Immunogenicity and safety of a novel therapeutic hepatitis C virus (HCV) peptide vaccine: a randomized, placebo controlled trial for dose optimization in 128 healthy subjects.
ABSTRACT As interferon/ribavirin-based standard therapy is curative in only about half of HCV patients, there remains an important need for alternatives including vaccines. The novel peptide vaccine IC41 consists of five synthetic peptides harboring HCV T cell epitopes and poly-L-arginine as synthetic adjuvant. In this randomized, placebo-controlled trial, 128 HLA-A2 positive healthy volunteers received four s.c. vaccinations of seven different doses IC41, HCV peptides alone, poly-l-arginine alone or saline solution, every 4 weeks. IC41 was safe and well tolerated. Mild to moderate local reactions were transient. Immunogenicity was assessed using T cell epitope specific [3H]-thymidine proliferation, IFN-gamma ELIspot and HLA-tetramer assays. IC41 induced responses in all dose groups. Higher responder rates were recorded in higher dose groups and increasing number of vaccinations were associated with higher responder rates and more robust responses. Poly-L-arginine was required for the aimed-for Th1/Tc1-type immunity (IFN-gamma secreting T cells).
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ABSTRACT: Hepatitis C virus (HCV) infects an estimated more than 150 million people and is a leading cause of liver disease worldwide. The development of direct-acting antivirals (DAAs) will markedly improve the outcome of antiviral treatment with cure of the majority of treated patients. However, several hurdles remain before HCV infection can be considered a menace of the past: High treatment costs will most likely result in absent or limited access in middle and low resource countries and will lead to selective use even in wealthier countries. The limited efficacy of current HCV screening programs leads to a majority of cases being undiagnosed or diagnosed at a late stage and DAAs will not cure virus-induced end-stage liver disease such as hepatocellular carcinoma. Certain patient subgroups may not respond or not be eligible for DAA-based treatment strategies. Finally, reinfection remains possible, making control of HCV infection in people with ongoing infection risk difficult. The unmet medical needs justify continued efforts to develop an effective vaccine, protecting from chronic HCV infection as a mean to impact the epidemic on a global scale. Recent progress in the understanding of virus–host interactions provides new perspectives for vaccine development, but many critical questions remain unanswered. In this review, we focus on what is known about the immune correlates of HCV control, highlight key mechanisms of viral evasion that pose challenges for vaccine development and suggest areas of further investigation that could enable a rational approach to vaccine design. Within this context we also discuss insights from recent HCV vaccination studies and what they suggest about the best way to go forward.Journal of Hepatology 11/2014; 61(1). DOI:10.1016/j.jhep.2014.09.009 · 10.40 Impact Factor
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ABSTRACT: Introduction: Hepatitis C virus (HCV) chronically infects about 150 million people worldwide. Antiviral treatment can stop and even reverse the progression of the disease. Several antivirals have been developed. However, about 10,000 compounds are tested for each drug that eventually reaches the market. It would be useful to learn from these failures, for example, by reporting the candidate drugs that were discontinued and the reason for discontinuation. Areas covered: This article focuses on the anti-HCV drug candidates discontinued between 1 January 2012 and 1 January 2014. Expert opinion: In detail, 17 drugs were discontinued. Of these: 10 were NS5B inhibitors, 3 were NS5A inhibitors, 2 were immunostimulants, 1 was a therapeutic and prophylactic vaccine and 1 an NS3 inhibitor. Only 3 candidates were discontinued in the preclinical phase, and 14 were discontinued during clinical development (8 in Phase II and 6 in Phase I). Most discontinuations were attributed to corporate strategic decisions. The authors believe that learning from HCV drug development failures will help pharmaceutical companies and researchers to develop better strategies for the future. It is therefore important that this information is made available.Expert Opinion on Investigational Drugs 11/2014; 24(2):1-13. DOI:10.1517/13543784.2015.982274 · 4.74 Impact Factor
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ABSTRACT: The recognition of the problem of viral hepatitis, while health problem and their individual and collective consequences date back centuries, however the identification of causative agents is relatively recent, the first to be identified was the hepatitis B virus in 1965, and other later. While public health problem worldwide and in Brazil, WHO estimates and MS already pointed million infected and thousands of cases of illness and deaths since the 1980s. Over the past 30 years, significant progress has been made, regarding the prevention, control, development of laboratory tests, vaccines and therapeutic drugs. The Health Department of São Paulo State, recognizing the importance of viral hepatitis in the context of Brazilian public health, launched in 2001, the State Program for Prevention and Control of Viral Hepatitis. This program is, by placing a synthetic form, the following objectives: Increase the detection of patients with viral hepatitis, reduce the appearance of new cases, and reduce the mortality rate from chronic viral hepatitis serotypes B and C. The objective of this study is to evaluate the implementation process of the diagnosis and its network components of PEHV - Serology; Biopsy and Molecular Biology. The latter component is of particular importance due to the technological development process. Evaluative questions were: 1. The PEHV implemented its component laboratory diagnosis. 2. Interventions are achieving some effect on the diagnostic network. - Immediate goal. 3. The effects on the network diagnostic influenced the other program components, specifically Epidemiological Surveillance and Assistance. – Does it possible to identify which part of the intervention goal was responsible for mediate results? 4. Which Factors are associated with these effects? This evaluative research, due to the complexity of the program used an approach by "Triangulation Method" - Documentary analysis, interviews with key actors in the process and analysis of historical series of indicators using the laboratory diagnosis as "Tracer" for PEHV. For analysis of the time, series used the methodology VII of "interrupted time series" with multivariate regression. The results allow the following conclusions: 1 - The PEHV implemented its component laboratory diagnosis of clear and consistent manner. Interventions effectively exerted influence on laboratory indicators. 2 - The diagnostic performance of network influences the other components of the program, the increase in serology tests corresponds to an increase in notifications and increases development of molecular biology corresponds to the increase in access to treatment. 3 - Although some interventions may appear to have a greater influence in the observed effects, it is not possible to establish a specific and individualized causation of these interventions in these effects. 4 - The figure of the "tracer", proved useful in conducting analyzes, however, in our view, the indicators laboratory should not be used alone for such evaluations. 5 - Coverage of liver biopsy proved to be a critical point of PEHV, and requires specific actions for addressing them 6 - The strategy of search patients with viral hepatitis by increasing the availability of serological tests should be revised in order to increase their efficiency.09/2014, Degree: Doctor, Supervisor: José da Rocha Carvalheiro