Assessment and treatment of chronic hepatitis b

Abstract

Provided herein are methods for administering hepatitis B virus surface antigen (HBsAg) to a subject suffering from chronic hepatitis B to differentiate between responder subjects and non-responder subjects that the administration of HBsAg results in an increased response to HBV antibody levels, and treating chronic hepatitis B in responder subjects using HBV therapy. Also provided are methods of excluding unresponded subjects outside a clinical study.

Description

Cross Reference to Related Applications

[0001] This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application Serial No. 63 / 522,851, filed June 23, 2023, the contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] Provided herein are methods for treating chronic hepatitis B, comprising administering a hepatitis B surface antigen prior to administering a second therapy. BACKGROUND

[0003] Chronic hepatitis B (CHB) caused by long-term infection with hepatitis B virus (HBV) remains a public health problem, affecting an estimated 296 million people worldwide, and is a major factor in the development of cirrhosis and its complications, including hepatocellular carcinoma and end-stage liver disease. CHB patients typically exhibit weak or absent viral-specific antibody responses or T cell reactivity, which is described as an “exhausted” state characterized by poor effector antibody responses or cytotoxic activity, impaired cytokine production, and sustained expression of multiple inhibitory receptors, which impede viral clearance and recovery from hepatitis (Ye et al., 2015, Cell Death & Disease, 6(3):e1694).

[0004] Current treatments for CHB suppress HBV DNA but rarely eradicate the virus. These treatments include: (i) nucleoside / nucleotide reverse transcriptase inhibitors (NrtIs), such as lamivudine, entecavir, tenofovir alafenamide, tenofovir disoproxilfumarate, adefovir dipivoxil, and telbivudine; and (ii) immunomodulatory agents pegylated interferon-alpha (PEG-IFNα). Prolonged NrtI treatment has led to the emergence of HBV strains resistant to NrtIs. Furthermore, NrtI treatment fails to clear HBV cccDNA from infected cells, and the production of viral proteins (especially HBV surface antigen (HBsAg)) may persist, detectable in the blood (Scaglione and Lok, 2012, Gastroenterology 142:1360-1368). PEG-IFNα treatment has limited duration, and subjects responding to PEG-IFNα may maintain virological or serological responses (e.g., HBsAg clearance in serum) after discontinuation; unfortunately, however, the response rate to PEG-IFNα treatment is relatively low.

[0005] The failure of NrtI therapy to achieve a functional cure and the limitations of PEG-IFNα therapy highlight the need for effective and well-tolerated HBV therapies. Summary of the Invention

[0006] According to one embodiment of this disclosure, a method for treating hepatitis B virus (HBV) infection in a subject suffering from chronic hepatitis B is provided, the method comprising: a) administering HBV surface antigen (HBsAg) to the subject; and b) administering an HBV therapy other than said HBsAg to the subject at least 4 weeks after the initial dose of HBsAg.

[0007] In some embodiments, the initial dose of HBV therapy is administered after at least two doses of HBsAg, or after at least three, four, or five doses of HBsAg. In some embodiments, the initial dose of HBV therapy is administered at least eight weeks after the initial dose of HBsAg, or at least nine, ten, eleven, twelve, thirteen, fourteen, or fifteen weeks after the initial dose of HBsAg.

[0008] In some embodiments, the subject had not received treatment for the HBV therapy prior to HBsAg administration. In some embodiments, the subject had not received interferon treatment prior to HBsAg administration. In some embodiments, the subject had not received treatment for the HBV infection prior to HBsAg administration.

[0009] In some implementations, the HBsAg is administered at a dose of 20 µg to 100 µg every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W).

[0010] In some implementations, the HBV therapy is selected from anti-HBsAg siRNA, interferon α (IFNα), pegylated interferon α (PEG-IFNα), HBV neutralizing mAbs, and combinations thereof.

[0011] In some embodiments, the HBV therapy comprises anti-HBsAg siRNA. In some embodiments, the anti-HBsAg siRNA is administered at a dose of 100 mg to 400 mg every two weeks (Q2W), every three weeks (Q3W), every four weeks (Q4W), every five weeks (Q5W), or every six weeks (Q6W).

[0012] In some embodiments, the HBV therapy further comprises pegylated interferon alpha (PEG-IFNα). In some embodiments, the PEG-IFNα is administered at 50 to 500 µg once weekly, 100 to 300 µg once weekly, or 180 µg once weekly.

[0013] In one embodiment, a method for treating hepatitis B virus (HBV) infection in a subject with chronic hepatitis B is also provided, the method comprising: administering to the subject 20 µg to 100 µg of HBV surface antigen (HBsAg) per dose, once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W); and 100 mg to 400 mg of anti-HBsAg siRNA per dose, once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), or once every six weeks (Q6W); wherein the treatment comprises administering at least four (or five, six, seven, eight, or ten) doses of each of HBsAg and siRNA.

[0014] In some embodiments, the HBsAg comprises virus-like particles (VLPs) containing HBV surface envelope proteins Pre-S1, Pre-S2, or S. In some embodiments, the VLP comprises HBV surface envelope proteins Pre-S1, Pre-S2, and S.

[0015] In some implementations, the siRNA is elebsiran.

[0016] In some embodiments, the subject is also administered a nucleoside / nucleotide reverse transcriptase inhibitor (NrtI). In some embodiments, the method further includes discontinuing the administration of the NrtI if the subject meets one or more of the discontinuation criteria. In some embodiments, the discontinuation criteria include (a) HBsAg < LLOQ (lower limit of quantitation), (b) HBV DNA < LLOQ, (c) undetectable HBeAg, and (d) ALT (alanine aminotransferase) ≤ 2 x ULN (upper limit of normal).

[0017] In one aspect, this article provides a method for excluding subjects with chronic hepatitis B (CHB) from a clinical study, the method comprising: (a) screening a group of CHB subjects by administering HBV surface antigen (HBsAg) to the CHB subjects, wherein each CHB subject has a predetermined baseline HBV antibody concentration prior to HBsAg administration, and wherein each CHB subject who does not produce a response to HBsAg administration that results in a baseline HBV antibody concentration greater than their baseline HBV antibody concentration is excluded from the clinical study; and (b) conducting the clinical study, wherein HBV therapy is administered to CHB subjects who have not been excluded from the clinical study.

[0018] In some implementations, each CHB subject who did not produce a response to HBsAg administration that resulted in a post-baseline HBV antibody concentration greater than 5 times their baseline HBV antibody concentration was excluded from the clinical study.

[0019] In some implementations, (i) for each CHB subject with a predetermined baseline HBV antibody concentration at or below the detection limit (e.g., ≤2 IU / L), the subject is excluded from the clinical trial unless the CHB subject's post-baseline HBV antibody concentration is above the detection limit (e.g., >2 IU / L); and (ii) for each CHB subject with a predetermined baseline HBV antibody concentration above the detection limit (e.g., >2 IU / L), the subject is excluded from the clinical trial unless the subject's post-baseline HBV antibody concentration is at least twice their predetermined baseline HBV antibody concentration.

[0020] In some implementations, a CHB subject is excluded from the clinical trial unless the baseline post-HBV antibody concentration is greater than 4 IU / L, greater than 5 IU / L, greater than 10 IU / L, greater than 12 IU / L, greater than 15 IU / L, greater than 20 IU / L, greater than 25 IU / L, greater than 30 IU / L, greater than 50 IU / L, greater than 100 IU / L, greater than 150 IU / L, greater than 200 IU / L, greater than 250 IU / L, or greater than 300 IU / L.

[0021] In some implementations, the CHB subjects achieved viral suppression via a nucleoside / nucleotide reverse transcriptase inhibitor (NrtI) prior to HBsAg administration.

[0022] In some implementations, the HBV antibody concentration is the serum anti-HBs concentration.

[0023] In some implementations, the HBV therapy does not include the HBsAg.

[0024] In one aspect, this article provides a method for selecting a subject with chronic hepatitis B (CHB) for hepatitis B virus (HBV) therapy, comprising: (a) determining the subject's baseline HBV antibody concentration before administering HBV surface antigen (HBsAg) to the CHB subject; (b) administering the HBsAg to the subject; (c) determining the subject's post-baseline HBV antibody concentration after the subject has been administered HBsAg, wherein if the post-baseline HBV antibody concentration is greater than the baseline HBV antibody concentration, the subject is selected for HBV therapy, otherwise the subject is excluded from the HBV therapy; and (d) administering the HBV therapy to the selected subject.

[0025] In some implementations, if the post-baseline HBV antibody concentration is greater than 5 times the baseline HBV antibody concentration, the subject is selected for HBV therapy; otherwise, the subject is excluded from the HBV therapy.

[0026] In some implementations, a subject is selected for the HBV therapy if (i) the subject's baseline HBV antibody concentration is at or below the detection limit (e.g., ≤2 IU / L) and the subject's post-baseline HBV antibody concentration is above the detection limit (e.g., >2 IU / L); or (ii) the subject's baseline HBV antibody concentration is above the detection limit (e.g., >2 IU / L) and the subject's post-baseline HBV antibody concentration is at least twice the subject's baseline HBV antibody concentration; otherwise, the subject is excluded from the HBV therapy.

[0027] In some implementations, the subject achieved viral suppression via a nucleoside / nucleotide reverse transcriptase inhibitor (NrtI) prior to HBsAg administration.

