Catch me if you can! Is there protection from HCV (re)infection?

Developing a prophylactic vaccine protecting from chronic hepatitis C virus (HCV) infection remains a high priority in efforts to end this world wide pandemic [1]. There is broad consensus that a successful prophylactic vaccine should induce both humoral and T cell responses for highest efficacy in preventing chronic infection [2]. However, detailed characteristics of T cell and antibody responses that a vaccine must elicit for effective protection await full definition. It also remains open whether sterilizing immunity against different HCV strains is a realistic goal. In contrast, protection from persistence appears more feasible, based on observations that, although spontaneous clearance of acute HCV infection is often followed by reinfections in high risk populations, the likelihood of repeated HCV clearance is high [3].

In this issue of Gut [4], Chumbe et al. aimed to define whether specific characteristics of the antibody response after a primary infection relate to real protection from reinfection. For this, they longitudinally evaluated HCV-specific antibody profiles in participants from the MOSAIC cohort of people living with HIV (PLWH) who continued to have high risk for HCV exposure after a primary infection that in most individuals was terminated with IFN-α therapy. This cohort offered a unique opportunity for stratifying participants into distinct risk profiles and infection events as participants were continuously followed with regular collection of serum samples and detailed behavioural and reinfection monitoring. Importantly, 18 of 31 individuals did not experience a second HCV infection within a follow up period between approximately 3 to 6 years after primary clearance, despite continued behaviours that should have entailed similar risks for HCV infection as in the 13 people who were reinfected. Latent profile analysis based on a set of sera collected from the cohort during primary clearance identified a coordinated humoral signature in individuals who resisted reinfection, characterized by moderate to high E1E2-binding antibody levels across multiple isotypes (IgM, IgG, IgG1, IgG3) together with measurable Fcγ-receptor and C1q engagement, suggesting important roles for antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent phagocytosis (ADCP), and complement activation. Importantly, this profile was not defined by a single dominant feature, but by the simultaneous presence of several qualitatively distinct antiviral functions. Individuals within this protective profile also exhibited the broadest and most potent neutralisation activity, spanning diverse HCV E1E2 genotypes. Their antibody responses targeted multiple antigenic regions within E1E2, including conserved, structurally constrained epitopes, thought to be associated with spontaneous clearance in natural infection [5]. The breadth of epitope recognition—rather than narrow targeting of immunodominant sites—was associated with both enhanced neutralization and higher Fc-effector readouts. Antibodies capable of engaging Fcγ receptors and activating complement can facilitate killing of infected hepatocytes, enhance opsonisation and phagocytic clearance of virions, and amplify innate antiviral signalling. Chumbe et al. suggest that anti-E2 IgM and IgG1/IgG3 driven Fc- and complement-mediated effector functions may act in concert with neutralisation during viral clearance. In light of contradictory data [6], these findings need to be confirmed, and the relative contributions of neutralisation versus Fc/complement effector mechanisms in clearance will need to be mechanistically and causally proven. However, beyond direct neutralisation and the induction of Fc-dependent cytotoxicity, phagocytosis, and complement activation, HCV-binding antibodies may also contribute to viral clearance by inhibiting viral entry post-attachment and inducing aggregation, immune-adherence–mediated clearance of opsonized virions, enhanced antigen presentation via immune complexes, and modulation of innate antiviral signalling.

What is puzzling about the differences in antibody profiles and FcγR/C1q engagement is that they were only observed early after resolution of primary infection and not in the follow up period, when one would expect a protective profile to be relevant. In our opinion, the lack of long-term differences in broadly neutralizing HCV antibodies argues against true protection from reinfection, e.g. sterilizing immunity, but rather points towards protection from chronic HCV viremia in subsequent short episodes of infection. Indeed, even the regular follow up in the MOSAIC cohort with a median time between visits of 56 days, but ranging up to 99 days, might have occasionally missed the often rather short episodes of viremia in reinfection [3, 7] that are the result of pre-existing HCV immune memory by CD4 and CD8 T cells as well as B cells and antibodies. In this context it might seem counterintuitive that the 4 PLWH who spontaneously resolved their primary infection were all in the reinfection category, but acute infections in the MOSAIC cohort are treated very early, so that more than 4 individuals might have cleared the infection even in the absence of treatment. In addition, early treatment might help to prevent the long-term consequences of chronic HCV viremia for the T cell response [8, 9] including people who would have proceeded to persistent viremia, enabling similarly short episodes of viremia in reinfections (Lauer lab, unpublished). In addition, there is also a possibility that a lack of actual HCV exposures could explain the two distinct outcome profiles, though the rigorous setup and implementation of the MOSAIC study should have minimized this possibility.

In summary, despite some uncertainties inherent to a long-term study of people at risk for HCV infection in a real world setting, the study by Chumbe et al. provides important data points for understanding how host immunity, including vaccine-induced responses, might protect from HCV infection. The data raise the possibility that not only protective but even sterilizing immunity to HCV may be achievable. And it suggests that vaccines should aim to elicit a multifunctional humoral response — broad, potent neutralising antibodies targeting conserved E1E2 epitopes, combined with robust FcγR- and complement-engaging subclasses (particularly IgG1 and IgG3) enabling ADCC, ADCP, and complement-mediated lysis. Rather than relying on neutralisation alone, a successful HCV vaccine may need to drive multidimensional antibody responses that integrate epitope breadth, functional avidity, and Fc-effector synergy to achieve meaningful protection against diverse circulating HCV strains and prevent reinfection. With Controlled Human Infection Models for evaluation of novel HCV vaccines [10, 11] on the horizon, assessing the complete functional profile of an HCV vaccine induced antibody response might be helpful to select the most promising candidates going forward.