Остановка Гепатит С4.3.0 Vaccines
4.3.0 Vaccines
Wouldn’t it be wonderful if, just like polio or smallpox, no one had to worry about catching Hep C ever again?
Vaccines do that. Unfortunately, there is no vaccine against Hep C, but researchers keep trying... and may be getting close.
There has been some discussion as to what type of vaccine would be best for the Hep C virus. Ideal would be a vaccine that would prevent
initial infection (prophylactic vaccine), but a vaccine that would prevent the infection from becoming chronic would be sufficient (therapeutic
vaccine). The problem is that the virus has so many strains and mutates so easily. An effective vaccine would have to work against at least one
genotype of the virus, preferably genotype 1, which is the most common. Other problems are developing a vaccine that confers lasting protection
and finding good models for testing
(www.brown.edu/Courses/Bio160/Projects2000/HepatitisC/hcvvaccines.html).
The search for a vaccine has suffered an important setback. It had been hoped that a “therapeutic” vaccine, to also cure those already infected, could be found. Therapeutic antibody treatments for hepatitis C haven’t been working, and now we may know why. Usually a virus replicates inside a cell, and large numbers of the virus burst out and start over again.
Some viruses don’t have to leave the cell, but can infect it by travelling directly from cell to cell. It looks like HCV uses both mechanisms, so the virus does not need to be released by a cell before it infects another cell, but can travel directly to the next cell, avoiding the body's neutralising antibodies and medical treatments. That may be why HCV antibodies don’t control the virus. The cell-to-cell transfer, a faster “route” to infect new cells, could explain HCV’s dramatic spread in acute cases.
This is not great news, but it is important information which may show scientists where to look for new targets for antiviral therapy. It is
still possible that an uninfected person can be protected by an HCV vaccine.
(http://news.bbc.co.uk/2/hi/health/7075569.stm
and www.natap.org Nov 2, 2007)
Types of possible vaccines:
Passive Immunization: One would think that having HCV antibodies would cure the disease and protect a person against re-infection, but it doesn’t work that way with the hepatitis C virus. Attempts at using this method on chimpanzees have seemingly failed. HCV hyperimmune globulin has worked, but doesn’t last and doesn’t protect against re-infection.
Aventis Pasteur, now Sanofi-Aventis (Lyons, FR) applied for a US patent for a vaccine of this sort in March 2003.
(http://164.195.100.11)
Envelope Glycoprotein Vaccines: This is the most encouraging vaccine possibility at this time. The vaccine causes the body to make antibodies to parts of the virus’ outer coating, called E1 and E2. This vaccine seems to be showing promise in chimpanzees [See 4.3.1 ChronVac-C]
Epitope Based Vaccines: This type of computer-generated vaccine is designed to make the body produce a strong immune
response (CD4+ and CD8+) using T cell epitopes. It is hoped that this technology won’t allow mutations to escape, and that it will cover several
genotypes, not just one. The disadvantages are that the technology requires large computer databases, and an effective vaccine would probably
have to include some protein from actual HCV.
(www.brown.edu)
Naked DNA Vaccines: “Naked” DNA means DNA that isn’t associated with a virus. Therapeutic DNA is introduced into a virus to
deliver it to the body. The “C” gene of the hepatitis C virus is often used in these experiments, because it is similar in all the genotypes.
Side effects of a vaccine of this type may be a problem, and safety may be an issue, although some researchers say there are no viral components
to cause unwanted immune responses, infections, or permanent changes in the cell's genetic makeup. DNA vaccines for hepatitis C are still in
pre-clinical stages of development, and they show great potential, even for therapeutic treatment.
