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

Recent Progress in the Model Systems for Vaccine Studies

The development of an infectious cell culture system for HCV in 2005[23,115,116] marked a major milestone for hepatitis C research. It has not only enabled in-depth studies of the HCV life cycle but has also aided HCV vaccine research. The cell culture system for HCV has not only been applied to study the efficiency of neutralizing antibodies,[46,117,118] but also to understand the mechanisms of immune evasion of HCV.[47,119] However, the infectious cell culture system relies primarily on a single HCV molecular clone derived from a Japanese genotype 2a infected patient with fulminant hepatitis (JFH1), replicate efficiently both in tissue culture and in animal models. Subsequently, intergenotypic chimeras consisting of the core through NS2 regions of representative genomes of all seven HCV genotypes have been constructed.[120–123] These tools have become indispensable for in vitro and in vivo assays of HCV entry and neutralization. However, a broad spectrum of infectious clones of all HCV genotypes capable of replicating in cell culture is still missing. Despite these advances, a huge gap still exists between in vitro experimental systems and clinical studies. Although the efficacy of preventive vaccines can be assessed in individuals with high risks of exposure, such as IDUs and healthcare workers, the low incidence rates of infection in developed countries requires a large number of participants to be recruited in order to detect statistically significant differences. Consequently, it may be more feasible to conduct clinical trials in developing countries with high prevalence and incidence rates of new infections. Testing of preventative and especially therapeutic vaccines in human trials without adequate preclinical safety assessment in animal models can be problematic, since vaccine induced and/or exacerbated responses may lead to more severe hepatitis and in worst-case scenario to acute liver failure. Furthermore, vaccine dosing, formulations and vaccination schedules often need to be empirically tested to define regimens that result not only in maximal immunogenicity but also efficacy. However, animal models that can be infected with HCV and thus are suitable for testing of vaccine candidates are sparse (Table 3).

Chimpanzees have been the central animal model to study HCV infection. Besides humans, they are the only species that is naturally susceptible to HCV infection. Chimpanzees partially recapitulate the natural course of infection in humans. While acute hepatitis is somewhat milder in chimpanzees than in humans, experimentally infected animals also frequently progress to chronicity.[74,124,125] Subclinical hepatitis, after many years of chronicity, however, is also not uncommon in humans without risk factors for rapid progression including, older age or alcohol intake. The chimpanzee model has been of critical importance for defining the nature of protective immunity following reinfection. Experiments in chimpanzees demonstrated that clearance of a primary infection with HCV does not provide sterilizing immunity against challenges with homologous or heterologous viruses.[83,84] However, despite their utility, the use of chimpanzees in biomedical research is intensely debated due to ethical concerns. In fact, strong public opposition against the use of large apes has led to the ban of chimpanzee research in many countries. Undoubtedly, an NIH moratorium on 'nonessential chimpanzee research'[204] is likely to constrain HCV vaccine development and HCV research in general in the future. Furthermore, experiments in chimpanzees are associated with very high cost, and usually only few animals, which are genetically heterogeneous, remain available. Consequently, the interpretation of data derived from experiments on a small number of chimpanzees is often statistically difficult.

Accessible animal models, in particularly immunocompetent small rodents and primates, are urgently needed. Significant progress has been recently made in attempts to adapt HCV to infect nonpermissive species and to engineer the host environment to provide an environment that is more conducive to viral infection. While many new tools are still in the early phases of development, they hold promise to dramatically improve our ability to preclinically assess vaccine candidates in the near future.