[0028] In some embodiments, the baseline and post-baseline HBV antibody concentrations are anti-HBs concentrations determined from serum samples collected from the subject. In some embodiments, the HBV therapy does not include HBsAg. In some embodiments, the HBV therapy is siRNA, interferon alpha (IFNα), pegylated interferon alpha (PEG-IFNα), HBV neutralizing mAb, or a combination thereof.

[0029] In one aspect, this article provides a method for treating HBV infection in a subject with chronic hepatitis B, the method comprising administering HBV therapy to the subject, wherein the subject's baseline post-administration HBV antibody concentration after HBsAg administration has been determined to be greater than the subject's baseline HBV antibody concentration before HBsAg administration.

[0030] In some implementations, the HBV therapy is administered when it has been determined that the subject's baseline HBV antibody concentration after HBsAg administration is greater than 5 times the subject's baseline HBV antibody concentration before HBsAg administration.

[0031] In some implementations, the HBV therapy is administered to a subject in the following manner: (i) the subject's baseline HBV antibody concentration is less than or equal to the detection limit (e.g., ≤2 IU / L), and the subject's post-baseline HBV antibody concentration is greater than the detection limit (e.g., >2 IU / L); or (ii) the subject's baseline HBV antibody concentration is greater than the detection limit (e.g., >2 IU / L), and the subject's post-baseline HBV antibody concentration is at least twice the subject's baseline HBV antibody concentration.

[0032] In some embodiments, the baseline and post-baseline HBV antibody concentrations are anti-HBs concentrations determined from serum samples collected from the subject. In some embodiments, the HBV therapy does not include HBsAg. In some embodiments, the HBV therapy is siRNA, interferon alpha (IFNα), pegylated interferon alpha (PEG-IFNα), HBV neutralizing mAb, or a combination thereof.

[0033] In one aspect, this article provides a method for treating HBV infection in a subject diagnosed with or suspected of having HBV infection, the method comprising: (a) administering HBsAg to the subject; (b) determining a baseline post-HBV antibody concentration in a serum sample collected from the subject after administration of HBsAg; and (c) administering HBV therapy to the subject if the baseline post-HBV antibody concentration is greater than the baseline HBV antibody concentration in a serum sample collected from the subject before administration of HBsAg.

[0034] In some implementations, the HBV therapy is administered when it has been determined that the subject's baseline HBV antibody concentration after HBsAg administration is greater than 5 times the subject's baseline HBV antibody concentration before HBsAg administration.

[0035] In some embodiments, the HBV therapy is administered to the subject if (i) the subject's baseline HBV antibody concentration is less than or equal to the detection limit (e.g., ≤2 IU / L) and the subject's post-baseline HBV antibody concentration is greater than the detection limit (e.g., >2 IU / L); or (ii) the subject's baseline HBV antibody concentration is greater than the detection limit (e.g., >2 IU / L) and the subject's post-baseline HBV antibody concentration is at least twice the subject's baseline HBV antibody concentration. In some embodiments, the baseline and post-baseline HBV antibody concentrations are anti-HBs concentrations. In some embodiments, the subject achieves viral suppression via NrtI prior to HBsAg administration. In some embodiments, the HBV therapy does not include HBsAg. In some embodiments, the HBV therapy is siRNA, interferon α (IFNα), pegylated interferon α (PEG-IFNα), HBV neutralizing mAb, or a combination thereof.

[0036] In one aspect, this article provides a method for treating HBV infection in a subject with chronic hepatitis B, wherein the subject has an HBV antibody concentration of less than 2 IU / L, the method comprising: (a) administering HBsAg to the subject; and (b) administering HBV therapy to the subject, wherein it has been determined that, after administration of HBsAg, the subject's HBV antibody concentration is at least 2 IU / L, at least 5 IU / L, at least 10 IU / L, at least 15 IU / L, at least 20 IU / L, at least 25 IU / L, at least 30 IU / L, at least 40 IU / L, at least 50 IU / L, at least 60 IU / L, at least 70 IU / L, at least 80 IU / L, at least 90 IU / L, at least 100 IU / L, at least 200 IU / L, at least 300 IU / L, at least 400 IU / L, at least 500 IU / L, at least 600 IU / L, at least 700 IU / L. IU / L, at least 800 IU / L, at least 900 IU / L, or at least 1000 IU / L. In some embodiments, the subject achieved viral suppression via NrtI prior to HBsAg administration. In some embodiments, the HBV antibody is anti-HBs. In some embodiments, the HBV therapy does not include HBsAg. In some embodiments, the HBV therapy is siRNA, interferon alpha (IFNα), pegylated interferon alpha (PEG-IFNα), HBV neutralizing mAb, or a combination thereof.

[0037] In one aspect, this article provides a method for treating HBV infection in a subject suffering from chronic hepatitis B, the method comprising administering a therapeutically effective amount of HBV therapy to the subject suffering from chronic hepatitis B, wherein, prior to administering the HBV therapy, the subject's HBV antibody concentration has been determined to be at least 10 IU / L, at least 15 IU / L, at least 20 IU / L, at least 25 IU / L, at least 30 IU / L, at least 40 IU / L, at least 50 IU / L, at least 60 IU / L, at least 70 IU / L, at least 80 IU / L, at least 90 IU / L, at least 100 IU / L, at least 200 IU / L, at least 300 IU / L, at least 400 IU / L, at least 500 IU / L, at least 600 IU / L, at least 700 IU / L, at least 800 IU / L, at least 900 IU / L, or at least 1000 IU / L. In some embodiments, the subject's HBV antibody concentration is an anti-HBs concentration. In some embodiments, the HBV therapy does not include HBsAg. In some embodiments, the HBV therapy is siRNA, interferon alpha (IFNα), pegylated interferon alpha (PEG-IFNα), HBV neutralizing mAb, or a combination thereof.

[0038] In one aspect, this document provides an HBV surface antigen (HBsAg) for use in the methods described herein.

[0039] In another aspect, this document provides the use of HBV surface antigen (HBsAg) and HBV therapy without HBsAg in the preparation of a kit for treating subjects with chronic hepatitis B who, prior to administration of the HBV therapy, exhibit an increased HBV antibody concentration after administration of HBsAg relative to their HBV antibody concentration prior to administration of HBsAg. In some embodiments, (i) the subject's HBV antibody concentration is less than 2 IU / L prior to administration of HBsAg; or (ii) the subject exhibits an increase in HBV antibody concentration greater than twice the HBV antibody concentration prior to administration of HBsAg. In some embodiments, the subject achieves viral suppression via NrtI prior to administration of HBsAg. In some embodiments, the HBV antibody is anti-HBs. In some embodiments, the HBV therapy is siRNA, interferon alpha (IFNα), pegylated interferon alpha (PEG-IFNα), HBV neutralizing mAb, or a combination thereof. Attached Figure Description

[0040] Figure 1 This is a schematic diagram of the research design scheme discussed in Example 8.

[0041] Figure 2 This shows the change in HBsAg levels in patients after treatment compared to baseline.

[0042] Figure 3 The study showed the anti-HBs antibody response after treatment. One participant withdrew from the study before week 8, and no post-baseline anti-HBs data were available. Detailed Implementation definition

[0043] It should be noted that the terms "an" or "a type" of an entity refer to one or more of that entity; for example, "an antibody" should be understood to mean one or more antibodies. Therefore, the terms "an," "one or more," and "at least one" are used interchangeably in this document.

[0044] It should be further understood that wherever the implementation scheme is described with “comprising” in this document, similar implementation schemes described with “consisting of” and / or “substantially consisting of” are also provided.

[0045] The term "therapeutic effective amount," "effective dose," "effective quantity," or "therapeutic effective dose" for a therapeutic agent (e.g., anti-HBsAg siRNA) refers to any amount, when used alone or in combination with another therapeutic agent, that protects a subject from the development of disease or symptoms originating from CHB (including, for example, liver failure or liver cancer), or promotes disease remission (demonstrated by, for example, a reduction in viral load determined by measuring HBV DNA levels or HBV antigen levels, a reduction in the severity of disease symptoms, an increase in the frequency and duration of asymptomatic periods, or prevention of damage or disability caused by disease distress). The ability of a therapeutic agent to promote disease remission can be assessed using a variety of methods known to those skilled in the art, such as in human subjects during clinical studies, in animal model systems that predict human efficacy, or by detecting the activity of the agent in in vitro assays.

[0046] The terms "subject / object," "individual," "animal," "patient," or "mammal" refer to any subject requiring diagnosis, prognosis, or treatment, particularly a mammalian subject. In some embodiments, the subject refers to a human. In some embodiments, the subject is a human with chronic hepatitis B ("CHB subject").

[0047] As used herein, phrases such as “to a patient in need of treatment” or “subject in need of treatment” include subjects who would benefit from administration of the compositions of this disclosure, such as mammalian subjects, for example, for use in detection, diagnostic procedures and / or treatment. Assessment and treatment of chronic HBV

[0048] This study found that BRII-179 (a virus-like particle (VLP) containing the three surface envelope proteins (L, M, S) of HBV) can induce a significant anti-HBs (hepatitis B surface antibody) response in some (but not all) chronic HBV (cHBV) infected individuals (Example 1). Furthermore, in a subset of CHB patients receiving combination therapy with BRII-835 and PEG-IFNα, as well as add-on therapy with BRII-179 and PEG-IFNα, a robust anti-HBs response was associated with persistent HBsAg (hepatitis B surface antigen) seroclearance.

