Investigational HCV Vaccine Found Safe but Not Effective

February 23, 2021
Kenneth Bender, PharmD, MA

An investigational HCV vaccine induced immunologic response and was well tolerated, but did not protect against infection.

The first clinical trial of a vaccine candidate for chronic hepatitis C virus (HCV) infection in at-risk persons who inject drugs demonstrated that it was safe and induced T-cell response, but determined that it was not effective in preventing chronic infection.

“Understanding how the virus evaded the vaccine induced immune response will guide subsequent vaccine development strategies,” principle investigator Andrea Cox, MD, PhD, Division of Infectious Diseases, Viral Hepatitis Center, Johns Hopkins University, Baltimore, MD, told ContagionLive.

“This is the first vaccine trial in people at risk for HCV infection and the first time such an investigation has been possible," Cox said.

The vaccination utilized a heterologous prime and booster strategy, with each viral vector-based vaccine encoding nonstructural proteins of HCV genotype 1b. The initial injection with chimpanzee adenovirus 3 vector (ChAd3) was followed on day 56 with a modified vaccinia Ankara (MVA) vector vaccine booster.

“Many studies have shown in head-to-head comparisons for a variety of pathogens that heterologous prime boost strategies are superior to homologous prime and boost with vectored vaccines,” Cox noted.

“The reason is in part that immune responses develop against the vectors and if the same vector us used again for boost, the vectored vaccine boost can be cleared quickly, diminishing the quality of the boost,” she explained.

Cox and colleagues identified 548 participants for the phase 1-2 randomized, double-blind, placebo-controlled, multi-site trial conducted from 2012 through 2018.The phase 2 trial commenced after 68 participants completed the phase 1 safety data monitoring; with 274 participants in both the active and placebo vaccination groups. Participants were healthy HCV-uninfected adults who had injected drugs within 90 days before randomization.

"Because persons who inject drugs have the highest incidence of HCV infection, targeting this population for testing and implementing preventive vaccines is critical," Cox and colleagues wrote."However, it is also challenging.Scheduling interim analyses to assess retention was important and ongoing outreach was essential to maximize participant engagement."

The primary efficacy end point was chronic HCV infection, defined as viremia persisting for 6 months.All participants were followed for 20 months, and for 9 months after infection, detected by monthly qualitative HCV RNA testing and confirmed with quantitative HCV RNA and genotype testing.

The investigators reported that, in the modified intention-to-treat population, chronic HCV infection developed in 19 participants in the vaccine group and 17 in the placebo group (hazard ratio, 1.66; 95%CI, 0.79 to 3.50; vaccine efficacy, -66%; 95% CI, -250 to 21).

"The statistical analysis indicated that the goal of 60% efficacy would not be met with a longer trial or with more participants," Cox indicated."Thus, a longer trial with more participants was not predicted to alter the outcome of the trial."

The investigators considered several possible factors that might have contributed to the lack of efficacy, including that adenoviral vectors can be less immunogenic in persons with vector cross-reactive antibodies, and this may be more common among persons who inject drugs.In addition, they suggest that previous exposure to trace amounts of HCV which are insufficient to induce serocoversion could reduce immune responses during subsequent infection.They also note that the vaccine did not contain HCV envelope proteins, which are the targets of neutralizing antibodies.

"The next steps will...include a vaccine designed to induce neutralizing antibody responses as well as T-cell responses," Cox commented."The mRNA vaccines have been so effective against SARS-CoV-2 that this platform will be considered for other pathogens, including HCV."