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Targets of protective immunity and opportunities in hepatitis C virus vaccine development

Nature Reviews Immunology (2025)Cite this article

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Abstract

Hepatitis C virus (HCV) remains a serious global health burden that affects nearly 50 million people worldwide. Despite the availability of highly effective direct-acting antiviral drugs, the lack of an effective HCV vaccine hinders control and elimination worldwide, wherein new infections and overall prevalence remain high. HCV vaccine development faces challenges including high genetic diversity of the virus, unclear correlates of protective immunity, and lack of robust in vivo models for vaccine testing. Despite these obstacles, the landscape of HCV vaccine development is rapidly evolving. Innovative strategies, including subunit, virus-like particle, viral vector, DNA and RNA vaccines, show promising results, and controlled human infection models offer a unique, albeit ethically complex, opportunity to accelerate vaccine development. Collaborative efforts among academia, industry, governmental agencies and regulatory bodies are crucial for optimizing vaccine strategies, overcoming current challenges and effecting advances towards global HCV elimination through vaccination.

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Fig. 1: Overview of immune responses to infection.
Fig. 2: HCV envelope proteins, structures and targets of neutralization.
Fig. 3: Phylogenetic trees of HCV, influenza A, HIV-1 and HBV and potential targets of T cell-based HCV vaccines.
Fig. 4: Genomic structure of the IFNL gene family and associated polymorphisms impacting HCV clearance.

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Acknowledgements

The authors thank K. Mouzannar and R. Umarova for the graphical assistance and S. K. Hwang and B. Rehermann for reviewing the manuscript. This publication was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) within the National Institutes of Health (NIH). The contributions of the NIH author(s) were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. However, the findings and conclusions presented in this paper are those of the author(s) and do not necessarily reflect the views of the NIH or the US Department of Health and Human Services.

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  1. These authors contributed equally: Seung Bum Park, Paul Zimmer-Harwood.

Authors and Affiliations

  1. Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA

    Seung Bum Park & T. Jake Liang

  2. Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK

    Paul Zimmer-Harwood

  3. 1Day Sooner, Claymont, DE, USA

    Paul Zimmer-Harwood

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S.B.P. and P.Z.-H. prepared the draft of the manuscript. S.B.P., P.Z.-H. and T.J.L. discussed, reviewed and edited the manuscript before submission.

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Park, S.B., Zimmer-Harwood, P. & Liang, T.J. Targets of protective immunity and opportunities in hepatitis C virus vaccine development. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01215-9

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