[0049] BRII-179, also known as VBI-2601, is a VLP-based recombinant protein immunotherapy agent composed of three HBsAg forms: small, medium, and large S proteins that form the HBV envelope. The large S protein contains N-terminal preS1 and preS2 domains and an adjacent small S protein. The medium S protein contains preS2 and an adjacent small S protein. The preS1 domain contains several relatively conserved B cell and T helper cell epitopes. Therefore, BRII-179 utilizes the PreS1, PreS2, and S protein components as an immunogen in therapeutic applications of HBsAg containing preS1 / S2. Furthermore, BRII-179 uses aluminum phosphate adjuvant to enhance Th1 T cell and humoral immunity.

[0050] BRII-835, also known as elebsiran and VIR-2218, is a synthetic RNA interference (RNAi) therapeutic agent designed to target HBV transcripts containing a region of the HBx gene that is common to all HBV transcripts and highly conserved among HBV genotypes. It is conjugated to an N-acetylgalactosamine (GalNAc) ligand to facilitate delivery to hepatocytes via the desialylate glycoprotein receptor (ASGPR).

[0051] Interferon-alpha (IFNα) induces interferon-stimulated genes at multiple points in the HBV lifecycle through various pathways, thereby being used to treat hepatitis B by increasing viral RNA degradation and preventing viral damage. IFNα also stimulates cell-mediated immune responses, targeting infected hepatocytes and leading to a reduction in cells carrying intrahepatic HBV cccDNA (covalently closed circular DNA) molecules responsible for persistent HBV infection. Furthermore, it can reshape the immune landscape to induce adaptive immunity by coordinating various immune cells, including NK cells, macrophages, dendritic cells (DCs), and T cells. PEGylated IFNα (PEG-IFNα) allows for weekly injections. PEG-IFNα is associated with a variety of side effects, including flu-like symptoms, neutropenia, thrombocytopenia, depression, and less commonly, exacerbation or manifestation of autoimmune diseases and hepatitis flare-ups. The main advantages of PEG-IFNα in the treatment of chronic hepatitis B (CHB) are limited treatment duration, lack of resistance, and the potential for immune-mediated control of HBV infection, with the possibility of achieving sustained virological responses after discontinuation of treatment, particularly HBsAg seroclearance in a subset of CHB patients. However, functional cure following PEG-IFNα monotherapy is limited to a small percentage of CHB patients (<10%).

[0052] The effects of adding BRII-179 as a therapeutic agent against other HBV therapies were evaluated. As shown in Example 7, BRII-835 alone restored HBV surface antigen-specific T-cell responses in only a small percentage (20%) of participants. Adding BRII-179 (with or without adjuvant IFN-α) induced improved HBV surface antigen-specific T-cell responses (70%). Furthermore, the combination of BRII-179 and BRII-835 resulted in a higher proportion of participants with a greater degree of T-cell response (>20-fold from baseline) compared to BRII-179 monotherapy (40% vs. 25%). Regarding antibody responses, cohort A, with BRII-835 alone, did not induce an antibody response ( Figure 3 BRII-179 (with or without the adjuvant IFN-α) induced a potent anti-HBs response, typically peaking after 5 doses, with some participants reaching the detection limit of 1000 IU / L. By week 40, over 40% of participants in cohorts B and C had developed high anti-HBs titers (>100 IU / L).

[0053] In some implementations, for combination therapy including BRII-179 and one or more other HBV therapies, BRII-179 administration may be initiated prior to the other therapies. It is envisioned that such a treatment regimen would not only leverage the synergistic effects between the therapies but also allow the patient's response to BRII-179 to serve as a biomarker guiding subsequent treatment.

[0054] In one respect, this article provides a method for treating HBV infection in subjects who are diagnosed with or suspected of having HBV infection.

[0055] In some embodiments, this document provides a method for treating CHB in a subject of need, comprising administering hepatitis B surface antigen (HBsAg) and HBV therapy to the subject. In some embodiments, the HBV therapy does not include administering HBsAg to the subject.

[0056] In some embodiments, at least the first dose of HBsAg is administered to the subject before HBV therapy is administered. In some embodiments, HBV therapy is not initiated until after the second dose of HBsAg. In some embodiments, HBV therapy is not initiated until after the third dose of HBsAg. In some embodiments, HBV therapy is not initiated until after the fourth dose of HBsAg. In some embodiments, HBV therapy is not initiated until after the fifth dose of HBsAg. In some embodiments, HBV therapy is not initiated until HBsAg administration is completed.

[0057] In some embodiments, HBV therapy is initiated one week after the initial HBsAg dose. In some embodiments, HBV therapy is initiated two weeks after the initial HBsAg dose. In some embodiments, HBV therapy is initiated at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 weeks after the initial HBsAg dose.

[0058] In some embodiments, the subjects treated herein were treatment-naïve prior to HBsAg administration. In other words, the subject had not received treatment for CHB. In some embodiments, the subject had not received therapy such as interferon. In some embodiments, the subject had not received at least one HBV therapy (e.g., anti-HBsAg siRNA) administered after HBsAg administration. In some embodiments, the subject had not received either interferon or anti-HBsAg siRNA treatment.

[0059] In some embodiments, the subject has not received treatment with a nucleoside / nucleotide reverse transcriptase inhibitor (NrtI) prior to HBsAg administration. In some embodiments, the subject has received or is currently receiving NrtI treatment.

[0060] In some embodiments, this document provides a method for treating hepatitis B virus (HBV) infection in a subject with chronic hepatitis B, the method comprising: administering to the subject 20 µg to 100 µg of HBV surface antigen (HBsAg) per dose, every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W); and 100 mg to 400 mg of anti-HBsAg siRNA per dose, every two weeks (Q2W), every three weeks (Q3W), every four weeks (Q4W), every five weeks (Q5W), or every six weeks (Q6W). In some embodiments, the treatment comprises administering at least four doses of each of HBsAg and siRNA. In some embodiments, the treatment comprises administering at least five, six, seven, eight, nine, or ten doses of each of HBsAg and siRNA.

[0061] In some implementations, this document provides a method comprising administering hepatitis B virus (HBV) therapy to a CHB subject, wherein the CHB subject has been determined to have a baseline post-HBV antibody concentration after administration of hepatitis B surface antigen (HBsAg) that is greater than the CHB subject's baseline HBV antibody concentration before administration of HBsAg.

[0062] In some embodiments, this document provides a method for selecting CHB subjects for HBV therapy, comprising: (a) determining a baseline HBV antibody concentration in a biological sample from the CHB subject; (b) administering HBsAg to the CHB subject; (c) after the CHB subject has been administered HBsAg, determining a post-baseline HBV antibody concentration in a biological sample from the CHB subject, wherein if the post-baseline HBV antibody concentration is greater than the baseline HBV antibody concentration, the subject is selected for the HBV therapy, otherwise the subject is excluded from the HBV therapy; and (d) administering the HBV therapy to the selected subject.

[0063] In some embodiments, the method includes: (a) administering HBsAg to a CHB subject; (b) determining the anti-HBs concentration in a biological sample collected from the subject after HBsAg administration; and (c) administering HBV therapy to the subject if the anti-HBs concentration in the biological sample collected from the subject after HBsAg administration is greater than the baseline anti-HBs concentration in the biological sample collected from the subject before HBsAg administration.

[0064] In some embodiments, this document provides a method for treating HBV infection in a CHB subject, wherein the CHB subject has a baseline HBV antibody concentration of less than 2 IU / L, the method comprising: (a) administering HBsAg to the CHB subject; and (b) administering HBV therapy to the CHB subject, wherein it has been determined that after administration of HBsAg, the subject's baseline post-HBV antibody concentration reaches or exceeds 2 IU / L.

[0065] In some embodiments, this document provides a method for treating HBV infection in a CHB subject, wherein the baseline HBV antibody concentration of the CHB subject is between 0 and 4 IU / L, the method comprising: (a) administering HBsAg to the CHB subject; and (b) administering HBV therapy to the CHB subject, wherein it has been determined that the subject's baseline post-HBV antibody concentration is higher than 10 IU / L after administration of HBsAg.

[0066] In some implementations, the baseline HBV antibody concentration of the CHB subject is between 0 and 10 IU / L.

[0067] In some embodiments, this document provides a method for treating HBV infection in a CHB subject with a predetermined baseline HBV antibody concentration, the method comprising: (a) administering HBsAg to the CHB subject; and (b) administering HBV therapy to the CHB subject, wherein it has been determined that, following the administration of HBsAg, the subject's baseline post-HBV antibody concentration is at least 5 times the predetermined baseline HBV antibody concentration.

[0068] In one aspect, this document provides methods for excluding subjects with chronic hepatitis B (CHB) from clinical studies. In some embodiments, the method includes screening a group of CHB subjects by administering HBV surface antigen (HBsAg) to each CHB subject, wherein each CHB subject has a predetermined baseline HBV antibody concentration, and CHB subjects who do not produce a response to HBsAg administration with a baseline HBV antibody concentration greater than their baseline HBV antibody concentration are excluded from clinical studies. In some embodiments, the method further includes conducting the clinical study, wherein HBV therapy is administered to CHB subjects who have not been excluded from the clinical study.

[0069] In some implementations, this document provides a method for selecting subjects for a clinical study in which HBV therapy is administered to selected subjects, the method comprising: (a) determining the baseline HBV antibody concentration of a subject before administering HBsAg to a subject with CHB; (b) administering the HBsAg to the subject; (c) determining the post-baseline HBV antibody concentration of the subject after administering HBsAg, wherein if the post-baseline HBV antibody concentration is greater than the baseline HBV antibody concentration, the subject is selected for inclusion in the clinical study; and (d) conducting the clinical study in which HBV therapy is administered to the selected subjects.

