A two stage, phase I/II, double-blinded, randomized, placebo-controlled study of hepatitis C virus (HCV)uninfected male and female injection drug users (IDU) aged 18 to 45. AdCh3NSmut1 and MVA-NSMut HCV vaccine will be administered to 68 (+/-4) volunteers in stage 1. A planned interim analysis of safety and immunogenicity will be conducted. If no safety signal is detected and there is evidence of a measurable immune response to HCV then 472 (+/-4) volunteers will be enrolled in stage 2. Primary objectives are to 1) assess the safety of AdCh3NSmut1 and MVA-NSmut compared to placebo when administered to HCV-uninfected IDUs and 2) determine if AdCh3NSmut1 and MVA-NSmut HCV vaccines will reduce incidence of chronic HCV infection compared to placebo among HCV-uninfected IDUs. Planned study duration is approx 63 months (accrual time, 2 months vaccination, 18 months follow-up, and 9 months extended observation for subjects becoming viremic in the last month of follow-up).

A two stage, phase I/II, double-blinded, randomized, placebo-controlled study of hepatitis C virus (HCV)uninfected male and female injection drug users (IDU) aged 18 to 45. In this clinical trial AdCh3NSmut1 and MVA-NSMut HCV vaccine will be administered intramuscularly to 68 (+/-4) evaluable volunteers in stage 1. A planned interim analysis of safety and immunogenicity will be conducted based on data through 1 week after receipt of the second vaccination. If no safety signal is detected and there is evidence of a measurable immune response to HCV then an additional 472 (+/-4) volunteers will be enrolled in stage 2. The primary objectives of this study will be 1) to assess the safety of the new candidate hepatitis C virus vaccines, AdCh3NSmut1 and MVA-NSmut, compared to placebo when administered to HCV-uninfected injection drug users (IDUs) and 2) to determine if AdCh3NSmut1 and MVA-NSmut HCV vaccines will reduce incidence of chronic HCV infection compared to placebo among HCV-uninfected IDUs. The secondary objective of this study will be to evaluate the immunogenicity of the new candidate hepatitis C virus vaccines, AdCh3NSmut1 and MVA-NSmut, compared to placebo when administered to HCV-uninfected IDUs.The planned duration of the study is approximately 63 months total including accrual time for subjects (assuming 31 months of screening/enrollments, plus 3 months of halted enrollment for the first interim analysis), 2 months vaccination, 18 months follow-up of each enrolled subject, and 9 months extended observation (monthly), from the time of infection, for subjects becoming viremic in the last month of follow-up.

Inclusion Criteria:

- Comprehension of informed consent. - 18-45 year old men or women with acknowledged active IDU in the past 90 days and have no travel plans that would interfere with ability to meet the study visit schedule. - In good general health as determined by a participating study physician and results within acceptable ranges for clinical laboratory evaluations as detailed in Appendix A. - Negative for antibodies to hepatitis C virus (anti-HCV). - Negative for HCV RNA. - Negative antibodies to HIV. - Negative for HBsAg. - Able and willing (in the Investigator's opinion) to comply with all study requirements. - Willing to allow the investigators access to their medical records. - Willingness to practice continuous effective contraception from the screening visit through 90 days after the last vaccination (males and females). - Among females, a negative pregnancy test within 24 hours prior to vaccination. - Agreement to refrain from blood donation during the course of the study or after the study. - Provide written informed consent prior to initiation of any study procedures. - Willing to provide contact information for study follow-up activities, including the address, name and contact information of three people who can be contacted to facilitate follow-up compliance.

Exclusion Criteria:

- The subject is currently participating in a study that involves an experimental agent (vaccine, drug, biologic device, blood product, or medication) or has received an experimental agent within 30 days prior to enrollment in this study, or expects to receive another experimental agent during participation in this study. - Prior receipt of a recombinant simian or human adenoviral vaccine or MVA vaccine. - Administration of immunoglobulins and/or any blood products within the 90 days preceding the planned administration of the vaccine candidate. - Any confirmed or suspected immunosuppressive or immunodeficient state, including: HIV infection; asplenia; recurrent, severe infections. - History of allergic disease or reactions likely to be exacerbated by any component of the vaccine (i.e., known hypersensitivity to aminoglycosideantibiotics or to egg proteins). - History of clinically significant contact dermatitis or other significant dermatological conditions such as psoriasis. - Any history of anaphylaxis in reaction to vaccination. - Pregnancy, lactation or willingness/intention to become pregnant during the study. - History of cancer (except for successfully treated basal cell carcinoma of the skin and cervical carcinoma in situ). - History of severe psychiatric illness, including severe depression, history of suicidal ideation, suicidal attempts, or psychosis requiring medication. The subject has a diagnosis of schizophrenia, bi-polar disease, or other severe (disabling) chronic psychiatric diagnosis that is uncontrolled and would interfere with the ability to adhere to the protocol. - Any other serious chronic illness requiring hospital specialist supervision. - Suspected or known current alcohol abuse as defined by a score of 10 or more on the Alcohol Use Disorders Identification Test (AUDIT) C test (a standardized screening tool used to identify hazardous drinkers or those with active alcohol use disorders, including abuse or dependence). - At high risk of HIV infection by the following criteria (adapted from HIV Network for Prevention Trials (HIVNET) behavioral criteria for high risk of HIV): (1) sexually active male who has sex with men (MSM), defined as (i) male who has had anal sex with male sexual partner or partners in the past year or (ii) a male who exchanged sex with male partner(s) for money or drugs in the past year; and (2) female and in a current relationship with a high risk male (active MSM, HIV positive male). - Any other significant disease, disorder or finding, which, in the opinion of the Investigator, may put the subject at risk because of participation in the study, may influence the result of the study, or may influence the subject's ability to participate in the study. - History of or current diagnosis of Diabetes mellitus. - History of or current diagnosis of autoimmune disease. - History of or current cardiac disease including history of myocardial infarction or arrhythmia. - Current diagnosis of active liver disease. - History of seizure disorder or currently taking anti-convulsant therapy that would interfere with safety evaluation. - Uncontrolled hypertension (defined as systolic blood pressure being greater than 140mm Hg or diastolic blood pressure being greater than 90mm Hg). - History of splenectomy. - Long term immunosuppressive use (defined as taken for 14 days or more in total at any time during the past 180 days) of high dose oral or parenteral glucocorticoids (high dose defined as prednisone >/=20 mg total daily dose, or equivalent dose of other glucocorticoids); or high-dose inhaled steroids (high dose defined as >800 mcg/day of beclomethasone dipropionate or equ ivalent); or any use of hepatotoxic or non-FDA approved medication. - Have an acute illness, including an oral temperature greater than or equal to 100.4 degrees Fahrenheit, within 7 days prior to the first vaccination. - Immunization against another pathogen within 14 days of planned injection. Second vaccination exclusion criteria: The following events associated with vaccine immunization constitute absolute contraindications to further administration of vaccine. The subject will not receive additional vaccination, but will continue with scheduled follow-up procedures except vaccination. 1. Anaphylactic reaction following administration of vaccine. 2. Pregnancy. If a woman reports having a positive home urine pregnancy test or a positive in clinic urine pregnancy test prior to a scheduled second vaccination, she is not eligible to receive the study vaccine. If she later returns to clinic and reports having a negative home urine pregnancy test and this is confirmed by a negative in clinic urine pregnancy test and a negative blood pregnancy test she may be eligible for the second vaccination if she is still within the vaccination window and no other exclusion criteria are met. The following adverse events constitute contraindications to administration of vaccine at that point in time. If any one of these adverse events occurs at the time scheduled for vaccination, the subject may be vaccinated at a later date (within 28 days of scheduled administration) or withdrawn at the discretion of the investigator. The subject will not receive additional vaccination, but will continue with all scheduled follow-up procedures except vaccination. 3. Acute disease at the time of vaccination (acute disease is defined as the presence of a moderate or severe illness with or without fever). The vaccine dose can be administered to persons with a minor illness such as diarrhea, mild upper respiratory infection with or without low-grade febrile illness, i.e., temperature of <38°C (100.4°F). 4. Temperature of >38°C (100.4°F) at the time of vaccination. 5. Immunization against another pathogen within 14 days of vaccination

Solicited reactogenicity symptoms were collected before vaccination, and then daily for 8 days post-vaccination (Day 0-7) after each vaccination on a memory aid. Unsolicited adverse events were collected through Day 90. At visits following Day 90 up to Day 140, only SAE's were collected.

For events solicited on the memory aid, a participant was considered to have 1 event if it was reported as experienced at any time in the 8 day period after a vaccination. Participants are analyzed as treated, one participant randomized to placebo received vaccine.