Hepatitis C Virus (HCV) is a blood-borne virus that preferentially infects human hepatocytes (liver cells) and is intricately adapted to the environment of the liver. The virus is usually transmitted through contaminated needles during intravenous drug use, and medical procedures such as transplantation of infected organs or transfusion of infected blood. HCV screening of donated blood has significantly decreased the risk of iatrogenic transmission of the virus, but many developing countries do not have adequate blood screening policies in place. Currently, an estimated 130-150 million people worldwide are chronically infected with HCV. From that number, 15-45% of the infected will spontaneously clear the virus without any treatment, but the remaining 55-85% will develop chronic HCV infection, which carries an increased risk of developing cirrhosis of the liver and liver cancer. Many of those chronically infected with HCV do not know that they are infected because the virus is often asymptomatic for years, causing liver damage in silence. Liver disease and liver failure resulting from chronic HCV infection remains the leading cause of liver transplantation.
The usual course of HCV treatment is a combination of the antiviral drugs pegylated interferon, which induces the immune system to an antiviral state; and ribavirin, a synthetic guanosine analog that inhibits synthesis of viral RNA. Unfortunately, these drugs are sometimes unavailable in developing countries, and furthermore, are often poorly tolerated by the patients who take them. Many undergoing pegylated interferon/Ribavirin treatment experience a number of unpleasant side-effects, including flu-like symptoms such as headaches, muscle pain, and gastrointestinal problems. Recent advances in HCV therapies have led to new drugs that are better tolerated by the patient, such as the orally administered Daclatasvir, which targets the viral nonstructural protein NS5A and appears to interfere with viral replication. However, these drugs are prohibitively expensive, and are only available in wealthy, developed nations. The majority of people infected with HCV are in resource-poor countries that do not have access to these new drugs. In addition, many of these drugs available do not provide protection from re-infection, and there currently is no HCV vaccine. It is difficult to develop a vaccine that protects against a virus as genetically diverse as HCV is.
One HCV vaccine development strategy is to focus on the powerful T-cell responses seen in HCV-infected individuals who spontaneously clear the virus during primary infection. An interesting study by Klenerman's and Barnes's groups at University of Oxford published in Science Translational Medicine this month reports a new HCV vaccine that not only showed strong HCV-specific CD4+ and CD8+ T-cell response in 15 healthy human volunteers, but also appears to be safe and well-tolerated. The vaccine strategy has two parts. First, a replication-defective chimpanzee adenovirus vector (ChAd3) – that encodes the HCV polyprotein NS3-NS5B and a defective NS5B polymerase – delivers its genetic material to the patient’s genome. The patient’s cellular machinery synthesizes the delivered viral genes that the patient’s T-cells subsequently respond to. Secondly, the vaccine incorporates modified vaccinia Ankara (MVA), an attenuated (serially passaged hundreds of times through chicken embryo fibroblasts) vaccinia virus that is safe for the immunocompromised and also induces a strong immune response. The MVA also contains the same HCV nonstructural genes that ChAd3 encodes for. As an HCV vaccine, this combination of ChAd3 priming the host immune system and MVA adding an immunogenic boost shows promise with its ability to create a potent T-cell response against HCV infection, similar to the spontaneous clearance of HCV infection seen in 15-45% of individuals infected.
-- Audrey Lin