[0070] The phrase "responder CHB subject" as used in this article refers to a CHB subject whose HBV antibody concentration increased after administration of HBsAg.

[0071] The phrase “non-responder CHB subject” as used in this article refers to a CHB subject whose HBV antibody concentration did not increase after administration of HBsAg.

[0072] Without being limited to any particular theory or implementation method, it is believed that administration of HBsAg can induce a neonatal adaptive immune response and / or enhance pre-existing surface antigen-specific immune memory in responder CHB subjects, thereby achieving greater efficacy of subsequent HBV therapy. For example, identifying non-responder CHB subjects can avoid unnecessary costs and personal inconveniences or intolerance to HBV therapies that are unlikely to be effective for CHB treatment in non-responder CHB subjects. Increased HBV antibody response may be a surrogate marker of intrinsic HBV-specific immunity and may be positively correlated with the expected outcome of HBV therapy; conversely, lack of HBV antibody response may indicate weak or absent HBV-specific immunity and is negatively correlated with the expected outcome of HBV therapy.

[0073] Diagnosing CHB typically involves a series of medical examinations and evaluations. Initially, healthcare professionals perform a physical examination to look for signs of liver damage, such as jaundice, enlarged liver or spleen, and abdominal swelling. Blood tests are also commonly used to check for the presence of hepatitis B virus DNA, antigens, and antibodies, as well as liver function tests to assess the liver's ability to perform its functions.

[0074] In some embodiments of the methods provided herein, the CHB subject has achieved HBV suppression by, for example, treatment with a nucleoside / nucleotide reverse transcriptase inhibitor (NrtI). As used herein, “HBV suppression” means, in some embodiments, that the serum HBV DNA concentration is below the limit of detection (typically varying between about 2 IU / mL and 16 IU / mL depending on the detection system used; see, for example, Supplementary Table 1 and Supplementary Information in Kramvis et al., 2022, Nature Reviews Gastroenterology & Hepatology, 19: 727-745). In some implementations, “HBV viral suppression” means a serum HBV DNA concentration below 100 IU / mL, below 90 IU / mL, below 80 IU / mL, below 70 IU / mL, below 60 IU / mL, below 50 IU / mL, below 40 IU / mL, below 30 IU / mL, below 20 IU / mL, below 15 IU / mL, below 10 IU / mL, below 9.6 IU / mL, below 6.7 IU / mL, below 2.7 IU / mL, below 2.4 IU / mL, or below 2 IU / mL. Methods for detecting HBV DNA viral load are well known in the art (see, for example, Abe et al., 1999, J. Clin. Microbiol., 37(9):2899-2903; Kramvis et al., 2022, Nature Reviews Gastroenterology & Hepatology, 19: 727-745 and supplemental information). For example, samples can be tested for HBV DNA viral load using the Roche COBASE® HBV Quantitative Assay.

[0075] In some implementations, the CHB subject to be given HBsAg has been receiving NrtI treatment. NrtI therapies for treating HBV infection are known in the art and include, for example, lamivudine, entecavir, tenofovir alafenamide, tenofovir disoproxil fumarate, adefovir dipivoxil, and telbivudine.

[0076] In some implementations, the CHB subject had received NrtI and / or interferon (e.g., interferon α (IFNα) or pegylated interferon α (PEG-IFNα)) prior to HBsAg administration.

[0077] In some implementations, CHB subjects who were to be given HBsAg did not achieve viral suppression.

[0078] In some embodiments of the methods provided herein, HBsAg is present in the serum of the CHB subject for at least 6 months.

[0079] In some implementations, the CHB subject has occult HBV infection, characterized, for example, by detectable HBV DNA in a liver sample but negative for serum HBsAg.

[0080] It should be understood that in some embodiments of the methods provided herein, HBsAg is administered to the subject during the diagnostic phase, while HBV therapy is administered to the subject during the treatment phase. During the diagnostic phase, biological samples may be collected from the subject to determine whether the subject responds to HBsAg administration with an increased HBV antibody concentration; if so, the subject is selected for the treatment phase.

[0081] The HBV DNA S gene encodes three envelope / surface proteins within a single open reading frame containing three independent in-frame start codons. This structure defines three protein domains (Pre-S1, Pre-S2, and S), which form large (“Pre-S1”, containing all three domains), medium (“Pre-S2”, containing both the Pre-S2 and S domains), and small (“S”) surface proteins sharing a common C-terminal region (see, e.g., Seitz et al., 2020, Annu. Ref. Virol., 7:263-288). These three proteins form a globular structure on the viral surface, are highly antigenic, and are often the first serological markers to appear in serum after HBV infection, commonly used as diagnostic markers for acute and chronic hepatitis B.

[0082] The hepatitis B surface antigen (HBsAg) administered to subjects in the methods provided herein may comprise, for example, any one, a portion of, or a combination of large (Pre-S1), medium (Pre-S2), and small (S) HBV surface proteins. In some embodiments, the HBsAg is recombinant HBsAg. In some embodiments, the HBsAg is derived from human plasma. In some embodiments, the HBsAg is virus-like particles. Methods for producing HBsAg from cell cultures and generating virus-like particles are known in the art (see, for example, Wampler et al., 1985, Proc. Natl. Acad. USA, 82(20):6830-6834). Furthermore, prophylactic HBV vaccines containing HBsAg have been available for over 30 years and may be a source of HBsAg administered to subjects in methods provided herein, for example. Exemplary HBV vaccines include, for example, HEPLISAV-B (Dynavax Technologies Corporation), which is provided in a single 0.5 mL dose containing 20 µg HBsAg and 3000 µg CpG 1018 adjuvant; ENGERIX-B (GlaxoSmithKline Biologicals SA), which is provided in 0.5 mL (10 µg HBsAg) and 1 mL (20 µg HBsAg) doses and contains aluminum hydroxide adjuvant; and PREHEVBRIO (VBIVaccines), which contains small (S), medium (Pre-S2), and large (Pre-S1) hepatitis B surface antigens and is provided in a 1 mL (10 µg HBsAg) dose and contains aluminum hydroxide adjuvant.

[0083] In some implementations, the HBsAg consists of a small (S) protein as the sole hepatitis B surface antigen.

[0084] In some embodiments, the HBsAg administered to the subject comprises small (S), medium (Pre-S2), and large (Pre-S1) proteins and an aluminum phosphate adjuvant. The manufacture and administration of compositions comprising HBsAg and aluminum phosphate adjuvant are described in WO 2020 / 099927 A1. In some embodiments, the HBsAg administered to the subject is in the form of an HBsAg formulation as described in Example 1 of WO 2020 / 099927 A1, which is incorporated herein by reference in its entirety for all purposes. In some embodiments, the HBsAg administered to the subject is present in a composition comprising the S protein, Pre-S1 protein, and Pre-S2 protein, and an aluminum phosphate adjuvant, wherein the composition contains at least 20 µg / ml of HBsAg antigen and the amount of unadsorbed antigen is at least 30%. In some embodiments, the HBsAg administered to the subject is present in a composition comprising virus-like particles containing small (S), medium (Pre-S2), and large (Pre-S1) proteins.

[0085] In some embodiments, HBsAg is administered to the subject in a dosing regimen that administers a dose of HBsAg to the subject over several days or weeks. In some embodiments, HBsAg is administered as a single dose, optionally in two or more divided doses within a day. A single dose of HBsAg may comprise, for example, 1 µg to 100 µg of HBsAg. In some embodiments of the methods provided herein, the amount of HBsAg administered is between 5 and 100 µg, 5 µg and 80 µg, 10 and 100 µg, or 10 and 80 µg of HBsAg. In some embodiments, the amount of HBsAg administered to the subject is about 7 µg to about 60 µg, about 8 µg to about 50 µg, about 10 µg to about 60 µg, about 20 µg to about 60 µg, about 30 µg to about 50 µg, about 35 µg to about 45 µg, or about 10 µg to about 40 µg.

[0086] In some embodiments of the methods provided herein, HBsAg is administered in a single daily dose for 2, 3, 4, 5, 6, 7, 8, 9 or more days. These days may be consecutive or spaced apart, for example, by about 1 day (e.g., every other day), about 7 days (e.g., weekly), about 14 days (e.g., every 2 weeks), about 21 days (e.g., every 3 weeks), about 28 days (e.g., every 4 weeks), about 30 days (e.g., monthly), about 35 days (e.g., every 5 weeks), about 42 days (e.g., every 6 weeks), or about 60 days (e.g., every 2 months) or annually. In some embodiments, HBsAg is administered monthly, for example, for 4 to 5 months, or for example, for up to 9 months or longer.

[0087] In some embodiments of the methods provided herein, HBsAg is administered in a single dose of 10 to 100 µg every 1, 2, 3, 4, or 5 weeks. In some embodiments of the methods provided herein, HBsAg is administered in a single dose of 20 to 60 µg every 1, 2, 3, 4, or 5 weeks. In some embodiments of the methods provided herein, HBsAg is administered in a single dose of 30 to 50 µg every 1, 2, 3, 4, or 5 weeks. In some embodiments of the methods provided herein, HBsAg is administered in a single dose of 10 to 100 µg every 3 weeks. In some embodiments of the methods provided herein, HBsAg is administered in a single dose of 20 to 60 µg every 3 weeks. In some embodiments of the methods provided herein, HBsAg is administered in a single dose of 30 to 50 µg every 3 weeks. In some embodiments of the methods provided herein, HBsAg is administered in a single dose of 40 µg every 3 weeks. In some implementations of the methods provided herein, HBsAg is administered at doses of 20 µg to 100 µg every two weeks (Q2W), every three weeks (Q3W), or every four weeks (Q4W).

