Characteristics of an antibody profile associated with protection against hepatitis C virus reinfection in a high-risk cohort

Background Without a vaccine, HCV (re)infections continue to afflict individuals at high risk, for example, men who have sex with men (MSM). Objective To guide vaccine development, we assessed whether natural protection against observed HCV reinfection among MSM was associated with a distinct humoral immune profile. Design From a prospective cohort of HIV-positive MSM with acute HCV infection (MOSAIC, Dutch MSM Observational Study of Acute Infection with hepatitis C), we selected 13 cases who became HCV-reinfected (R) and 18 controls who remained free of observed reinfections (non-reinfected, NR) in 0.5–9.5 years after primary infection clearance, matched for calendar year of primary infection. At time point T 1 (29 days before to 78 days after primary clearance) and T 2 (3–6 months before R subjects’ first reinfection), we evaluated serum antibody responses against HCV’s E1E2 envelope glycoprotein. Based solely on E1E2-binding antibody levels and Fc-gamma receptor (FcγR)/C1q engagement at T 1 , we divided participants into subgroups using latent profile analysis. Results HCV-neutralising responses were observed mainly at T 1 (9/18 NR and 3/13 R participants). The NR group could be distinguished from the R group at T 1 by higher levels of E1E2-binding antibodies that bound FcγRs/C1q. Among four identified latent profiles, HCV reinfection prevalence was lowest in the profile defined by moderate to high levels of E1E2-binding antibodies (IgM/IgG/IgG1/IgG3) and FcγR/C1q engagement. This profile exhibited a relatively broad, potent HCV-neutralising capacity and the broadest epitope specificity. Conclusion We propose broad, potent serum Fc-mediated effector functions and neutralisation and a broad anti-E1E2 antibody epitope specificity as ingredients of HCV-protective immunity towards which vaccination approaches should aim.