An experimental vaccine against the chronic liver disease hepatitis C has shown promising results in its first clinical trial in humans, say researchers from the University of Oxford, UK, who write about their findings in the 4 January online issue of Science Translational Medicine. However, they caution there is still a long way to go before we have an effective vaccine ready for clinical use.
There is currently no vaccine for hepatitis C virus (HCV), a major pathogen transmitted through the blood that infects some 170 million people around the world. The infection can remain hidden without showing symptoms for years, and many people don't know they are infected.
The disease is now the main reason people in Western countries have liver transplants.
A feature of HCV is that its course is unpredictable. Some people can become infected and then gradually experience liver damage, while others, a small minority, seem to have sufficient immunity that they clear the virus soon after infection.
In the trial, the experimental vaccine generated immune responses similar to those seen in these few people with natural immunity.
The researchers hope their findings mean in time, it may be possible to develop a vaccine that will be broadly effective and offer lifelong protection against HCV, or help treat those already infected.
They warn however that several more studies over several years must be done first before such a hope can become a reality.
Senior investigator Paul Klenerman, a professor in the Nuffield Department of Clinical Medicine at Oxford University, told the press:
"The immune responses we've seen are exciting and we are beginning the next stage of trials. While we are hopeful, it could be a long road to any vaccine that protects people against hepatitis C."
A key feature of the study, is that the Oxford researchers, with colleagues from an Italian biotech company and the University of Birmingham in the UK, departed from a traditional approach and went in a new direction.
The reason they went a different way is because of another feature of HCV: it is always changing its make up, in that respect it is similar to HIV. This makes it difficult to pick a target that will be there for some time and make an effective building block for a vaccine.
So the researchers turned to a new idea: they picked a target in the virus that is less likely to change: an internal part, rather than the more traditional approach of picking something on the surface of the virus.
Klenerman explained:
"The outside shell of the hepatitis C virus is very variable but the inside of the virus is much more stable. That's where the engine of the virus is, where we may be able to successfully target many of the crucial pieces of machinery."
Choosing a more constant internal virus part as a target would also stimulate a different type of immune response from what had been attempted in previous studies to develop an HCV vaccine.
".. we need T cells and not antibodies to be able to react to the inner components of the virus," said Klenerman.
So he and his colleagues set out to boost HCV-specific T cells using a "recombinant adenoviral vector strategy" in human volunteers. In total, 41 healthy adults took part in the study.
In their paper the researchers describe how they adapted two adenoviruses to carry NS (nonstructural) proteins from HCV genotype 1B. One adenovirus was sourced from a rare human serotype (Ad6, human adenovirus 6) and the other from chimpanzee (ChAd3, chimpanzee adenovirus 3).
They found that:
"Both vectors primed T cell responses against HCV proteins; these T cell responses targeted multiple proteins and were capable of recognizing heterologous strains (genotypes 1A and 3A)."
The HCV-specific cells that the response elicited consisted of a broad range, including both CD4+ and CD8+ subsets, "secreted interleukin-2, interferon-[gamma], and tumor necrosis factor-[alpha]".
The researchers note that the response "... could be sustained for at least a year after boosting with the heterologous adenoviral vector", and that further study showed the presence of "... long-lived central and effector memory pools that retained polyfunctionality and proliferative capacity".
They conclude that the findings show it is possible, using an adenoviral vector strategy, to induce "sustained T cell responses" of sufficient size and quality to confer protective immunity and "open the way" for further research into an effective vaccine and treatment for HCV.
The purpose of this phase 1 study was primarily to establish the vaccine is safe, and to record the kind of immune response it generates. The results show that the vaccine appeared safe in the group that took part in the study, and no significant adverse reactions were reported.
Klenerman said they were excited by the immune responses they observed in this phase 1 trial and that the next phase is already under way.
The Oxford team is now starting a trial to see if the experimental vaccine can treat those already infected with HCV, and they also want to continue to develop it to elicit stronger immune responses.
"T cell responses often become weak in those with chronic hepatitis C infections," said Klenerman. "It may be that using a vaccine to boost their immunity could become part of any treatment with other drugs."
Another team in the US also looking to conduct a larger trial in an at-risk population to see if the vaccine can protect against HCV infection.
Funds from the European Commission, the UK Medical Research Council, the Wellcome Trust, the Oxford Biomedical Research Centre, and the Oxford Martin School at the University of Oxford, helped pay for this phase 1 study.
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