[0088] HBsAg can be administered, for example, intramuscularly or subcutaneously. In some embodiments, HBsAg is administered with an adjuvant, such as aluminum hydroxide adjuvant, CpG 1018 adjuvant, or aluminum phosphate adjuvant.

[0089] It should be understood that, typically in the methods provided herein, HBsAg is administered as a diagnostic agent to identify CHB subjects prior to administering HBV therapy to them. In some embodiments of the methods provided herein, HBsAg is administered to the subject in the absence of any additional therapeutic agents for treating hepatitis B virus infection.

[0090] In some implementations of the methods provided herein, HBsAg is administered to the subject concurrently with NrtI and / or interferon (e.g., IFN or PEG-IFN) prior to HBV therapy.

[0091] The concentration of HBV antibodies in a subject can be determined using assays known in the art. HBV antibodies are produced by the immune system in response to the hepatitis B virus and may include, for example, hepatitis B surface antigen antibodies (anti-HBs); hepatitis B e antigen antibodies (anti-HBe); and hepatitis B core antigen antibodies (anti-HBc). Anti-HBc can be an IgM subtype (typically present in the early stages of acute HBV infection) or an IgG subtype (persistent throughout life and is a marker of past or current infection).

[0092] In some embodiments of the methods provided herein, the HBV antibody includes anti-HBs, anti-HBe, and anti-HBc. Therefore, it should be understood that in some embodiments, the HBV antibody concentration is the concentration of anti-HBs, anti-HBe, and anti-HBe.

[0093] In some embodiments of the methods provided herein, the HBV antibody is anti-HBs. Therefore, it should be understood that in some embodiments, the HBV antibody concentration is the anti-HBs concentration.

[0094] The concentration of HBV antibodies in a subject can be determined by collecting biological samples from the subject. These biological samples can be, for example, blood samples, serum samples, or plasma samples.

[0095] In some implementations, the biological sample is a plasma sample.

[0096] In some implementations, the biological sample is a serum sample.

[0097] In some embodiments of the methods for determining HBV antibody concentration provided herein, the HBV antibody concentration is a serum HBV antibody concentration. In some embodiments, the HBV antibody concentration is a serum anti-HBs concentration. In some embodiments, the HBV antibody concentration is a plasma anti-HBs concentration.

[0098] Assays and kits for detecting HBV antibodies are commercially available in a variety of formats (see, for example, Supplementary Table 1 and Supplemental Information in Kramvis et al., 2022, Nature Reviews Gastroenterology & Hepatology, 19: 727-745, which list commercially available kits, which are incorporated herein by reference). Enzyme-linked immunosorbent assay (ELISA) kits use enzyme-based colorimetric or fluorescent detection systems to identify the presence of specific antibodies in biological samples. Rapid diagnostic tests (RDTs) use lateral flow immunoassay technology. Chemiluminescent immunoassay (CLIA) kits utilize chemiluminescent detection methods to measure HBV antibodies. Radioimmunoassay kits use radioactive tracers to measure the binding of HBV antibodies in biological samples. Exemplary commercially available quantitative HBV antibody kits include, for example, DIASOURCE Anti-HBs Elisa (DIASoureImmunoAssays SA, Belgium), ELECSYS® HBsAG II quant II immunoassay (Roche Diagnostics), ARCHITECT AUSAB immunoassay (Abbott Laboratories), and VITROS® Anti-HBs assay (Ortho-Clinical Diagnostics).

[0099] Depending on the specific kit or assay used, the limit of detection (LLOD) for HBV antibody concentrations (e.g., anti-HBs concentrations) can range from 1 IU / L to 5 IU / L. Therefore, in some embodiments, the phrase "limit of detection" or "LLOD" used herein for HBV antibody concentrations (e.g., anti-HBs concentrations) is 2 IU / L.

[0100] In this article, the term “baseline” (e.g., “baseline HBV antibody concentration”, “baseline anti-HBs concentration”, “baseline plasma HBV antibody concentration”, “baseline serum HBV antibody concentration”, “baseline plasma anti-HBs concentration”, “baseline serum anti-HBs concentration”, etc.) used to describe antibody concentration refers to the antibody concentration measured in a biological sample collected from a subject before administering HBsAg to the subject.

[0101] In this article, the term “post-baseline” (e.g., “post-baseline HBV antibody concentration”, “post-baseline anti-HBs concentration”, “post-baseline plasma HBV antibody concentration”, “post-baseline serum HBV antibody concentration”, “post-baseline plasma anti-HBs concentration”, “post-baseline serum anti-HBs concentration”, etc.) used to describe antibody concentration refers to the antibody concentration measured in biological samples collected from subjects after HBsAg has been administered to them.

[0102] In some implementations of the methods provided herein, HBV therapy is administered to subjects in whom HBV antibody concentrations (e.g., anti-HBs concentrations) increase following administration of HBsAg.

[0103] In some implementations, HBV therapy is administered to subjects with a baseline HBV antibody concentration (e.g., anti-HBs concentration) greater than 10 IU / L, greater than 50 IU / L, greater than 100 IU / L, greater than 150 IU / L, greater than 200 IU / L, greater than 250 IU / L, or greater than 300 IU / L.

[0104] In some embodiments of the methods provided herein, HBV therapy is administered to a subject after the subject’s baseline HBV antibody concentration (e.g., anti-HBs concentration) is determined to be greater than his / her baseline HBV antibody concentration (e.g., anti-HBs concentration).

[0105] In some embodiments of the methods provided herein, the subject's HBV antibody concentration (e.g., anti-HBs concentration) may be undetectable prior to HBsAg administration. In some embodiments, the subject's baseline HBV antibody concentration is less than 0.5 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 1 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 2 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 3 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 4 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 5 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 6 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 7 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 8 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 9 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 10 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 11 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 12 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 13 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 14 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 15 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 20 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 30 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 40 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 50 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 60 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 75 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is less than 100 IU / L.

[0106] In some embodiments of the methods provided herein, the subject's HBV antibody concentration (e.g., anti-HBs concentration) prior to HBsAg administration can be between 0 IU / L and 5 IU / L, or between 2 IU / L and 10 IU / L. In some embodiments, the subject's baseline HBV antibody concentration is greater than 10 IU / L, greater than 25 IU / L, greater than 50 IU / L, greater than 100 IU / L, or greater than 200 IU / L.

[0107] In some embodiments of the methods provided herein, HBV therapy is administered to the subject if (i) the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is at or below the detection limit (e.g., 2 IU / L) and the subject's post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is above the detection limit (e.g., 2 IU / L); or (ii) the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is greater than the detection limit (e.g., 2 IU / L) and the subject's post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 5 times the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration).

[0108] In some embodiments of the methods provided herein, where the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is below the limit of detection (e.g., 2 IU / L), if the subject's post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 2 IU / L, at least 5 IU / L, at least 10 IU / L, at least 15 IU / L, at least 20 IU / L, at least 25 IU / L, at least 30 IU / L, at least 40 IU / L, at least 50 IU / L, at least 60 IU / L, at least 70 IU / L, at least 80 IU / L, at least 90 IU / L, at least 100 IU / L, at least 200 IU / L, at least 300 IU / L, at least 400 IU / L, at least 500 IU / L, at least 600 IU / L, at least 700 IU / L, at least 800 IU / L, at least 900 IU / L, or at least 1000 IU / L, the detection limit is determined. If the concentration is IU / L, then HBV therapy is administered to the subject.

[0109] In some embodiments of the methods provided herein, where a subject's baseline HBV antibody concentration (e.g., anti-HBs concentration) is above the limit of detection (e.g., 2 IU / L), HBV therapy is administered to the subject if the subject's post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least twice the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, HBV therapy is administered to the subject if the subject's post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least three times the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, HBV therapy is administered to the subject if the subject's post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least four times the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, HBV therapy is administered to the subject if the subject's post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least five times the subject's baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, HBV therapy is administered to a subject if their post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 6 times their baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, HBV therapy is administered to a subject if their post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 7 times their baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, HBV therapy is administered to a subject if their post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 8 times their baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, HBV therapy is administered to a subject if their post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 9 times their baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, HBV therapy is administered to a subject if their post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 10 times their baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, HBV therapy is administered to a subject if their post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 11 times their baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, HBV therapy is administered to a subject if their post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 12 times their baseline HBV antibody concentration (e.g., anti-HBs concentration).In some embodiments, HBV therapy is administered to a subject if their post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 13 times their baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, HBV therapy is administered to a subject if their post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 14 times their baseline HBV antibody concentration (e.g., anti-HBs concentration). In some embodiments, HBV therapy is administered to a subject if their post-baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 15 times their baseline HBV antibody concentration (e.g., anti-HBs concentration).

