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Therapeutic HCV Vaccine
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from Jules: at Friday's Hep C oral session there was a presentation by Kelly on her lab's work on developing a HCV vaccine that would boost CD4 T-cell response as experienced by individual's who are exposed to HCV but clear it, the results are preliminary, nothing has been studied in humans to test the hypothesis: "polyfunctional CD4+ and CD8+ HCV specific T cell responses are generated"
First Vaccine for Viral Hepatitis C Could Become a Reality
Apr 1, 2011 - 11:30:19 AM
www.healthnewsdigest.com
BERLIN, April 1, 2011 -- Early data from phase I trials of an HCV vaccine presented today at the International Liver Congress(TM) show encouraging results, with high immunogenicity and good safety profile.(1),(2)
In the first study[1], a therapeutic T-cell vaccine, based on
novel adenoviral vectors was used on a small population of treatment naive
patients with chronic genotype 1 HCV infection. Intra-muscular vaccination
was administered 2 or 14 weeks into a 48-week course of treatment with
Peg-IFNa2a/ribavirin. 50% of vaccinated patients had CD4+ and CD8+ HCV
specific T-cell responses as detected by ELISpot at 2-8 weeks post boost,
showing a strong immunogenicity for the vaccine. Local and systemic adverse
events to vaccination were mild, with no evidence of liver immunopathology
(measured by liver transaminase levels).
The second study[2] looked at the potential for a prophylactic
vaccine based on similar novel adenoviral vectors technology (
replicative-defective human Ad6 and a novel simian AdCh3 vector that encode
1985 amino-acids derived from the NS3-5 region of a genotype-1b strain). 27
healthy volunteers were vaccinated following a double prime, heterologous
boost strategy. The vaccine induced polyfunctional CD4+ and CD8+ T cells
responses which were maintained up to 52 weeks post prime. Overall
vaccination was very well tolerated with mild/moderate local and systemic
reactions and no serious adverse advents.
Professor Heiner Wedemeyer, EASL's Secretary General
commented: "Vaccines are an exciting area of research now with the potential
to add to the range of treatments available for patients with chronic viral
hepatitis. These are early data but results are very encouraging indeed and
as experts, we look forward to more scientific evidence being made available
to support this new technology as a future treatment option as well as
potentially preventing infection."
Previous research and data presented at the International
Liver Congress shows that vaccination with adenoviral vectors induced highly
potent and durable T-cell responses in healthy human and that similar vectors
may prevent chronic infection in animals.(3) This is the first time the
immunogenicity and safety of vaccination was tested on HCV patients and
healthy subjects.
A THERAPEUTIC VACCINE FOR HCV BASED ON NOVEL, RARE, ADENOVIRAL VECTORS
C. Kelly1*, A. Folgori2, S. Capone2, E. Stafford3, D. O'Donnell3, K. Gantlett4, J. Collier5, A.C. Brown6, R. Huddart6, I. Humphreys6, A. Kurioka6, R. Townsend6, L. Swadling6, V. Ammendola2, S. Colloca2, M. Naddeo2, L. Siani2, C. Traboni2, R. Cortese2, A. Nicosia2, P. Klenerman1, E. Barnes1
1Nuffield Department of Medicine & NIHR BRC, University of Oxford, Oxford, UK, 2Okairos, Pomezia, Italy, 3Hepatology & NIHR BRC, 4Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, 5Hepatology, John Radcliffe Hospital, 6Nuffield Department of Medicine, University of Oxford, Oxford, UK. *christabel.kelly@ndm.ox.ac.uk
Background and aims: We have recently shown that vaccination with adenoviral vectors based on rare human and simian serotypes encoding the non-structural proteins of HCV induces highly potent, multi-specific and durable T-cell responses in healthy humans and that similar vectors may prevent chronic infection in chimpanzees following a heterologous viral challenge. In this phase-I clinical trial we assess the safety and immunogenicity of these vectors for the first time in HCV infected patients.
Methods: Patients with treatment naïve chronic genotype-1 HCV infection are vaccinated (i.m.) with novel replication-defective adenoviral vectors encoding 1985 amino-acids derived from the NS3-5 region of a genotype 1b strain in a dose escalation (5x108vp, 5x109vp, 2.5 x1010vp) vaccination strategy. Patients receive simian AdCh3 as a single or double prime and a heterologous boost with a human Ad6 vector 10 weeks later. The first vaccination is administered 2 or 14 weeks into a 48-week course of PEG-IFNa2a/ribavirin. Immunogenicity and antigenic mapping is assessed by ex-vivo IFNg-ELISpot (using 6 peptide pools and single peptides spanning the HCV immunogen) and ICS assays. A control cohort of patients treated with PEG-IFNa2a/ribavirin alone, are included in the study.
Results: 10 patients have received both prime and boost vaccines at 2.5 x1010vp. Five patients responded to vaccination with the average peak HCV specific T cell response 939 (range 62-2954) SFU/106 PBMC as assessed by ELISpot. Peak responses are detected 2-8 weeks post boost. ICS shows that polyfunctional CD4+ and CD8+ HCV specific T cell responses are generated. Fine epitope mapping shows multiple antigenic targets may be generated and are frequently those previously described in the setting of acute HCV infection. Vaccination is very well tolerated. Local and systemic adverse events are mild with no evidence of liver immunopathology as measured by liver transaminases. In the control cohort HCV specific T-cell responses to the non-structural proteins were very weak or undetectable.
Conclusions: We have generated a novel T-cell vaccine based on adenovirus vectors from rare serotypes expressing HCV NS proteins, that is safe and highly immunogenic in patients with chronic HCV infection.
About EASL
EASL is the leading European scientific society involved in promoting
research and education in hepatology. EASL attracts the foremost hepatology
experts and has an impressive track record in promoting research in liver
disease, supporting wider education and promoting changes in European liver
policy.
[1] Kelly C et al. A therapeutic vaccine for HCV based on novel, rare,
adenoviral vectors. Abstract presented at the International Liver
Congress(TM) 2011. (750)
[2] Barnes E. Phase I trials of a highly immunogenic and durable T-cell
vaccine for Hepatitis C virus based on novel, rare, adenoviral vectors.
Abstract presented at the International Liver Congress(TM) 2011. (2104)
[3] Folgori A et al. A T-cell HCV vaccine eliciting effective immunity
against heterologous virus challenge in chimpanzees. Nature Medicine - 12,
190 - 197 (2006)
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