Introduction
Nearly 50 million people are living with a hepatitis C virus (HCV) infection globally. Directly acting antiviral (DAA) drugs have been available for HCV since 2015 and are nearly 100% effective with few side effects. Despite this, there is still an estimated 1 million new HCV infections each year, and this number is rising [Hiebert-Suwondo et al. 2025; WHO 2024]. It is clear a prophylactic vaccine is needed to achieve the World Health Organisation (WHO) 2030 elimination targets [Barnes et al. 2023], but such vaccines have been stuck in a testing bottleneck for decades.
The Hepatitis C Inoculum Trial (HIT) aims to break through this bottleneck. Led by the University of Oxford and registered on ISRCTN, it is the first stage towards building a controlled human infection model (CHIM) for HCV, a vital step to combatting HCV on the global scale by re-framing the way new vaccines are tested.
What is Hepatitis C and why is it so difficult to beat?
Hepatitis C virus (HCV) is a virus that affects the liver and is spread by contact with infected blood. Almost three quarters of people infected have no symptoms and can spread the virus without realising. Around a quarter of people will naturally clear an HCV infection within six months, but for the remaining three quarters the virus stays in their liver and causes scar tissue (fibrosis) to build up over several decades. 20-30% of people with fibrosis develop cirrhosis, and 1 in 20 of these will develop liver cancer (hepatocellular carcinoma; HCC) each year. HCV is responsible for nearly 250,000 deaths per year from HCC and other liver related diseases [WHO 2024].
DAA drugs can cure nearly every HCV case but are expensive, require 8-12 weeks of daily tablets, and are therefore impractical for people most at-risk, particularly people who inject drugs. Crucially, treatment does not prevent re-infection and new infections are outpacing DAA cures.
How would an HCV vaccine change this?
An HCV vaccine would prime the immune system to recognise and clear an HCV infection before treatment is needed. This will break transmission chains and drive down new infections. Vaccines are the most scalable way to help at-risk populations across the globe: they are inexpensive to manufacture in bulk, would likely require no more than three doses, and would protect against both initial and repeat infections.
Why do we not have an HCV vaccine yet?
There are a growing number of candidate vaccines, the bottleneck is testing them. HCV cannot readily be grown in a laboratory, there are no suitable animal models, and clinical trials in naturally infected cohorts are inefficient and prohibitively time and resource intensive [Barnes et al. 2023; Page et al 2021].
How will the HIT Study change this?
The aim of this project is to change the way HCV vaccines are tested. The Hepatitis C Inoculum Trial (HIT) is the first step towards developing a controlled human infection model (CHIM) for HCV – a world first for any blood-borne virus. A CHIM would allow new HCV vaccines to be tested efficiently in small studies using known-infected volunteers, drastically reducing the time and cost before these vaccines can reach the people who need them [Alter et al. 2023; Barnes et al. 2023].
We will bank a large volume of plasma from up to 10 HCV+ donors diagnosed with chronic (n<5) or acute (n<5) genotype 1 or 3 infection, rigorously test it to confirm it contains only HCV and no other pathogens, and sequence the specific HCV strain to confirm it has no mutations that can cause treatment resistance. Safe plasma will then become the ‘inoculum’, the standardised infectious material that will be used in later CHIM studies.
What will happen after the study?
The second stage in developing the HCV CHIM is a planned follow-on study involving around 20 consenting volunteers to confirm that the banked inoculum can safely establish HCV infection in healthy volunteers and be cured with DAAs without unsafe side effects.
Once this is established, the resulting HCV CHIM will then be made available for clinical trials to test experimental vaccines. In these trials, volunteers would receive a novel HCV vaccine before being infected with the banked plasma to determine if the vaccine-induced immune response can clear the virus without treatment. After a brief observation period – dictated by the vaccine’s mechanism – DAAs would be given to anyone who remains HCV positive.
Is an HCV CHIM safe?
An HCV CHIM is now possible because of the near 100% DAA cure rates, and the rigour of the ethical review and consent procedures. HCV related liver damage – fibrosis and cirrhosis – takes decades of infection to develop. In HCV CHIM studies, consenting healthy volunteers will be infected for the minimal observation period needed to assess whether a vaccine works (less than six months) then promptly treated with DAAs to fully clear any remaining virus. Such short-duration HCV infections are not associated with long-term liver damage [Yates et al. 2021].
Who is the research team?
The HIT study is a collaboration lead by Ellie Barnes, professor of hepatology and experimental medicine at the University of Oxford who has spent over 15 years developing HCV vaccines, and includes Graham Cooke from Imperial College London, Azim Ansari from the University of Oxford, Philip Mueleman from Ghent University, and the participant advocacy non-profit organisation 1DaySooner. Participants will be recruited through community hepatitis clinics (Oxford University Hospitals) and sexual health clinics (56 Dean Street and Mortimer Market Centre).
Funding statement
This research is funded by philanthropic donation from Coefficient Giving and Founder’s Pledge. The views expressed are those of the author(s) and not necessarily those of the funders. The funders of the study have no role in study design, data collection, data analysis, or data interpretation.
Further information
To get in touch with the HIT study team please contact the project manager oliver.sampson@ndm.ox.ac.uk or chief investigator ellie.barnes@ndm.ox.ac.uk.
Registered at
https://www.isrctn.com/ISRCTN12181449
References
[Alter et al. 2023] Joint statement in support of hepatitis C human challenge studies, Lancet Gastroenterology & Hepatology, 8(11):967-969. https://doi.org/10.1016/S2468-1253(23)00314-X
[Barnes et al. 2023] Implementation of a controlled human infection model for evaluation of HCV vaccine candidates, Hepatology, 77(5):1757-1772. https://doi.org/10.1002/hep.32632
[Hiebert-Suwondo et al. 2025] A 2024 global report on national policies, programmes, and progress towards hepatitis C elimination: findings from 33 hepatitis elimination profiles. Lancet Gastroenterology. 10(7):685-700. https://doi.org/10.1016/S2468-1253(25)00068-8
[Page et al. 2021] Randomized Trial of a Vaccine Regimen to Prevent Chronic HCV Infection, NEJM, 384:541-549. https://doi.org/10.1056/NEJMoa2023345
[WHO 2024] World Health Organisation Global Hepatitis Report 2024, ISBN: 978-92-4-009167-2.
[Yates et al. 2021] Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans. Nature Immunology. 22(8): 1020–1029. https://doi.org/10.1038/s41590-021-00979-1