[0110] In some embodiments of the methods provided herein, HBV therapy is administered to subjects identified as “responder subjects” at the diagnostic stage who meet any one or more of the following criteria (A) to (C): (A) a baseline HBV antibody concentration (e.g., anti-HBs concentration) at or below the limit of detection (e.g., ≤2 IU / L), and a post-baseline HBV antibody concentration (e.g., anti-HBs concentration) of at least 5 IU / L, or at least 10 IU / L, at least 12 IU / L, at least 15 IU / L, at least 20 IU / L, at least 30 IU / L, at least 40 IU / L, at least 50 IU / L, at least 60 IU / L, at least 70 IU / L, at least 80 IU / L, at least 90 IU / L, at least 100 IU / L, or at least 110 IU / L; (B) a baseline HBV antibody concentration (e.g., anti-HBs concentration) above the limit of detection (e.g., >2 IU / L). (IU / L), and the baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 2, at least 3, at least 4, at least 5, at least 6, or at least 7 times greater than the subject's baseline HBV antibody concentration; or (C) the baseline HBV antibody concentration (e.g., anti-HBs concentration) is at least 10 IU / L, at least 12 IU / L, at least 15 IU / L, at least 20 IU / L, at least 30 IU / L, at least 40 IU / L, at least 50 IU / L, at least 60 IU / L, at least 70 IU / L, at least 80 IU / L, at least 90 IU / L, at least 100 IU / L, or at least 110 IU / L.

[0111] Biological samples collected after HBsAg administration for determining HBV antibody concentration (e.g., anti-HBs concentration) can be collected at any time during the diagnostic phase, for example, after administration of the first dose of HBsAg (e.g., when a single dose is administered), and / or between multiple doses of HBsAg (when more than one dose is administered), and / or after administration of the last dose of HBsAg (when more than one dose is administered).

[0112] Samples collected after HBsAg administration for determining HBV antibody concentrations (e.g., anti-HBs concentrations) can be collected, for example, at any time between 1 day and approximately 12 months after HBsAg administration. In some embodiments, baseline HBV antibody concentrations are determined from samples collected 2 to 8 months after HBsAg administration. In some embodiments, baseline HBV antibody concentrations are determined from samples collected 3 to 6 months after HBsAg administration. In some embodiments, baseline HBV antibody concentrations are determined from samples collected 2 weeks to 6 months after HBsAg administration. In some embodiments, baseline HBV antibody concentrations are determined from samples collected 5 days to 4 months after HBsAg administration. In some embodiments, baseline HBV antibody concentrations are determined from samples collected 7 days to 3 months after HBsAg administration. In some embodiments, baseline HBV antibody concentrations are determined from samples collected 7 days to 2 months after HBsAg administration. In some implementations, baseline HBV antibody concentrations are determined from samples collected two weeks to one month after HBsAg administration.

[0113] In some implementations, CHB is treated by administering HBV therapy to the responder CHB subject at a therapeutically effective dose.

[0114] As used herein, the term "treatment" refers to the treatment of existing HBV infection (e.g., CHB) or the prevention (i.e., protection) of serious liver diseases caused by CHB, such as cirrhosis and hepatocellular carcinoma. Therefore, it should be recognized that the treatment referred to herein may be preventative in some embodiments. In some embodiments, treatment of HBV infection (e.g., CHB) results in a reduction in HBV DNA, or a reduction in hepatitis B e antigen, or a reduction in serum alanine aminotransferase (ALT), or a reduction in hepatitis B surface antigen, or any combination thereof. In some embodiments, treatment of HBV infection may be a functional cure, i.e., HBsAg and HBV DNA are undetectable in the subject for 6 months without any HBV therapy. The phrase "therapeutic effective dose" as used herein refers to a therapeutic dose used alone or in combination with other therapies to treat HBV infection (as defined above as "treatment").

[0115] The HBV therapy administered to the subject can be any therapy used to treat HBV infection (e.g., CHB).

[0116] In some implementation schemes, HBV therapy is used in clinical trials.

[0117] In some embodiments, the HBV therapy is a monotherapy or combination therapy selected from the following HBV therapies: (i) nucleoside / nucleotide reverse transcriptase inhibitors (NrtIs), such as lamivudine, entecavir, tenofovir alafenamide, tenofovir disoproxil fumarate, adefovir dipivoxil, and telbivudine; (ii) immunomodulators, such as interferon alpha (IFNα) and pegylated interferon alpha (PEG-IFNα); and (iii) small interfering RNAs (siRNAs) that target HBV RNA, such as AB-729, ALG-125755, ALG-125918, ARB-1467, ARC-520, JNJ-3989, RG-6346, VIR-2218 (BRII-835 or elebsiran), and WO 2016 / 077321 A1 and WO 2020 / 036862. Those described in A1; (iv) HBV neutralizing monoclonal antibodies (mAbs), such as those described in WO / 2017 / 060504 A1, WO 2020 / 132091 A2, WO 2022 / 164805 A1, WO2021 / 012135 A1, and U.S. Patent No. 10,544,205 B2, including, for example, VIR-3434 (BRII-877), HH-003, HH-006, BJT-778, and lenvervimab (GC1102); (v) sodium / bile acid cotransporter (also known as NTCP) inhibitors, such as myrcludex B (bulevirtide); (vi) capsid assembly modulators, such as ABIHO731, ABI-H3733, and NVR. 3-778, RO7049389, JNJ-56136389, ALG-000184, and GLS4JHS; (vii) COPS3 inhibitors, such as those described in US 20230122751 A1; (viii) SARAF inhibitors, such as those described in US 2023 / 0120063 A1; (ix) antisense oligonucleotides (ASOs), such as bepirovirsen, GSK3389404, RO7062931, and ALG 020572; (x) Toll-like receptor (TLR) agonists, such as vestolimod (GS-9620; a TLR7 agonist), RO7020531 (a TLR7 agonist), and JNJ-777. 64794964 (TLR7 agonist), selgantolimod (GS-9688; TLR8 agonist) and AIC649 (TLR9 ​​agonist);(xi) Checkpoint regulators, such as ASC22 (anti-PDL1), cimiprimab (anti-PD1), and nivolumab (anti-PD1); (xii) Inhibitor of Apoptosis (IAP) antagonists, such as APG-1387; (xiii) Farnesol X receptor (FXR) agonists, such as EYP001; and (xiv) therapeutic vaccines, such as ABX203 (HeberNasvac), GS-4774, HepTcell, AIC649, HB 110, VTP 300, JNJ-64300535, BRII-179 (VBI-2601), TG-1050, and INO-1800.

[0118] In some embodiments, the HBV therapy is selected from NrtI, siRNA, IFNα, PEG-IFNα, HBV-neutralizing mAb, or combinations thereof. In some embodiments, the HBV therapy is selected from siRNA, IFNα, PEG-IFNα, HBV-neutralizing mAb, or combinations thereof. In some embodiments, the HBV therapy is selected from siRNA, IFNα, PEG-IFNα, or combinations thereof. In some embodiments, the HBV therapy is siRNA. In some embodiments, the HBV therapy is a combination of siRNA and IFNα. In some embodiments, the HBV therapy is a combination of siRNA and PEG-IFNα. In some embodiments, the HBV therapy is a combination of HBV-neutralizing mAb and PEG-IFNα. In some embodiments, the HBV therapy is PEG-IFNα.

[0119] In some implementations, the HBV therapy is a combination of NrtI and interferon (e.g., IFNα or PEG-IFNα).

[0120] In some implementations, the HBV therapy is administered in combination with HBsAg.

[0121] In some implementations, the HBV therapy does not include HBsAg.

[0122] In some embodiments of siRNA administration (alone or in combination with HBV therapy), the siRNA is an N-acetylgalactosamine (GalNAc)-conjugated HBV dsRNA described in Table 2 of WO 2020 / 036862 A1, which is incorporated herein by reference in its entirety for all purposes. In some embodiments, the siRNA is Elebsiran (CAS No. 2648009-64-5) (also known as VIR-2218 and BRII-835).

[0123] In some embodiments where an HBV neutralizing antibody is administered alone or in combination, the HBV neutralizing antibody is VIR-3434 (BRII-877).

[0124] In some embodiments, the HBV therapy is a combination of siRNA and an HBV neutralizing antibody. In some embodiments, the HBV therapy is a combination of siRNA, an HBV neutralizing antibody, and PEG-IFNα. For example, in some embodiments, the siRNA is Elebsiran (CAS No. 2648009-64-5; VIR-2218; BRII-835), and the HBV neutralizing antibody is VIR-3434 (BRII-877).

[0125] In some implementations, the HBV therapy is a combination of Elebsiran (CAS No. 2648009-64-5) and PEG-IFNα.

[0126] In some implementations, the siRNA (e.g., elebsiran) is administered in a single daily dose for 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 or more days. These days may be consecutive or may be spaced apart, for example, by about 1 day (e.g., every other day), about 7 days (e.g., weekly), about 14 days (e.g., every 2 weeks), about 21 days (e.g., every 3 weeks), about 28 days (e.g., every 4 weeks), about 30 days (e.g., monthly), about 35 days (e.g., every 5 weeks), about 42 days (e.g., every 6 weeks), or about 60 days (e.g., every 2 months) or annually.

[0127] In some embodiments of the methods provided herein, the siRNA (e.g., elebsiran) is administered in a single dose of 20 to 500 mg every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., elebsiran) is administered in a single dose of 30 to 400 mg every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., elebsiran) is administered in a single dose of 40 to 250 mg every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., elebsiran) is administered in a single dose of 50 to 200 mg every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., elebsiran) is administered in a single dose of 75 to 150 mg every 1, 2, 3, 4, 5, or 6 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., elebsiran) is administered in a single dose of 80 to 120 mg every 1, 2, 3, 4, 5, or 6 weeks.

