Implementation of a controlled human infection model for evaluation of HCV vaccine candidates

Barnes E, Cooke GS, Lauer GM, Chung RT • 2023

Hepatitis C virus (HCV) remains a major global health concern. Directly acting antiviral (DAA) drugs have transformed the treatment of HCV. However, it has become clear that, without an effective HCV vaccine, it will not be possible to meet the World Health Organization targets of HCV viral elimination. Promising new vaccine technologies that generate high magnitude antiviral T and B cell immune responses and significant new funding have recently become available, stimulating the HCV vaccine pipeline. In the absence of an immune competent animal model for HCV, the major block in evaluating new HCV vaccine candidates will be the assessment of vaccine efficacy in humans. The development of a controlled human infection model (CHIM) for HCV could overcome this block, enabling the head-to-head assessment of vaccine candidates. The availability of highly effective DAA means that a CHIM for HCV is possible for the first time. In this review, we highlight the challenges and issues with currently available strategies to assess HCV vaccine efficacy including HCV 'at-risk' cohorts and animal models. We describe the development of CHIM in other infections that are increasingly utilized by trialists and explore the ethical and safety concerns specific for an HCV CHIM. Finally, we propose an HCV CHIM study design including the selection of volunteers, the development of an infectious inoculum, the evaluation of host immune and viral parameters, and the definition of study end points for use in an HCV CHIM. Importantly, the study design (including number of volunteers required, cost, duration of study, and risk to volunteers) varies significantly depending on the proposed mechanism of action (sterilizing/rapid viral clearance vs. delayed viral clearance) of the vaccine under evaluation. We conclude that an HCV CHIM is now realistic, that safety and ethical concerns can be addressed with the right study design, and that, without an HCV CHIM, it is difficult to envisage how the development of an HCV vaccine will be possible.

Single-cell atlas of the liver myeloid compartment before and after cure of chronic viral hepatitis

Cui A, Li B, Wallace MS, Gonye ALK, Oetheimer C, Patel H, Tonnerre P, Holmes JA, Lieb D, Yao BS, Ma A, Roberts K, Damasio M, Chen JH, Piou D, Carlton-Smith C, Brown J, Mylvaganam R, Hon Fung JM, Sade-Feldman M, Aneja J, Gustafson J, Epstein ET, Salloum S, Brisac C, Thabet A, Kim AY, Lauer GM, Hacohen N, Chung RT, Alatrakchi N • 2023

Chronic viral infections present serious public health challenges; however, direct-acting antivirals (DAAs) are now able to cure nearly all patients infected with the hepatitis C virus (HCV), representing the only cure of a human chronic viral infection to date. DAAs provide a valuable opportunity to study immune pathways in the reversal of chronic immune failures in an in vivo human system.