(www.brown.edu/Courses/Bio160/Projects2000/HepatitisC/hcvvaccines.html)
Chiron Corporation is involved in clinical studies with naked DNA vaccines. (See 4.3.2 Chiron Vaccine)
Viral Vector Vaccines: These vaccines, like naked DNA vaccines, are designed to place foreign DNA into a cell to stimulate the immune system. Viral vector vaccines have an advantage because they allow specific host cells to be targeted, so that the vector will not enter the genetic material of the cell. Few vaccines like this have been tried, so little is known about how effective they are. (www.brown.edu/Courses/Bio160/Projects2000/HepatitisC/hcvvaccines.html)
Recombinant viruses can be used to deliver DNA efficiently. Experiments in animals have induced protective immunity to many viruses, and some are being tested for HCV vaccines. A favorite virus is the defective adenovirus because its natural “habitat” is the liver. However, the tragedy of death in a gene therapy trial using adenovirus has severely dampened the enthusiasm for the use of this viral vector in humans. (www.medscape.com/viewarticle/4108486)
There is an adenovirus vector called BID (BH3–interacting death domain death agonist), designed to cause cells infected with HCV NS3/NS4A protease to commit suicide (aptosis), stopping the progression of the disease. Studies done with chimeric mice at the Ontario Cancer Institute, and reported in the May 2003 issue of Nature Biotechnology, show the treatment to be effective, and nontoxic to healthy neighboring cells. “A targeted therapeutic approach using modified BID may be useful as a prophylactic against accidental virus exposure, in the early stages of hepatitis, during limited infection of the liver, or for ex vivo therapy of hepatocytes. It may also reduce virus loads in chronically infected patients, and in conjunction with interferon and ribavirin therapy, might eradicate HCV from the infected host," say the researchers (Reuters Health 05/01/03).
Peptide Vaccines: Researchers think this kind of HCV vaccine can work because helper T cells (some of our immune system’s
“soldiers”) recognize antigens (invaders) that they should attack, because of the peptide fragments bound to molecules on the surface of the
cells that carry the antigen (in this case, the HCV polyprotein). Peptides containing epitopes from the core regions of the virus have induced
strong immune responses in mice. A peptide called HVR1 contains a neutralizing epitope, so it is an attractive target for a vaccine, and this
strategy has seemed to work in trials with chimpanzees. Unfortunately, this peptide is subject to mutations. Because HVR1 contains a
neutralizing epitope, it is an attractive target for peptide-based vaccines, but this region of the virus mutates rapidly.
(http://www.medscape.com/viewarticle/4108487)
Recombinant Protein Subunit Vaccines: The first attempt to develop an HCV vaccine was by generating a recombinant protein subunit vaccine. Chiron used recombinant HCV E1 and E2 proteins in early vaccination studies. Results of experiments showed that the vaccine did not protect any of the chimpanzees when challenged with the virus, but self-limited infection occurred more frequently than in non-vaccinated animals. The results show that although no sterilizing immunity was achieved, chronic infection might be prevented.
4.3.1 ChronVac
ChronVac is what is termed a therapeutic vaccine, i.e., a vaccine given to people already infected with hepatitis C, with the intention of reinforcing their immune response. ChronVac-C® is also what is termed a “genetic vaccine”, which means that rather than just filling syringes with the vaccine, the vaccine's genetic code (DNA) is used. When the vaccine DNA is injected into muscle, it is absorbed by muscle cells, which then convert the DNA into protein, and produce the vaccine to activate the body's own immune response. (www.alacrastore.com/storecontent/markintel/LIFESCIENCEANALYTICS-50217368)
Inovio’s partner Tripep AB, of Sweden (now Din Bostad Sverige AB), received approval for a Phase I/II clinical trial of its DNA vaccine,
ChronVac-C®, to be injected with Inovio’s MedPulser® DNA Delivery System into muscle tissue. The trial was designed for twelve HCV+ patients,
and was the first study in humans with this form of delivery. Pre-clinical trials showed that this technology increases the potency of vaccines,
without having to use viral systems. ChronVac-C consists of synthetic DNA plasmids, which express antigens to cause a preventative or
therapeutic immune reaction to the disease.
(http://home.businesswire.com/portal/site/google/index.jsp?ndmViewId=newsview&newsId=20070816005
139&newsLang=en August 16, 2007) As of November 2007, the first patient has been treated. (www.natap.org)
12 treatment-naïve genotype 1 patients took part in a first clinical trial of ChronVac. They were divided into groups and given an injection to deliver HCV DNA into the deltoid muscle—167 B5g, 500 B5g or 1,5000 B5g—followed by two 60ms electrical pulses, in a process called ”electroporation”. The electrical pulse makes the membrane of the cell more porous and stimulates migration of the immune cells. The same procedure was repeated a total of 4 times, once a month.
