Hepatitis C Virus Vaccines in the Era of New Direct-acting Antivirals

Chao Shi; Alexander Ploss


Expert Rev Gastroenterol Hepatol. 2013;7(2):171-185. 

In This Article

HCV Vaccines

In general, vaccination has been considered the most effective approach for combatting infectious diseases. A lesson learned from fighting HIV is that emphasis on prevention as well as treatment is important for controlling the pandemic.[18] In addition to reducing the transmission with more efficient blood screening and prevention-focused programs for IDUs, a prophylactic vaccine for HCV will fill the gaps of treatment discussed earlier, and provide a long-term solution for the disease. The target population for the vaccine will be the high-risk groups in developed countries, including healthcare workers, IDUs and men who have sex with men, and the entire population of developing countries. Optimally, a putative HCV vaccine would be effective against all HCV genotypes, would have minimal side effects, administered in a single shot and could be produced and distributed at minimal cost. However, after more than two decades of research, no HCV vaccine is currently available.

The development of a vaccine for HCV is hampered by several challenges. The first is the tremendous genetic and antigenic diversity of the virus. Currently there are seven genotypes being recognized, with sequence dissimilarity of 30–35% across the genome.[19,20] Most genotypes contain genetic diversity within the group, and can be further categorized into viral quasispecies.[21] As a positive sense, single-stranded RNA virus, HCV replicates its genome rapidly through the highly error-prone polymerase. This feature, together with the remarkable capability of the virus to produce progeny during chronic infection, enables HCV to generate a vast reservoir of genetic diversity, which provides the basis for selecting a variant with higher replicative fitness and capability of immune evasion. This also suggests that HCV is more likely to escape the immune protection elicited by a vaccine designed for a limited number of epitopes. The new antiviral drugs are facing the same challenge, as HCV variants will emerge with mutated binding sites for inhibitors (reviewed in[22]). To avoid resistance, a combination of drugs acting with different mechanisms needs to be used. Similarly, a successful vaccine is likely to contain multiple conserved epitopes that minimize the risk of viral escape. Thus, many of the current vaccination approaches in clinical development, discussed in the following sections, include numerous viral proteins encompassing larger numbers of epitopes to alleviate this problem. Additional complexity stems from the putatively different sensitivities of usually linear T-cell epitopes and frequently conformational antibody epitopes to mutational sequence diversity. While amino acid mutations in critical residues can readily abrogate T-cell antigen recognition, sequence variations that do not alter shape or charge of a viral antigen may not necessarily affect antibody recognition. The second challenge for vaccine development is incomplete understanding in the immunology of HCV infection. This is largely due to a lag in the development of experimental systems. Researchers were not able to grow HCV and test the ability of antibodies to neutralize HCV in vitro until recently.[23–26] Because of a narrow species tropism of HCV, chimpanzees are the only in vivo experimental model with competent immune system available for HCV vaccine research, but those studies are limited due to ethical concerns, restricted availability and prohibitively high costs. As a result, much of our knowledge in HCV immunology relies on the studies of a very small number of animals. Clinical studies on infected patients have been informative and probably less biased by sample size, but are hampered by limited access to the relevant tissue compartment, that is, the liver and usually limited information on the dose, timing and antigenic composition of the transmitted viral genome. The lack of accessible animal models is also a hurdle for testing the efficacy of vaccine candidates.