Is a hepatitis C vaccine the key to eradication?

A hepatitis C virus (HCV) vaccine may be the answer for the global control of HCV infection, according to researchers of a recently published article in Gastroenterology.

“Despite development challenges, a prophylactic vaccine is necessary for global control of HCV,” wrote the authors, led by Justin R. Bailey, MD, PhD, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD. “Treatment does not eliminate all of the consequences of HCV infection, and prevention of chronic infection offers significant advantages over treatment.”

The authors posited that, regardless of risk factors, an HCV vaccine could decrease the global burden of this disease.

Drawbacks of direct-acting antivirals

HCV screening in developing countries is rare. Globally, most people with the disease go unnoticed until the onset of serious liver disease.

Although direct-acting antivirals (DAAs) that cure HCV are available, barriers to delivery and cost of treatment often result in only a select subset of infected individuals being treated, leaving those with limited accessibility without treatment.

Also, some people develop resistance to DAAs, and the authors of the current study predicted that such resistance will become more frequent in the setting of medication nonadherence. In addition, liver disease can still advance even after DAA treatment for HCV (eg, cirrhosis, hepatocellular carcinoma).

Finally, patients can become reinfected, making HCV elimination difficult. In particular, in individuals with ongoing risk of infection—such as those who inject drugs, men having sex with men, and health-care professionals with frequent exposure to blood and bodily fluids—immunity after effective treatment has been shown to be insufficient to prevent reinfection.

But even with an HCV vaccine with only moderate efficacy, high vaccination rates among high-risk patients would still have significant effects on transmission, the authors noted.

Barriers to hepatitis C vaccine

Certain barriers exist to the successful development of an HCV vaccine.

First, HCV is very genetically diverse—more so than even HIV—with 7 elucidated genotypes and 80 subtypes. Different genotypes vary on average by approximately 30% of amino acid content, with different subtypes varying by an average of about 15%.

Second, lack of in vitro systems to test HCV vaccine hampers the development of a vaccine. Currently, no immunocompetent small animal model can elucidate whether the HCV vaccine would elicit immune protection. Of note, the discovery of rat herpacivirus, a hepatitis-like virus, could yield new animal models; however, although the HCV and rat herpacivirus are structurally similar, they share limited sequence homology.

Third, researchers possess a limited understanding of protective immune responses, which makes development of an HCV vaccine difficult.

“It is a challenge to translate what we have learned about protective T-cell responses to design of vaccines that elicit these responses,” wrote Dr. Bailey and colleagues. “Immune responses that prevent persistence of infection could decrease HCV morbidity and mortality without reducing incidence of infection.”

In other words, to be of global benefit, vaccines need not provide sterilizing immunity but merely induce immune responses that reduce HCV clearance and prevent chronic infection.

Vaccine trials

To date, two vaccines have been tested in phase 1 trials to prevent infection solely by inducing T-cell mediated immunity.

The first vaccine was a prototype consisting of HCV Core protein and ISCOMATRIX adjuvant. The candidate was tested for its ability to induce T-cell responses in adults not at risk for HCV infection. Although the vaccine was well tolerated, T-cell response occurred in only 2 of 8 study participants who were administered the highest dose.

The second vaccine consisted of a replication defective chimpanzee adenovirus (ChAd) vector encoding NS3, NS4, and NS5 proteins and was also tested in healthy volunteers. This vaccine then served as basis for a vaccine trial in at-risk individuals.

The authors suggested that the key to controlling HCV involves screening on a broader scale, treatment of infected persons—including more focus on those with limited access—and prevention and harm-reduction strategies for those who are uninfected yet at risk.

“Vaccine strategies meant to overcome the enormous diversity of HCV must generate a broad immune response, capable of responding to abundant variations,” the authors concluded. “Selecting antigens to maximize the induction of T-cell and antibody responses that elicit successful responses remains an active area of research.”