There were no severe side effects. No patient in the first group had a reduced viral load, but two had a slight T cell response. In group 2, two patients had better T-cell responses and a viral load drop of 0.80 log and 1.5 log. In the third group, one had an HCV T-cell response. Two had viral load drops of 1.2 log and 2.4 log. The four patients’ viral load drops lasted 2 to over 10 weeks. A Phase I/IIa trial is underway. (EASL 2009)
STANDARD THERAPY + ChronVac-C: Six genotype 1 (GT1) patients took part in a clinical trial. They were given a series of 4 vaccinations with ChronVac-C, and were then put on standard therapy. Surprisingly, 5 of the 6 patients had an SVR (Sustained Viral Response), testing undetectable 6 months after treatment, compared to the usual 40-45% for GT1 with standard therapy alone, or 60-70%, adding a protease inhibitor. This was a very small but encouraging study. (http://hcvadvocate.blogspot.com/2011/03/unusually-high-cure-rate-recorded-after.html)
On March 14, 2011, Inovio’s partner, ChronTech (formerly Tripep), began a Phase IIb trial of ChronVac-C using Inovio's electroporation delivery technology. The product was combined with pegIFN/RBV. The Phase II trial enrolled 32 treatment-naïve genotype 1 patients, who will be given the vaccine once, and treated again in 4 weeks, followed by pegIFN/RBV. 20 patients will receive the vaccine plus pegIFN/RBV, and the other 12, pegIFN/RBV alone. If the results are similar to those in the first trial, the researchers hope that the treatment could become standard. They also hope that the product can shorten treatment time. (www.hivandhepatitis.com/hepc/news/2011/03182011b.html)
4.3.2 Novartis-Okairos-Chiron Vaccine
Chiron was developing a genetically engineered HCV vaccine. The company was studying two possible vaccines, including a recombinant vaccine and a second-generation DNA vaccine to induce a cellular immune response. They hoped to have one or both vaccines available around 2010, to be used in combination with standard treatment to boost immunity. (www.chironvaccines.com/company/vaccineshepatitiscvaccine.php).
Chiron provided HCV antigens, and CSL provided its Isomatrix technology. ISCOM, an immune stimulating complex, intended to improve the immune response induced by vaccines. ISCOM is made from the bark of the Quillaia saponaria molina tree, mixed with lipids. (www.csl.com.au/)
A Phase II trial—much larger than the previous one—took place at Saint Louis University with 200 patients.
The vaccine was tested in
humans in previous studies, but this time it was tested with a different adjuvant (a drug to help the body respond better to vaccines). The
research was sponsored by the National Institutes of Health and Chiron Corp. (www.medicalnewstoday.com/articles/42781.php)
Novartis has acquired Chiron. Okairos, a Merck spinoff, and Novartis Vaccines & Diagnostics, both European vaccine companies, will be working together with other European groups and an institution from Egypt to do pre-clinical and clinical trials to develop a vaccine against HCV. Okairos has a gene-based candidate designed for the NS region of the virus, which induces powerful T-cell immune responses, lowering the reproduction of the virus. Another drug candidate uses the ability of the proteins that envelope the virus to create neutralizing antibodies. The two vaccines will be combined to protect people from several genotypes. Since Novartis has acquired Chiron, they will take advantage of their expertise, as well. The companies hope to set an example for further vaccine trials. (www.altaweb.it/hepacivac/)
Since the Hep C virus mutates rapidly, the scientists picked a target inside the virus where it is more stable and less likely to change than on the surface. This is a new approach and may produce a different kind of immune response. The scientists took genetic material from HCV and used it to change 2 common cold viruses (adenoviruses), so they could carry genotype 1b proteins.
One adenovirus came from a human and the other, from a chimpanzee. Both adenoviruses activated T cell responses, prompting them to perhaps recognize genotypes 1a and 3a as well. They could then provoke an immune response against hepatitis C. This strategy is called a “recombinant adenoviral vector strategy.” The response could be sustained for at least 1 year, providing immunity worthy of more research.
The Phase I trial studied 41 healthy volunteers and proved the product to be safe. Phase 2 studies are underway, and the researchers will see if the product can treat those who have the virus. The vaccine may fit well into a cocktail of direct-acting antivirals (DDA’s), to boost immunity.
The company will continue trying to make the product more powerful, but to take the product to market takes years. Phase II trials are
underway, and a larger one for the at-risk population is being planned, to see if it can prevent infection.