[0128] In some embodiments of the methods provided herein, the siRNA (e.g., elebsiran) is administered in a single dose of 50 to 50 mg every 4 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., elebsiran) is administered in a single dose of 75 to 150 mg every 4 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., elebsiran) is administered in a single dose of 80 to 120 mg every 4 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., elebsiran) is administered in a single dose of 90 to 110 mg every 4 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., elebsiran) is administered in a single dose of about 100 mg every 4 weeks. In some embodiments of the methods provided herein, the siRNA (e.g., elebsiran) is administered at a dose of 100 mg to 400 mg every two weeks (Q2W), every three weeks (Q3W), every four weeks (Q4W), every five weeks (Q5W), or every six weeks (Q6W).

[0129] The siRNA (e.g., elebsiran) can be administered, for example, intramuscularly or subcutaneously.

[0130] In some embodiments, the PEG-IFNα is administered as a single daily dose for 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 45, 48, 50, or 60 days or more. These days may be consecutive or may be spaced apart, for example, by about 1 day (e.g., every other day), about 7 days (e.g., weekly), about 14 days (e.g., every 2 weeks), about 21 days (e.g., every 3 weeks), about 28 days (e.g., every 4 weeks), about 30 days (e.g., monthly), about 35 days (e.g., every 5 weeks), about 42 days (e.g., every 6 weeks), or about 60 days (e.g., every 2 months) or annually.

[0131] In some embodiments of the methods provided herein, the PEG-IFNα is administered as a single dose of 50 to 500 µg every 1, 2, or 3 weeks. In some embodiments of the methods provided herein, the PEG-IFNα is administered as a single dose of 100 to 300 µg every 1, 2, or 3 weeks. In some embodiments of the methods provided herein, the PEG-IFNα is administered as a single dose of 150 to 240 µg every 1, 2, or 3 weeks. In some embodiments of the methods provided herein, the PEG-IFNα is administered as a single dose of 170 to 190 µg every 1, 2, or 3 weeks.

[0132] In some embodiments of the methods provided herein, the PEG-IFNα is administered once weekly in a single dose of 50 to 500 µg. In some embodiments of the methods provided herein, the PEG-IFNα is administered once weekly in a single dose of 100 to 300 µg. In some embodiments of the methods provided herein, the PEG-IFNα is administered once weekly in a single dose of 150 to 240 µg. In some embodiments of the methods provided herein, the PEG-IFNα is administered once weekly in a single dose of 170 to 190 µg.

[0133] The PEG-IFNα can be administered, for example, intramuscularly or subcutaneously.

[0134] In one aspect, this document provides compositions for use in the methods described herein. In some embodiments, the composition is HBsAg for use in the methods described herein. Suitable HBsAg compositions may be any of those described herein. In some embodiments, the composition is an HBV therapy for use in the methods described herein. Suitable HBV therapy may be any of those described herein.

[0135] In one aspect, this document provides a kit comprising HBsAg and HBV therapy for use with the methods described herein. The composition suitable for HBsAg and HBV therapy can be any of those described herein.

[0136] In some embodiments, this document provides the use of HBV surface antigen (HBsAg) and HBV therapy without HBsAg in the preparation of a kit for treating a subject with chronic hepatitis B, wherein the subject, prior to administration of the HBV therapy, exhibits an increased serum anti-HBV antibody concentration after administration of HBsAg, relative to the subject's serum anti-HBV antibody concentration prior to administration of HBsAg.

[0137] In some implementations, the treatment effectively achieves disease remission in CHB subjects. For example, disease remission can be measured as a reduction in viral load or HBV antigen seroclearance (e.g., by measuring HBV DNA levels or antigen levels), but is not limited to these.

[0138] In some implementations, HBV DNA levels or antigen levels are reduced by at least approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99%. In some implementations, the reduction in HBV DNA levels or antigen levels to the desired level is sustained for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 1 year, 2 years, or 5 years. Example Example 1: CHB Respondent Subject

[0139] This example demonstrates that CHB subjects are differentiated into subjects who develop anti-HBs upon administration of HBsAg (responder CHB subjects) and subjects who do not exhibit such a response (non-responder CHB subjects).

[0140] A clinical study was conducted as described in Ma et al., 2021, JHEP Reports, 3(3):100361, in which HBsAg was administered to non-cirrhotic CHB subjects who were under viral suppression with NrtI treatment. HBsAg is BRII-179 (also known as VBI-2601), a virus-like particle containing all three (Pre-S1, Pre-S2, and S) HBV surface envelope proteins. Subjects were randomly assigned to receive NrtI only (cohort A), 20 µg BRII-179 plus NrtI (cohort B), 20 µg BRII-179 plus 3 MIU IFN plus NrtI (cohort C), 40 µg BRII-179 plus NrtI (cohort D), and 40 µg BRII-179 plus 3 MIU IFN plus NrtI (cohort E). Serum HBsAg and anti-HBs antibodies were quantified using the ELECSYS HBsAg II QUANT II kit and the ELECSYS ANTIHBs II kit / Cobas e411 / e601 (Roche Diagnostics, Germany), respectively, according to the manufacturer's instructions. The number of subjects observed to have a positive response (i.e., an increase in antibody concentration after baseline) is shown in Table 1 below. Table 1: Anti-HBs response of BRII-179 in CHB subjects* Example 2: Administration of HBV therapy to CHB responders

[0141] This predictive embodiment demonstrates the exemplary administration of HBV therapy to a responder CHB subject. Responder CHB subjects identified by an increase in anti-HBs following HBsAg administration (e.g., the responder CHB subject identified in Example 1) may receive HBV therapy as described below.

[0142] The HBV therapy can be a combination of siRNA and PEG-IFNα. Specifically, the siRNA can be BRII-835 (also known as elebsiran and VIR-2218), which is a synthetic N-acetylgalactosamine-conjugated small ribonucleic acid designed to silence transcripts of all HBV genotypes. BRII-835 has been administered at single doses up to 900 mg in healthy volunteers and subjects with chronic HBV infection (see, e.g., AASLD 2022, VIR-2218-1001 study: Preliminary 48-week safety and efficacy data of VIR-2218 monotherapy and in combination with peginterferon α in participants with chronic HBV infection; ClinicalTrials.gov identifier: NCT03672188; and Gupta et al., 2021, Drugs in R&D, 21:455-465).

[0143] The main exclusion criteria for subjects to receive this therapy can be as follows: 1. Having received other siRNA or interferon-based therapies within 12 months before screening. 2. Significant fibrosis or cirrhosis. 3. Having contraindications to the use of PEG-IFNα or being unable to self-administer or assist in the administration of PEG-IFNα, including but not limited to the following laboratory abnormalities: a) Hemoglobin < 100 g / L. b) Absolute neutrophil count < 1,500 / mm 3 . c) Platelet count < 90,000 / mm 3 . 4. Active HIV, HCV or HDV infection. 5. Renal insufficiency, with an estimated glomerular filtration rate (eGFR) ≤ 60 ml / min / 1.73m 2 . 6. Having a history of allergy or intolerance to interferon / peginterferon.

[0144] The dose and regimen of the HBV therapy administered to responder CHB subjects can be: 100 mg of BRII-835 by subcutaneous (SC) injection once every four weeks, and 180 μg of PEG-IFNα by SC injection once a week for 48 weeks.

[0145] It is possible to monitor whether CHB subjects achieve HBV DNA suppression (<LLOQ) accompanied by the disappearance of HBsAg (<0.05 IU / mL) to evaluate the efficacy. Example 3: Administration of HBV therapy to responder CHB subjects

[0146] This predictive example demonstrates an exemplary administration of an HBV therapy to responder CHB subjects, wherein the HBV therapy comprises siRNA and PEG-IFNα. The dosage and regimen of the HBV therapy administered to responder CHB subjects can be: 200 mg of BRII-835 by subcutaneous (SC) injection once every four weeks, and 180 μg of PEG-IFNα by SC injection once a week for 48 weeks. The CHB subjects can be monitored for achievement of HBV DNA suppression (<LLOQ) accompanied by HBsAg loss (<0.05 IU / mL) to evaluate efficacy. Example 4: Administration of HBV Therapy to Responder CHB Subjects

[0147] This predictive example demonstrates an exemplary administration of an HBV therapy to responder CHB subjects, wherein the HBV therapy comprises an HBV-neutralizing mAb and PEG-IFNα. The dosage and regimen of the HBV therapy administered to responder CHB subjects can be: 300 mg of BRII-877 (an HBV-neutralizing antibody, also known as VIR-3434) by SC injection once a month, and 180 μg of PEG-IFNα by SC injection once a week for 6 months or longer. The CHB subjects can be monitored for achievement of HBV DNA suppression (<LLOQ) accompanied by HBsAg loss (<0.05 IU / mL) to evaluate efficacy. Example 5: Administration of HBV Therapy to Responder CHB Subjects

[0148] This predictive example demonstrates an exemplary administration of an HBV therapy to responder CHB subjects, wherein the HBV therapy comprises a combination of siRNA, an HBV-neutralizing mAb, and PEG-IFNα. The dosage and regimen of the HBV therapy administered to responder CHB subjects can be: 100 mg or 200 mg of BRII-835 by SC injection once every four weeks, 100 mg or 150 mg of BRII-877 by SC injection once a month, and 180 μg of PEG-IFNα by SC injection once a week for 48 weeks. The CHB subjects can be monitored for achievement of HBV DNA suppression (<LLOQ) accompanied by HBsAg loss (<0.05 IU / mL) to evaluate efficacy. Example 6: Administration of HBV Therapy to Responder CHB Subjects

[0149] This predictive example demonstrates an exemplary administration of a HBV therapy to responder CHB subjects, the HBV therapy comprising a combination of siRNA and a HBV-neutralizing mAb. The dosage and regimen of the HBV therapy administered to responder CHB subjects can be: 100 mg or 200 mg of BRII-835 by SC injection once every four weeks, and 100 mg or 150 mg of BRII-877 by SC injection once a month for 48 weeks. The CHB subjects can be monitored for achievement of HBV DNA suppression (<LLOQ) accompanied by disappearance of HBsAg (<0.05 IU / mL) to evaluate efficacy. Example 7: Preliminary Safety and Efficacy of the Combination Therapy of BRII-835 and BRII-179 for Chronic HBV Infection

[0150] This example tested the safety and efficacy of a combination therapy comprising BRII-835 and BRII-179 for the treatment of chronic HBV infection in a Phase II trial.

