Lara C. Pullen, PhD
November 06, 2014
A prophylactic hepatitis C virus (HCV) vaccine produces a long-lasting, sustained T-cell response that is characteristic of the T-cell response associated with a controlled HCV infection. Researchers have evaluated the vaccine in humans, and it is now ready for phase 2 efficacy studies.
Leo Swadling, a graduate student in the Nuffield Department of Medicine at the University of Oxford in the United Kingdom, and colleagues published the results from the phase 1 trial published online November 5 in Science Translational Medicine. They described their heterologous T-cell vaccine, which combines replication-defective chimpanzee adenovirus (ChAd3) and modified vaccinia Ankara (MVA) vectors, both encoding the HCV nonstructural (NS) proteins. The vaccine is referred to as ChAd3/MVA.
T-cell immunity appears to be critical in protection against natural infection from HCV. In particular, CD4+ T cells generate the CD8+ T-cell immunity that is associated with HCV viral control in both natural infection in humans and chimpanzee challenge studies. Thus, vaccinologists anticipate that an effective HCV vaccine will generate a robust T-cell response.
The ChAd3/MVA vaccine induced a large HCV-specific T-cell response in humans. In most individuals, vaccination induced T-cell responses against all six NS antigenic pools. Vaccination also increased CD8+ T-cell polyfunctionality. The investigators found no signs that the vaccine induced regulatory T cells that might suppress an anti-HCV immune response.
Vaccinated individuals possessed antigen-experienced T cells that were on a continuum from naive to memory populations. Vaccinated individuals also generated CD8+ memory T cells. All told, the phenotype of T cells after vaccination with ChAd3/MVA resembled T-cell populations after vaccination with the highly efficacious yellow fever and smallpox vaccines.
The ChAd3/MVA vaccine appeared to be significantly better than the previously tested ChAd3/Ad6 vaccine. It elicited a higher magnitude of T-cell response immediately, as well as long term after boost immunization.
The diversity of the HCV genome represents an additional barrier to the development of protective HCV vaccine. ChAd3/MVA appears to overcome this barrier though generation of cross-reactive T-cell responses between heterologous viral genotypes.
"I am impressed by the ability of this combination of ChAd3 prime/MVA boost with the NSmut HCV sequence to recapitulate the natural human immune response to HCV infection, to sustain a strong response, and to impart some cross-reactive response to other HCV genotypes. On a public health note, development of a vaccine against HCV has traditionally been challenging and the disease burden remains significant in the US. In particular, the disease is generally asymptomatic initially but has a high probability to become chronic, leading to bad outcomes," Litjen Tan, PhD, from the Immunization Action Coalition in St. Paul, Minnesota, told Medscape Medical News.
Several authors of the study are named inventors for patent applications covering the vaccine. Dr Tan has received honoraria from Baxter, Pfizer, Novartis, Temptime Corp, TruMedSystems, and Sanofi Pasteur for service as a scientific consultant.
Sci Transl Med. Published online November 5, 2014. Abstract