(http://www.natap.org/2012/newsUpdates/01061201.htm)
4.3.3 Chimigen
The Chimigen HCV vaccine candidate is a dendritic cell-targeted vaccine produced by ViRexx (Edmonton, AB)
(http://www.genengnews.com/news/bnitem.aspx?name=1124489XSLNEWSMLTONEWSMLWEB.xml 12/12/2005)
The company presented results showing that the
vaccine produced HCV antigen-specific T cells. The vaccine uses an insect cell expression system, giving it special immunological
characteristics. Researchers hope it may be a possible therapeutic vaccine for treating hepatitis C. (http://cnrp.ccnmatthews.com/client/virexx/release.jsp?actionFor=581279)
In May 0f 2007, ViRexx announced that it would collaborate with the National Research Council Canada's National Institute for Nanotechnology (NINT) and Defence Research and Development Canada, Suffield (DRDC Suffield). Researchers at NINT planned preclinical studies of the Chimigen HCV prophylactic and therapeutic vaccine candidate. (www.bioalberta.com/newsdetails.asp?ID=69)
4.3.4 VIDO Vaccine
Researchers at the University of Saskatchewan hope they have found a vaccine for hepatitis C that will also help those already infected (therapeutic vaccine). To make the vaccine, researchers took dendritic cells (key immune cells) from mice, exposed them to one of the most common proteins occurring in all HCV genotypes, and treated the cells with an immune stimulator.
They hope that by returning the activated cells, they can “teach” the original cells to activate an immune response. Researchers used another virus in the mice to simulate HCV. VIDO’s Hep C project will develop a DNA-based regime, using the HCV non-structural protein-3 (NS3) as a target for the dendritic cell-based vaccines. In encouraging lab trials, mice were injected with inactivated HCV particles. Their serum was then injected into samples of HCV+ human liver cells, suppressing the virus.
Construction began in June 2007 on InterVac, the International Vaccine Centre at the University of Saskatchewan, next door to VIDO (Vaccine
and Infectious Disease Organization). On September 16, 2011, InterVac held its grand opening ceremony. When the Centre opens in 2012, we should
see some exciting progress.
(www.vido.org/research/vaccinedev/hepatitis.php
www.vido.org/Introducingintervac/index.php and The StarPhoenix, Jan 11, 2006)
4.3.5 Toray Vaccine
Toray has been working together with the National Institute of Infectious Diseases (NIID)
and other institutions to develop a vaccine for hepatitis C. In laboratory experiments using cells, one of the vaccine candidates prevented 66%
of genotype 1a infections, the most common genotype in Japan, and 85% of genotype 2a infections. Experiments done in infected mice showed that
their virus was suppressed, as it was in human liver cells, when they were injected with serum obtained from those mice. The company needed a
way to develop their product for industrial production--a way to incubate the virus in large quantities, to concentrate and refine them. NIID
found a cell that is able to incubate the virus, and Tory can now concentrate the viruses, so the vaccine may be possible. The drug is expected
to prevent new infections and to cure patients already infected.
(
www.hepatitis-central.com/mt/archives/2007/09/future_hcv_medi.html 28
August 2007 and
www.eiu.com/index.asp?layout=ib3PrintArticle&article_id=1794748164&printer=printer&rf=0 Aug 11, 2009)
4.3.6 TG4040 Vaccine
Transgene's TG4040 is a recombinant poxvirus therapeutic vaccine that uses the MVA virus as a vector to
carry encoded HCV proteins NS3, NS4
and NS5B. The MVA vector is used with the smallpox vaccine.
Transgene conducted a Phase I trial in Canada for patients who relapsed after
standard treatment. The University of Montreal and the Canadian Network for Vaccines and Immunotherapies sponsored the trial. Data was expected
by the end of 2008. Another Phase I trial of the drug is treating 15 HCV+ naïve (never treated) patients in France.
(www.therapeuticsdaily.com/news/article.cfm?contentvalue=479710&contenttype=newsarchive&channelID=31 Oct. 01, 2007)
Results from their
153-patient Phase II trial (HCVac study) were presented at the AASLD 2011 conference in November. The vaccine was well-tolerated, and when
combined with pegIFN/RBV, gave excellent results at 12 weeks: 64% vs 30% early viral suppression with pegIFN/RBV alone. The drug was given in
subcutaneous injections. The company will look for partners to help develop treatments without interferon. Data can be seen at
www.transgene.fr.
