: from around 11,800 acute HCV cases in 2010 to 44,700 cases in 2017. People who inject drugs (PWID), especially young individuals, were shown to have a considerably greater frequency of HCV infection, which has been related to an ongoing opioid epidemic in the US. A systemic review that estimated 52.3% of PWID have been exposed to HCV based on anti-HCV antibodies demonstrated that the increased incidence and prevalence among PWID are not only present in the US. As a result, prevention through vaccination would be the best alternative to treatment in order to accomplish this goal. In fact, computer simulations have demonstrated that a vaccination with even a 30% efficiency would still dramatically lower the clinical burden of illness.

HCV is a single-stranded, positive-sense RNA virus that belongs to the Flaviviridae family's genus Hepacivirus. The viral genome is around 9 kb long and encodes a single polyprotein that is broken down by cellular and viral proteases into a number of functional fragments. It is possible to further separate the functional segments into structural and nonstructural (NS) components. Even if many of these components' roles are understood, the whole picture is still not clear. In the lipid envelope that surrounds the virus, HCV has three structural proteins. The primary roles of the structural proteins are to enable capsid structure assembly and cell entrance.

There are at least 67 different subtypes of HCV, the genome of which is approximately 9 kb length and has seven recognized genotypes. It will be extremely difficult to create a vaccine that is effective against all genotypes and subtypes given this genetic variety. In addition, the HCV NS5B polymerase, which is the target of medications like sofosbuvir, can produce 'quasispecies,' or genetically separate but related species, inside a single host. This is partly because NS5B lacks a way to catch replication mistakes before they are replicated. The creation of a widely reactive vaccination is further hampered by the selection for viral resistance to host immune responses by this production of quasispecies within a person.

The exact method by which HCV is naturally eliminated from the body is yet unknown. Neutralizing antibodies (nAb) against glycoprotein E2 have been linked to viral clearance in early studies in chimpanzees. Numerous investigations showed that nAb formation was accelerated during the initial stages of native infection in humans, and this was also correlated with a greater capacity to eliminate the virus. Human studies have demonstrated that acute HCV infection induced a potent T-cell response. Those who had spontaneous resolution consistently showed a robust and long-lasting CD8 T-cell response. These data clearly demonstrate the need for a vaccination that can induce both a nAb and a CMI response.

1.Animal Models

In order to understand the immune response in the creation of an HCV vaccine, chimpanzee models—which were originally employed to examine the impact of HCV in animals—have been crucial. There are several potential HCV vaccines, including virus-like particles, recombinant proteins, recombinant proteins and peptides, DNA and viral vectors, and recombinant protein-based approaches. These vaccines aim to stimulate humoral and/or cellular immunity. Some of them also concentrated on NS proteins and envelope proteins.

Two chimpanzee model studies have advanced to human trials. Recombinant E1 and E2 glycoproteins from a genotype 1a virus adjuvanted with MF59 (immunological adjuvant) were used in an antibody-based vaccine formulation that demonstrated a potent antibody response and delayed the start of viremia but did not provide sterilizing immunity. A recombinant chimpanzee adenovirus (serotype 3) prime and a modified vaccinia ankara (MVA) boost (to improve immunogenicity) expressing the NS3-5B proteins from a genotype 1b virus make up Glaxo Smith Kline's T-cell-based vaccination. Rapid recall of the memory T-cell response and reduction of acute-phase viremia were the outcomes of this heterologous challenge.Two studies assessed the efficiency of T-cell vaccination in reducing RHV persistence using a rat Hepacivirus infection paradigm. Inducing full protective immunity using a simian adenovirus vector vaccination proved successful in the rat RHV model. Rats were vaccinated with adenoviral vectors encoding RHV NS3-5B proteins, and this resulted in T-cell responses and a decrease in the frequency of CHC infection. Increased protection against viral persistence was obtained by include the E1 and E2 glycoproteins as vaccine targets.

2.Human Models

Numerous human clinical studies have been conducted as a result of the encouraging results in animal models. Different vaccine types, including glycoproteins and viral vectors, have been utilized in these clinical investigations.

