Repeated exposure to heterologous hepatitis C viruses associates with enhanced neutralizing antibody breadth and potency

Abstract

A prophylactic hepatitis C virus (HCV) vaccine that elicits neutralizing antibodies could be key to HCV eradication. However, the genetic and antigenic properties of HCV envelope (E1E2) proteins capable of inducing anti-HCV broadly neutralizing antibodies (bNAbs) in humans have not been defined. Here, we investigated the development of bNAbs in longitudinal plasma of HCV-infected persons with persistent infection or spontaneous clearance of multiple reinfections. By measuring plasma antibody neutralization of a heterologous virus panel, we found that the breadth and potency of the antibody response increased upon exposure to multiple genetically distinct infections and with longer duration of viremia. Greater genetic divergence between infecting strains was not associated with enhanced neutralizing breadth. Rather, repeated exposure to antigenically related, antibody-sensitive E1E2s was associated with potent bNAb induction. These data reveal that a prime-boost vaccine strategy with genetically distinct, antibody-sensitive viruses is a promising approach to inducing potent bNAbs in humans.

Convergent antibody responses are associated with broad neutralization of hepatitis C virus

“…We included subjects who spontaneously cleared infection and subjects with persistent infection and found high and low neutralization breadth in both groups (Figure 1; Supplemental Table 1). Subjects with high neutralization capacity (neutralization score > 10) had a longer duration of infection than subjects with low neutralization capacity (Table 1), as expected based on prior studies showing a correlation between duration of infection and development of neutralizing antibodies (10,11,34). It is important to note that two subjects cleared without producing broadly neutralizing plasma.…”

Taking cues from convalescence to improve vaccines against hepatitis C virus

“…The Frumento et al ( 13 ) study was limited by the small sample size and lack of patient diversity. All patients were drug users and White; the majority were male and infected with genotype 1 HCV.…”

“…Notably, most of the vaccine strategies developed for HCV to date focus on a single virus or a combination of viruses to maximize genetic diversity. The study by Frumento et al ( 13 ) sheds light on why these vaccine strategies might have been unsuccessful. They propose, instead, a different approach in which repeated exposure to genetically distinct but antigenically similar HCV strains, based on observations of which repeated natural exposures, increased neutralizing antibody potency and breadth ( Figure 1 ).…”

“…In this issue of the JCI , Frumento et al describe how they took advantage of the information provided by studies of convalescent individuals ( 13 ). The authors focused on four key patient populations: (a) individuals who were infected and subsequently cleared multiple genetically distinct HCV strains (reinfection clearance); (b) individuals who cleared a primary infection, but did not clear a secondary infection with genetically distinct virus (reinfection persistence); (c) individuals who were sequentially infected with 2 distinct strains (persistence strain switch); and (d) individuals who were persistently infected with a single strain (persistence single strain).…”

“… Frumento et al ( 13 ) studied four different patient populations longitudinally. The HCV antibody response was evaluated using an HCVpp assay in which serological samples were compared with reference antibodies (mAbs) that had known neutralizing epitopes.…”