Hepatology Digest: Your presentation is on vaccines for the treatment of HBV and HCV. What is a therapeutic vaccine? As I understand it， one of the major problems with a person who has contracted hepatitis B for instance， is that they don’t get an appropriate T cell response. How is a therapeutic vaccine going to give them an appropriate T cell response?
Dr Sallberg: It’s a great question and very relevant. The liver is a highly effective tolerogen; it is not supposed to produce any antigens or proteins that are going to raise an immune response because that causes liver disease. The liver has a very important regulatory role in shutting down T cells. That is why activation of T cells inside the liver is not that frequent. In chronic HBV the T cells are polarized， and in chronic HCV the T cells are dysfunctional. So what is needed is an appropriate activation of T cells outside the liver and that is why the crucial thing when you perform a therapeutic vaccination is that you have the correct antigen so the T cells are as healthy as possible. Secondly， the local environment where you activate the T cells should be highly immunogenic. You should have the correct host immunomodulation; you should have the correct cytokine environment. It is the mix of all these things which is why we can in several different animal models， break immunological tolerance. For example， in hepatitis B， there is a tremendous amount of viral antigen produced during the infection. Most of these antigens and particularly the surface antigens are secreted into the circulation and an antigen in the circulation is highly effective in dampening or inhibiting a T cell response. If you give another antigen， for example a core antigen or something that is not secreted， when you treat the patient with antivirals， the antigens disappear from the liver which alleviates the pressure on the T cells from these antigens and they can become immunogenic. One would think that the concept of therapeutic vaccination is something that has never been tested but actually we have used it for over fifty years in the treatment of allergies which is exactly what this is. It’s called hypersensitization but it is actually a therapeutic vaccination.
Hepatology Digest: So if you start introducing core antigens that something like entecavir is already reducing so that the core antigens are not suppressing T cells so much， won’t you be worsening the problem with more core antigens?
Dr Sallberg: That is the key. You put them in a different place. You introduce the core antigens at a highly immunogenic site. For example， you can give it in the skin; you can give it intramuscularly together with different adjuvants; you can give it as a genetic immunogen. But the key thing is that you give it outside of the liver where there will be a local production of a good proinflammatory immune response so there will be production of gamma-interferon and interleukin-12. Then there will be an activation of an antiviral immune response itself. Both HBV and HCV have a tendency to promote anti-inflammatory responses producing interleukin-10 or interleukin-4 which suppresses the antiviral response. In contrast， what you want to activate is called the T helper 1 cell (Th1) response with gamma-interferon promoting activation of cytotoxic T cells and so forth.
Hepatology Digest: So if you put this into a site where there is not a lot of antigen of what you are putting in and at manageable levels， it can launch an antiviral response as opposed to response suppression? So not only are we talking about dividing patient outcomes into individualized medicine but we are also compartmentalizing the body further as well.
Dr Sallberg: Exactly. That is perfectly true. If you have an infection and that infection itself is not immunogenic enough under the conditions that are present， then you can give a similar antigen (usually a modified version of the same antigen) and if you give it in the correct way， you will get immune activation.
Hepatology Digest: Most of the therapeutic vaccines that have been tried have not been particularly successful. I believe there is only one in phase III. What is the current status of therapeutic vaccines?
Dr Sallberg: You are right. If we are talking about hepatitis B then I don’t think there has been any vaccine that has been successful yet. I think that is because in hepatitis B the load of antigen is so high that you really need to suppress virus production very effectively for at least six months to a year. That we can now do with the new drugs， entecavir and tenofovir. The old drugs such as lamivudine were not potent enough in suppressing antigen production unlike with the new drugs. So I think combinations with the new drugs will be a very good base for therapeutic vaccines. In hepatitis C， there are at least three vaccines that have reached phase II: the Transgene MVA-based vaccine who have recently issued press releases that combination of standard of care which in that case is interferon and ribavirin， increases the rapid response rate early in therapy which suggests that it should also increase cure rates; Globeimmune， who have shown that they can increase cure rates by 10%-15%; and then there is the vaccine that I have been participating in developing with a Swedish company called ChronTech. That is a DNA-based vaccine that we give with electroporation. We have seen the same that when we combine vaccination and then starting patients on standard of care， you increase the cure rate. So there is no solid evidence but there are a number of small studies now coming out showing that there may be a clear beneficial clinical effect of therapeutic vaccine. Even though the concept of therapeutic vaccines has been around for decades， it is only now that we are starting to see some clinically beneficial effects.
Hepatology Digest: In your abstract you mention that the role for therapeutic vaccines in HCV is in combination with DAAs to replace interferon or ribavirin， but the data you are talking about is in combination with standard of care. Why are we only using them with interferon and ribavirin right now?
Dr Sallberg: Unfortunately， you have to use the drugs that are available. The development of the therapeutic vaccines began before the DAAs became available so that is why all of the studies that started two or three years ago have been conducted with interferon and ribavirin. The exciting studies will involve the immune-modulating and immune-activating effects of the vaccine as the new mechanism of action in combination with the direct-acting antivirals. So there will be a completely complementary mechanism of action to those drugs and hopefully we are not going to have side effects as you do have interferon which is an immunomodulatory drug. Ribavirin may or may not be an immunomodulatory drug. Conceptually I think it is very attractive combining the DAAs with the vaccine. I also think the recent failures in the hard-to-treat patients suggest that we most likely will need some immune-activating component in a highly effective HCV therapy.
发表于 2012-6-26 07:36
