Abstract
Identification of immunogenic targets against hepatitis B virus (HBV)-encoded proteins will provide crucial advances in developing potential antibody therapies. In this study, 63 treatment-naïve patients with chronic HBV infection and 46 patients who achieved hepatitis B surface antigen loss (sAg loss) following antiviral treatment were recruited. Moreover, six patients who transitioned from the hepatitis B e antigen-positive chronic infection phase (eAg+CInf) to the hepatitis phase (eAg+CHep) were enrolled from real-life clinical practice. Additionally, telbivudine-treated eAg+CHep patients and relapsers or responders from an off-treatment cohort were longitudinally studied. The frequencies and function of B cells were assessed by flow cytometry. We devised a peptide array composed of 15-mer overlapping peptides of HBV-encoded surface (S), core (C), and polymerase (P) proteins and performed a screening on B-cell linear epitopes with sera. Naïve B cells and plasmablasts were increased, whereas total memory, activated memory (AM), and atypical memory (AtM) B cells were reduced in sAg- patients compared with sAg+ patients. Importantly, longitudinal observations found that AtM B cells were associated with successful treatment withdrawal. Interestingly, we identified six S-specific dominant epitopes (S33, S34, S45, S76, S78, and S89) and one C-specific dominant epitope (C37) that reacted with the majority of sera from sAg- patients. Of note, more B-cell linear epitopes were detected in CHep patients with alanine aminotransferase (ALT) flares than in nonflare CInf patients, and five B-cell linear epitopes (S4, S5, S10, S11, and S68) were overwhelmingly recognized by ALT flare patients. The recognition rates of epitopes on C and P proteins were significantly increased in CHep patients relative to CInf patients. Strikingly, a statistically significant elevation in the number of positive epitopes was observed when ALT nonflare patients shifted into the flare phase. Moreover, S76 identified at baseline was confirmed to be associated with a complete response after 48 weeks of telbivudine therapy. Taken together, we identified several functional cure-related B-cell linear epitopes of chronic HBV infection, and these epitopes may serve as vaccine candidates to elicit neutralizing antibodies to treat HBV infection.
Highlights
An effective preventative vaccine has successfully protected newborns from hepatitis B virus (HBV) infection, approximately 300 million people with persistent positivity of hepatitis B surface antigen are at high risk of developing HBV-related liver diseases worldwide [1]
We investigated the percentage of total B cells, naïve B cells, plasmablasts, total memory, resting memory (RM), activated memory (AM), and atypical memory (AtM) B-cell subsets in patients with different immune statuses of HBV infection as well as healthy controls (HCs) (Table 1 and Supplementary Figure 1A)
A decreased proportion of AM or AtM B cells was observed in patients who achieved surface antigen (sAg) loss, and RM B cells were the dominant phenotype in all phases (Figure 1B and Supplementary Figure 1B)
Summary
An effective preventative vaccine has successfully protected newborns from hepatitis B virus (HBV) infection, approximately 300 million people with persistent positivity of hepatitis B surface antigen (sAg) are at high risk of developing HBV-related liver diseases worldwide [1]. The detection of hepatitis B surface antibody (sAb) is associated with virus control and disease resolution, and hepatitis B core antibody (cAb), a marker of past or current HBV exposure, is associated with acute liver damage. Epitope-based therapeutic vaccines and corresponding neutralizing antibodies have shown unique advantages in suppressing virus replication and decreasing sAg levels [9,10,11,12]. A recent phase 2, randomized, controlled open-label study showed that a designed therapeutic vaccine targeting HBV-encoded S, C, and X proteins failed to decrease the levels of sAg, despite inducing robust immunologic enhancement [13]. Promising alternative novel epitopes urgently need to be identified as immunotherapeutic targets to eradicate HBV
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