2.1 Glycoprotein Vaccines in Human Models

The immunogenicity of an HCV recombinant E1 and E2 glycoprotein as a potential vaccine has been investigated in a few Phase 1 studies. 60 healthy people participated in a four-dose, randomized, double-blind, placebo-controlled research that Frey designed using the HCV E1/E2 vaccination. This study showed that participants' lymphocyte proliferation responses to E1/E2 did not significantly differ among groups in terms of negative impacts. Overall, the vaccination was well tolerated, and a strong humoral and cell-mediated immune response was elicited—interestingly, this response was not dose-dependent. 

Patients were also given the recombinant glycoproteins E1E2 from a single HCV strain by Law as vaccinations. Three of the vaccinations in this investigation had widespread cross-neutralizing reactions, and at least one vaccine was pan-genotypic with responses against all HCV genotypes. This study employed 16 distinct vaccines. This trial showed that, despite differences in the structure of the E1/E2 glycoproteins, a vaccine derived from a single strain of HCV could potentially be used across different genotypes, even though only a small percentage of the vaccines tested in this trial produced enough cross-neutralizing antibodies. Leroux employed a 3:4 dosage regimen on 20 male volunteers to generate a cellular immunological response, with all but one of their subjects showing a definite T helper type 1 response.

2.2 Viral Vector Vaccines in Human Models

It has been attempted to use viral vectors in other human Phase 1-2 clinical studies to elicit an immune response to viral HCV; GT1b NS3-NS5B has attracted particular attention. Page most recently produced HCV-specific T-cell responses in 68 subjects in a Phase 1-2 randomized, double-blind, placebo-controlled experiment using a recombinant chimpanzee adenovirus 3 vector priming vaccine (ChAd3-NSmut) and a recombinant modified vaccinia ankara boost (MVA-NSmut). The incidence of CHC infection was not decreased compared to the placebo group, despite the fact that the research did induce T-cell responses against HCV proteins, hence it did not ultimately prevent CHC infection.

This result was hypothesized to be caused by reduced innate vaccination immunogenicity in the research population of drug users. The vector used in Swadling's work, which encodes the NS3, NS4, NS5A, and NS5B proteins of HCV genotype 1B, demonstrated a robust, long-lasting T-cell response in both CD4+ and CD8+ cells. Although the study did not explicitly characterize this activation of T cells as conferring HCV protection, it did highlight viral vectors as a possible method in the creation of a preventative HCV vaccine. Barnes primed T-cells to react to several HCV strains in a way that was consistent with protective immunity in a Phase 1 experiment using two unusual serotype adenoviral vectors. With CD4+ and CD8+ T-cell responses that were detectable a year later to a wide range of antigens, this strategy was highly immunogenic and well tolerated. Hartnell created a vaccination regimen using replication-defective and serologically distinct chimpanzee adenovirus (ChAd3, ChAd63) vector priming followed by MVA boosts for simultaneous delivery of HCV NS and HIV-1 conserved (HIVconsv) region immunogens. 

This allowed him to extrapolate the need for HCV vaccination to also include HIV-1 vaccination. These vaccinations were safely administered together without affecting each vaccine's immunogenicity. To improve HCV-specific T-cell induction, Esposito created MHC class II invariant chain-adjuvanted viral vectored vaccinations for humans. Overall, this T-cell immunity may be crucial for HCV management and, ideally, will increase the effectiveness of the vaccination.

The last ten years have seen a substantial advancement in the development of a widely reactive HCV vaccine, with several studies in both animal and human models. The fact that all of the aforementioned trials are still in their early stages indicates that there are regrettably still major limits in vaccine development. In order to incorporate both an antibody response and a strong T-cell response into a successful vaccine, a deeper comprehension of the underlying processes by which immune cells mediate both short- and long-term protection is required. Additionally, technical developments have not yet been widely used or studied, including the use of computational tactics like computer-generated HCV viral vaccine sequences to induce a cross-reactive T-cell response, which has been found to be successful. 

Testing successful vaccinations is still difficult, and some experts have argued that developing a human infection model using a limited number of human volunteers would be an important and beneficial next step. The general public perception of HCV is that it exclusively affects underserved populations, which has diminished interest as seen by the absence of financing, according to other specialists. According to a Lancet report, there were just 2 human clinical studies for HCV in 2019 compared to 39 human clinical trials for HIV vaccines. This shows that in order for the research to advance more swiftly, greater public education on the pervasive nature of HCV and its implications for public health is also required.