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GS-4774
Has anyone heard anything about Gilead GS-4774? This is a Tarmogen T cell immunity stimulator.
Maybe I can finally make one of these! I tried 2wise and there was always something.
I still think they need to use these vaccines with interferon to boost their effect. Maybe with TDF to hit HBV from all three angles.
I still think they need to use these vaccines with interferon to boost their effect. Maybe with TDF to hit HBV from all three angles.
Another great post. Gilead has also begun a Phase 2 trial of GS4774:
"This study is to evaluate the safety, tolerability, and efficacy of GS-4774 in adults with chronic hepatitis B infection (CHB) and who are currently not on treatment. Participants will be randomized to receive tenofovir disoproxil fumarate (TDF) alone or GS-4774 plus TDF for 20 weeks. After Week 20, GS-4774 will be discontinued. All participants will continue on TDF and will be followed for an additional 28 weeks. Following completion of the 48 week study period, all participants will be eligible for a 3 year registry study."
The trial will take take place in the US, Italy, Canada,Korea, New Zealand, Romania, and Taiwan.
"This study is to evaluate the safety, tolerability, and efficacy of GS-4774 in adults with chronic hepatitis B infection (CHB) and who are currently not on treatment. Participants will be randomized to receive tenofovir disoproxil fumarate (TDF) alone or GS-4774 plus TDF for 20 weeks. After Week 20, GS-4774 will be discontinued. All participants will continue on TDF and will be followed for an additional 28 weeks. Following completion of the 48 week study period, all participants will be eligible for a 3 year registry study."
The trial will take take place in the US, Italy, Canada,Korea, New Zealand, Romania, and Taiwan.
Recent paper on GS-4774 got published in Vaccine.
http://www.sciencedirect.com/science/article/pii/S0264410X14009530
http://www.sciencedirect.com/science/article/pii/S0264410X14009530
Yes and no. The Chinese had investigated three 3 therapeutic vaccines in the last few years, two by listed companies, one by a well-known academic. The two by listed companies, both completed Phase 2 clinical trials, but results were disappointing, no or slightly better than the control groups. Being commercial companies, they disclosed the minimum information and outsiders cannot learn from their experiences. The one investigated by Prof Wen, a novel HBsAg and HBsAb complex, completed phase 3. Again the results are no better than the control(placebo is Alum) group, even though the loss of HbeAg was as high as 30%. I am sure lessons will be learned from this study, one of them being too much and too frequent injections of the vaccine, driving, as Studyforhope described, the immune system "crazy" and exhausted.
The France has also been studying several therapeutic vaccines, but progress is very slow.
Cuba has of course completed a successful Phase 3 of their NASVAC vaccine. Unfortunately, we don't know whether it will be further developed.
I am sure a lot of the concepts behind these vaccines were tested on animals. Prof Wen when she began her work, spent a million US dollars to purchase a genetically modified mice from overseas.
The France has also been studying several therapeutic vaccines, but progress is very slow.
Cuba has of course completed a successful Phase 3 of their NASVAC vaccine. Unfortunately, we don't know whether it will be further developed.
I am sure a lot of the concepts behind these vaccines were tested on animals. Prof Wen when she began her work, spent a million US dollars to purchase a genetically modified mice from overseas.
As always, THANKS very much for the kind explanation.
Is this therapeutic vaccine the first such attempt by the pharma industry? Any idea if this has been tested in primates or mice?
Is this therapeutic vaccine the first such attempt by the pharma industry? Any idea if this has been tested in primates or mice?
I wish I can give you a good explanation, but it is a bit beyond me because immunology is so complex. I will try, but others can correct me.
The current HBV vaccine consists of the HBsAg antigen, a protein. It is very effective in inducing the production of HBsAb, antibodies to the surfact(envelope) antigen. These circulating antibodies will attach to the surface of circulating HBV viral particles and prevent the viral particle from entering a liver cell - therefore no infection.
However, in order to cure patients with liver cells infected already by the virus, we need to induce production of cytotoxic T cells, so called cd8+ T cells that specifically recognise HBV infected liver cells, thus killing or controlling these infected cells. Because HBV viral proteins are produced inside infected liver cells, the surface of these cells express epitopes of these viral proteins in MHC class I complexes. So a therapeutic vaccine has to induce the production of these HBV specific cd8+ T cells.
In order to induce the production of these T cells, special immune cells must present HBV viral antigens in MHC class 1 and 2 complexes. GlobeImmune scientists believes they can achieve this. GS4774 consists of heat killed yeast cells. These yeast cells have inserted into them, DNA that codes for the production of HBV surface, core, and x proteins. So I presume these cells, before they were heat killed, produce these HBV viral proteins inside the cell. When these cells , heat killed and then injected into a patient. The patient's APC (antigen presenting cell) such as the dendritic cells, will engulf these heated killed yeast cells, process and present various HBV viral epitopes in both MHC class 1 and 2 complexes to the immune system. So HBV specific Cd8+ T cells will be produced. Also antibodies to the yeast cells are also produced, the scientists say.
So this is the first half of the story. But a chronic HepB person already has these HBV specific cd8+ T cells, but they are not "effective" due to various factors caused by the immune braking system and HBV evasive mechanism. Whether these freshly produced T cells will meet the same fate or not is what we have to wait and see.
Just my own understanding..
The current HBV vaccine consists of the HBsAg antigen, a protein. It is very effective in inducing the production of HBsAb, antibodies to the surfact(envelope) antigen. These circulating antibodies will attach to the surface of circulating HBV viral particles and prevent the viral particle from entering a liver cell - therefore no infection.
However, in order to cure patients with liver cells infected already by the virus, we need to induce production of cytotoxic T cells, so called cd8+ T cells that specifically recognise HBV infected liver cells, thus killing or controlling these infected cells. Because HBV viral proteins are produced inside infected liver cells, the surface of these cells express epitopes of these viral proteins in MHC class I complexes. So a therapeutic vaccine has to induce the production of these HBV specific cd8+ T cells.
In order to induce the production of these T cells, special immune cells must present HBV viral antigens in MHC class 1 and 2 complexes. GlobeImmune scientists believes they can achieve this. GS4774 consists of heat killed yeast cells. These yeast cells have inserted into them, DNA that codes for the production of HBV surface, core, and x proteins. So I presume these cells, before they were heat killed, produce these HBV viral proteins inside the cell. When these cells , heat killed and then injected into a patient. The patient's APC (antigen presenting cell) such as the dendritic cells, will engulf these heated killed yeast cells, process and present various HBV viral epitopes in both MHC class 1 and 2 complexes to the immune system. So HBV specific Cd8+ T cells will be produced. Also antibodies to the yeast cells are also produced, the scientists say.
So this is the first half of the story. But a chronic HepB person already has these HBV specific cd8+ T cells, but they are not "effective" due to various factors caused by the immune braking system and HBV evasive mechanism. Whether these freshly produced T cells will meet the same fate or not is what we have to wait and see.
Just my own understanding..
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