(www.hivandhepatitis.com/hepatitis-c/hepatitis-c-topics/hcv-treatment/3400-aasld-recombinant-hepatitis-c-vaccine-tg404-shows-promise-in-phase-2-trial)
4.3.7 Intercell's vaccine (IC41)
Intercell's vaccine (IC41) contains eight T-cell antigens, combined with a poly-arginine adjuvant (IC30). It was developed in partnership with Novartis. The product was studied in a Phase II trial which enrolled 50 naïve genotype 1 patients who received 8 injections of the drug bi-weekly for 14 weeks, producing a significant reduction in viral load, while being very safe. In the second week after the last injection, a 0.2 log viral load drop was observed. Full data was expected in early in 2008. The drop increased with each application. In patients with a high viral load, there was an average drop of 0.4 log. (www.biopharma-reporter.com 21/08/2007)
Intercell and Romark are working together on a European Phase II clinical trial combining Intercell’s IC41 with nitazoxanide, Romark’s antiviral candidate. IC41 contains eight T-cell antigens, combined with a poly-arginine adjuvant. 60 treatment-naïve patients will be treated. In a Phase II trial, IC41 was able to reduce the viral load in HCV+ patients. Nitazoxanide (AKA Alinia) is an oral drug, a thiazolide that inhibits synthesis of some of the proteins of the HCV virus. In a previous trial in 50 treatment-naïve genotype 1 patients with high viral loads, the results showed viral load reductions of over 75% (0.6 log), and the reduction had been sustained at 6-months after the end of treatment. Romark will be recruiting for Phase III clinical trials of nitazoxanide plus peginterferon. (www.intercell.com/main/forbeginners/news/news-full/article/intercell-and-romark-join-forces-in-combining-therapies-against-hepatitis-c/ Oct 21, 2010)
4.3.8 Kurume Peptide Vaccine
Researchers from Kurume University, Japan, conducted a Phase I trial of a personalized peptide
vaccine in 12 genotype 1b non-responder patients. The patients’ T cells and plasma IgG were tested, and 4 peptides were chosen as possible
candidates. Only the peptides causing a reaction were given twice a week at different doses. There were no severe side effects. There was a good
immune reaction to at least one of the peptide candidates after the 7th dose. ALT was reduced in 5 patients, and viral load was reduced in 3
patients after the 14th dose.
(Vaccine, 2007;25(42):7429-35 www.newsrx.com/article.php?articleID=788039&f=wu22 NOV 19, 2007)
4.3.9 Tarmogen (GI-5005)
GI-5005 is a recombinant Saccharomyces Cerevisiae expressing an HCV NS3-Core Fusion Protein. GlobeImmune began recruiting people for clinical trials in July 2005. (www.clinicaltrials.gov) Their Phase Ib trial in Hep C patients showed safety and efficacy of their vaccine candidate – one of their therapeutic vaccine products called Tarmogen. There were mild injection site reactions and a few other minor complaints. Tarmogen generated an HCV-specific immune response, and lowered ALTs and viral load. (www.fdanews.com/rxti/newsletter/article?issueId=10967&articleId=100771 Nov. 8, 2007)
The GI-5005 Phase II trial enrolled 140 genotype 1 patients. 74% were treatment-naïve. GI-5005 is designed to cause HCV-specific T-cell responses to help the body clear the virus. Patients received standard therapy (SOC) with or without GI-5005. GI-5005 was injected subcutaneously once a week for five weeks, then once every 2 weeks, for a total of 12 weeks, followed by SOC plus monthly injections of GI-5005 for 48 weeks. The EVR in naïve patients was 94%.
That is about a 10% improvement over SOC. RVRs were twice more frequent with triple therapy than SOC. There were no serious side effects related to GI-5005. Also, blood tests indicating fibrosis (Fibrotest) and necrosis (Actitest) showed a 14% advantage with the triple therapy over SOC.
The
trial has not finished yet. (EASL 2009)
The Phase II trial of GI-5005 has been terminated due to side effects and abnormal lab tests in some
of the subjects and an investigation is underway. (www.biospace.com/newsstory.aspx?StoryID=237817&full=1 10/26/2011)
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