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Experimental Hepatitis C Vaccine Triggers T-Cell Responses in Early Clinical Trial

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An investigational adenovirus-based hepatitis C virus (HCV) vaccine induced sustained T-cell responses and cytokine production in a small Phase 1 study of healthy volunteers, according to findings reported in the January 4, 2012, issue of Science Translational Medicine.

While the recent advent of direct-acting antiviral drugs has ushered in a new era of hepatitis C treatment, an effective vaccine is still out of reach. HCV vaccine research is difficult because the virus mutates rapidly to evade the immune system and viral isolates are highly variable.

Eleanor Barnes and Paul Klenerman from the Oxford University and colleagues aimed to develop a vaccine that can elicit HCV-specific T-cell responses able to protect people against hepatitis C.

Numerous studies have shown that host T-cell responses are critical for spontaneous HCV clearance, the study authors noted as background, and preclinical studies suggest this type of response is required for a vaccine to confer protective immunity.

The researchers designed recombinant vaccine vectors made up of HCV proteins delivered by adenoviruses, the type of virus that causes the common cold.

According to their first report, they tested a variety of adenoviruses for HCV vaccine suitability. Recombinant vectors based on human adenovirus type 5 (Ad5) have been shown to induce protective immune responses against various pathogens. However, they are not as effective for individuals -- representing a majority of the population -- who have previously been exposed to and developed neutralizing antibodies against Ad5.

The investigators therefore tested rare human adenoviruses, against which most people would not have antibodies, but these proved to be "far less potent" than Ad5 as vaccine vectors. Next, they looked at more than 1000 chimpanzee adenovirus strains to determine if they would be neutralized by human antibodies and able to grow in human laboratory cell lines. The potency of chimpanzee adenovirus vectors varied widely in mice, and a subset were found to be safe and potent in Phase 1 human clinical trials.

As described in the other report, the team tested 2 replication-defective adenovirus vectors -- the rare human serotype Ad6 and chimpanzee adenovirus 3 (ChAd3) -- expressing NS (non-structural) proteins from HCV genotype 1b. The analysis included 41 healthy volunteers without hepatitis C.

Results

  • Both adenovirus vectors primed T-cell responses against HCV proteins, including both CD4 and CD8 cell subsets.
  • These T-cell responses targeted multiple HCV proteins, and were able to recognize HCV genotypes 1a and 3a, as well as 1b.
  • These HCV-specific T-cells secreted cytokines (chemical messengers) involved in immune response including interleukin 2, interferon gamma, and tumor necrosis factor alfa.
  • After a booster vaccine, T-cell responses were sustained for at least 1 year.
  • The researchers identified pools of long-lived central and effector memory T-cells that maintained functionality and ability to proliferate.

Based on these findings, the study authors wrote, "These data indicate that an adenoviral vector strategy can induce sustained T-cell responses of a magnitude and quality associated with protective immunity and open the way for studies of prophylactic [preventive] and therapeutic vaccines for HCV."

Immunological responses in people with chronic hepatitis C are typically both low in magnitude and narrowly focused on a small number of viral antigens, allowing the virus to escape immune control, they elaborated in their discussion. In this study, increased the breadth of responses to the experimental vaccines was associated with greater magnitude of response. "Because of the diversity of viral strains even within a single genotype or subtype, such breadth improves the chances of peptide recognition of the incoming strain, as well as limiting further escape in vivo," they wrote.

"The future development of a prophylactic vaccine will hinge on identifying not only the optimal priming/boosting regimen, but also a suitable high-risk cohort" in which this strategy can be evaluated in Phase 2 clinical trials, they continued. "Such cohorts have been identified in the United States, Canada, Australia, and the UK...In the United States, the predominant genotype in such groups is 1, and this will provide a crucial test of the success of this approach."

Such a strategy may also be used to develop a therapeutic vaccine to boost immunity in people who already have chronic hepatitis C. The fact that some people can naturally control HCV after infection suggests that this is an achievable goal, with the vaccine "accelerat[ing] the generation of immunity...after exposure" and "enhanc[ing] the chances of clearance."

"Overall, this work has shown that it is possible to generate very strong, broad, long-lasting, and functional T-cell responses against HCV in healthy donors using an adenovirus-based approach," the authors concluded. "The next critical step will be to test whether these populations can be protective in vivo, such as in a setting where HCV exposure is common, and therefore whether this or related strategies can provide an effective vaccine against HCV."

"The immune responses we've seen are exciting and we are beginning the next stage of trials," Klenerman said. "While we are hopeful, it could be a long road to any vaccine that protects people against hepatitis C."

Investigator affiliations: Nuffield Department of Medicine, University of Oxford, Oxford, UK; National Institute for Health and Research (NIHR) Biomedical Research Centre, John Radcliffe Hospital, Oxford, UK; NIHR Liver Biomedical Research Unit, University of Birmingham, Birmingham, UK; Jenner Institute, University of Oxford, Oxford, UK; Okairos, Rome, Italy; Istituto di Ricerche di Biologia Molecolare “P. Angeletti,” Rome, Italy; CEINGE, Naples, Italy;

1/10/12

References

E Barnes, A Folgori, S Capone, P Klenermanet al. Novel adenovirus-based vaccines induce broad and sustained T cell responses to HCV in man. Science Translational Medicine 4(115):115ra1. January 4, 2012.

S. Colloca, E Barnes, A Folgori, et al. Vaccinevectors derived from a large collection of simian adenoviruses induce potent cellular immunity across multiple species. Science Translational Medicine 4(115):115ra2. January 4, 2012.

Other Source

AAAS. Science Translational MedicinePress Package for January 4, 2012.