Infection with the hepatitis C virus (HCV) is a significant public health problem throughout the world and constitutes a major global cause of morbidity and mortality. Recent estimates indicate that the global rate of HCV seroprevalence increased to 2.8% in the last decade, which corresponds to >185 million cases of HCV worldwide.1 To reduce the global burden of HCV-associated disease, the World Health Organization stated that the rate of new HCV infections must be reduced 90% by 2030.2

In 2014, in the first significant breakthrough toward achieving this goal, oral, interferon-sparing, direct-acting antivirals, were approved for the treatment of HCV infection, making it possible to envision a cure for the first time. And although these drugs have revolutionized the treatment of HCV, providing better efficacy, dramatically increased tolerability, and ease of dosing when compared with previous interferon-based therapy, they are not a panacea.3

Related Articles

Unique HCV Features

HCV has several unique characteristics that complicate treatment. Infections with the virus typically remain subclinical for years, rarely manifesting any symptoms before the onset of advanced liver disease. Moreover, routine screening for HCV is rare in most parts of the world, including the United States, so the majority of people who are infected with subclinical HCV have not been diagnosed at any given time point.

There are other, major impediments to slowing the spread of the disease. Drug resistance is problematic and was an issue with interferon-based treatments before the advent of direct-acting antivirals. This is likely to get worse as treatment expands to populations that are less likely to reliably comply with treatment, including injection drug users and people in poor, rural environments with little ready access to health care.

Insufficient immunity, despite treatment, is not uncommon. Reinfection remains an issue, especially in individuals with ongoing risk for infection, including injection drug users, men who have sex with men, and healthcare workers with frequent exposure to blood and bodily fluids. In the past decade, injection drug users accounted for two-thirds of all new cases of HCV infection in this population. In fact, the incidence of new HCV infections were 10-fold higher with new HIV infections.4 One study of active injection drug users showed 6- and 18-month reinfection rates of 12.6 and 17.1 per 100 person years, respectively.2  

Furthermore, liver disease can progress and cancer can still develop even after effecting a cure of the HCV infection in patients with cirrhosis. As a result, HCV treatment has been decreasing globally since its peak in 2015.

To achieve the World Health Organization’s goal of reducing HCV infection rates by 90% before 2030, annual cure rates will have to consistently and significantly exceed new HCV infection rates. A 2016 survey demonstrated that nearly 60% of surveyed countries had more infections than cures in 2016, and few countries are expected to eliminate HCV before 2030. Consequently, control is unlikely to occur without improved focus on and success in reducing the number of new HCV infections in addition to cures.

HCV is the most common blood-borne virus for which there is no vaccine.4 Prevention of chronic infection offers significant advantages over treatment, so the development of an effective HCV vaccine to prevent disease transmission is essential to decrease the rate of new HCV infections.

Barriers to HCV Vaccine Development

Although live-attenuated and whole virus vaccines have proved effective against many viruses, they would not work against HCV because the risk of transmitting HCV is too great. HCV has 7 known genotypes and more than 80 subtypes, which exceeds the genetic diversity of HIV-1. Developing a vaccine that targets each variant is a challenge.

Until recently, researchers have not been able to culture HCV. Moreover, culture strains of HCV have shown adaptive mutations that increase the ability of the virus to replicate in vitro. It is unknown how this adaptive ability would affect replication in humans.

Incomplete understanding of protective immune responses is another important challenge to developing an HCV vaccine. Researchers have not yet been able to develop in vitro systems and immunocompetent small animal models that can determine whether a vaccine induces protective immunity against HCV.

An important goal of HCV vaccine research is to determine the mechanisms through which antigen-specific immune cell populations mediate long-term protection. A successful vaccine must generate a broad immune response targeting the different HCV variants in order to overcome HCV’s genetic diversity. Researchers are currently endeavoring to determine which antigens are likely to maximize T cell and antibody responses. So far, at least 4 types of HCV antigens have been identified and are being studied.2

It is also difficult to validate the efficacy of a new vaccine without testing it in populations of people who are at high risk of developing HCV without the risk of transmitting the disease, but high vaccination rates of high-risk individuals, such as injection drug users who are seronegative, could significantly impact disease transmission, even with a vaccine that is only 30% effective.2

Future Strategies

In an article recently published in Gastroenterology, Bailey et al posit that successful control of HCV infection will require a multi-pronged approach consisting of a combination of large-scale screening to identify infected individuals, treatment of infected persons, and prevention and harm-reduction strategies for uninfected but at-risk populations.2 They state that although pharmaceutical companies have invested more in drug development that vaccine development will require significant  investment from sources other than government and charitable foundations.

“A prophylactic HCV vaccine is an important part of a successful strategy for global control. Although development is not easy, the quest is a worthy challenge,” they concluded.


1. Petruzziello A, Marigliano S, Loquercio G, Cozzolino A, Cacciapuoti C.Global epidemiology of hepatitis C virus infection: An up-date of the distribution and circulation of hepatitis C virus genotypes. World J Gastroenterol. 2016;22(34):7824-7840.

2. Bailey JR, Barnes E, Cox AL. Approaches, progress, and challenges to hepatitis C vaccine development. Gastroenterology. 2019;156(2):418-430.

3. Mathur P, Kottilil S, Wilson E. Use of ribavirin for hepatitis C treatment in the modern direct-acting antiviral era. J Clin Transl Hepatol. 2018;6(4):431-437.

4. Rosen HR. “Hep C, where art thou”: what are the remaining (fundable) questions in hepatitis C virus research? Hepatology. 2017;65(1):341-349.