[0151] Adult chronic HBV patients who had received NrtI treatment for ≥12 months and had HBV DNA < LLOQ were enrolled. The participants were included in three cohorts. In Cohort A, each patient received 100 mg of BRII-835 by subcutaneous injection (SC) once every 4 weeks for 9 times while continuing NrtI treatment. In Cohort B, each patient received 100 mg of BRII-835 by SC once every 4 weeks for 9 times; starting from the 3rd dose, the patients also received 40 µg of BRII-179 + adjuvant 3 MIU of IFN-α by intramuscular injection (IM) for 9 times. Cohort C was different from Cohort B in that IFN-α was not administered together with BRII-179.

[0152] In all three cohorts, at the time of the last administration of BRII-835 and / or BRII-179, the patients were evaluated for meeting the NrtI discontinuation criteria, which were defined as undetectable HBsAg and HBeAg, alanine aminotransferase < 2 times the upper limit of normal value, and HBV DNA < LLOQ. Patients who met the NrtI discontinuation criteria were eligible to discontinue NrtI treatment and undergo NrtI discontinuation monitoring for 48 weeks. The demographics and baseline characteristics of the participants are shown in Table 2. Table 2. Demographics and Baseline Characteristics of the Participants

[0153] Safety assessment results (Table 3) showed that BRII-835 monotherapy or in combination with BRII-179 ± adjuvant IFN-α was well tolerated. Most treatment-associated adverse events (TEAEs) were grade 1 or 2 severity; no treatment-related TEAEs were grade 3 or severe. The most common TEAE in each cohort was injection site reaction (56.0%). The TEAEs with a higher incidence in cohort B (i.e., headache, fatigue, myalgia, and fever) were consistent with known side effects of IFN-α. Table 3. Treatment-related adverse events (TEAEs)

[0154] Regarding efficacy, a significant decrease in HBsAg was observed in patients treated with BRII-835 monotherapy or in combination with BRII-179 ± adjuvant IFN-α. Figure 2 (and Table 4). Furthermore, the average decrease in HBsAg relative to baseline was comparable across all cohorts. It is noteworthy that, as... Figure 2 As shown, the two patients who received combination therapy achieved HBsAg ≤ LLOQ (0.05 IU / mL) at week 40. Table 4. Mean (SD) change of HBsAg relative to baseline (log) 10 IU / mL

[0155] Regarding antibody response, cohort A, which used BRII-835 alone, did not induce an antibody response. Figure 3 BRII-179 induced a potent anti-HBs response, typically peaking after 5 doses, with some participants reaching the detection limit of 1000 IU / L. By week 40, over 40% of participants in cohorts B and C had developed high anti-HBs titers (>100 IU / L).

[0156] Two early responders were observed only in the BRII-179 + adjuvant IFN-α group (cohort B), whose antibody titers peaked after two doses of BRII-179. The percentage of participants with anti-HBs levels above 100 IU / L after 9 doses of BRII-179 + BRII-835 combination therapy (44%) was higher than that after BRII-179 monotherapy (4 doses, 17%). Figure 3 ).

[0157] The HBV surface antigen-specific T-cell responses of these patients were measured, and the results are shown in Table 5. Table 5. HBV surface antigen-specific T cell response

[0158] As shown in the table, BRII-835 alone restored HBV surface antigen-specific T-cell responses in only a small subset of participants. BRII-179, used in combination with BRII-835 (with or without adjuvant IFN-α), induced improved HBV surface antigen-specific T-cell responses. Comparable HBV surface antigen-specific T-cell responses were observed in both combination therapy cohorts receiving BRII-835 and BRII-179 (with or without adjuvant IFN-α).

[0159] Importantly, the proportion of participants who achieved a greater degree of T-cell response (>20-fold from baseline) with BRII-179 plus BRII-835 combination therapy was higher (40% vs. 25%) compared to BRII-179 monotherapy. Example 8. A phase 2, multicenter, open-label study investigating the efficacy and safety of a regimen containing BRII-179, BRII-835, and pegylated interferon-α (PEG-IFNα) for the treatment of chronic hepatitis B virus (HBV) infection.

[0160] This is a phase 2, single-arm, open-label study designed to evaluate the efficacy and safety of sequential BRII-179 therapy followed by BRII-835 and PEG-IFNα in participants with chronic HBV infection.

[0161] Preliminary studies indicate that in CHB patients receiving BRII-835+PEG-IFNα combination therapy, anti-HBs response is associated with the persistence of HBsAg seroclearance after end-stage intervention (EOT). In this study, all 4 / 13 participants who achieved HBsAg seroclearance after 48 weeks of combination therapy underwent anti-HBs seroconversion. Among participants who achieved HBsAg seroclearance at EOT, all participants with anti-HBs titers > 500 IU / L at EOT (4 / 4) maintained HBsAg seroclearance for 24 weeks after EOT; while participants with anti-HBs titers < 100 IU / L at EOT (3 / 3) experienced HBsAg rebound, suggesting that high anti-HBs titers at EOT are associated with the persistence of seroclearance. Furthermore, in CHB patients, the detection of anti-HBs-producing B cells in PBMCs at baseline may be an important immunological indicator for predicting the efficacy of IFNα treatment, indicating a higher chance of achieving functional cure with PEG-IFNα therapy. These findings suggest that the ability of CHB participants to generate humoral immune responses to HBsAg can be used to identify potential responders with milder impairment of endogenous anti-HBV immunity, in order to achieve and maintain sustained functional cure after receiving curative treatment.

[0162] As demonstrated in Example 1, even after 9 doses, BRII-179 induced a significant anti-HBs response only in a subset, not all, of chronic HBV participants, suggesting that BRII-179 can be used to identify CHB participants who are capable of eliciting a favorable antibody response, thereby increasing their likelihood of responding to BRII-835 + PEG-IFNα. Therefore, it is recommended to initiate a clinical study in which CHB participants will receive BRII-179 sequentially, followed by BRII-835 + PEG-IFNα. Participants will be assessed for meeting predefined anti-HBs response criteria upon completion of BRII-179 treatment. This study design will provide an opportunity to compare the effectiveness of a limited course of BRII-835 + PEG-IFNα between anti-HBs responders and non-responders after completion of BRII-179 treatment and to identify the optimal treatment combination with a favorable benefit / risk profile.

[0163] Data from this study will support further exploration of other curative treatments with limited durations to achieve clinically meaningful functional cures for chronic HBV infection.

[0164] Enrolled participants will receive BRII-179 sequentially, followed by BRII-835 and PEG-IFNα in combination, over a total dosing period of 64 weeks, as follows: — BRII-179 (Day 1 to Week 12): Participants will receive 5 doses of BRII-179 40 µg every 3 weeks (Q3W). — BRII-835 and PEG-IFNα combination therapy (weeks 16 to 64): Participants will receive 13 doses of BRII-835 100 mg every 4 weeks (Q4W) and 48 doses of PEG-IFNα 180 µg once a week (QW).

[0165] There will be a 24-week follow-up period after treatment. Participants who meet the criteria to discontinue their NrtI treatment will also be subject to a 24-week NrtI discontinuation monitoring period.

[0166] HBeAg-negative or HBeAg-positive chronic HBV-infected individuals are eligible to participate in this study. A total of 110 participants are planned, with a possible additional 40 variable participants. The total study duration for each participant will include a screening period (maximum 4 weeks), a treatment period (68 weeks), a follow-up period (24 weeks), and a NRTI discontinuation monitoring period (if applicable, 24 weeks). A schematic diagram of the study design is shown below. Figure 1 As shown. Inclusion criteria

[0167] Participants eligible for inclusion in this study must meet all of the following criteria. Unless otherwise stated, all laboratory testing requirements for inclusion will be performed by the central laboratory: 1. A signed and dated written informed consent form (ICF) prior to participation in the study. 2. Age 18 (or legal age of consent, whichever is higher) to 60 (inclusive). 3. Body mass index (BMI) ≥ 18 kg / m² and ≤ 32 kg / m². 4. Chronic HBV infection defined as serum HBsAg positivity for ≥6 months prior to screening. 5. Must be under NRTI treatment (including entecavir, tenofovir disoproxil fumarate, imipenemofovir, or tenofovir alafenamide) and have HBV-DNA < LLOQ for at least 6 months prior to screening (subject to local laboratory results). 6. HBsAg > 100 IU / mL and ≤ 3,000 IU / mL during screening. 7. HBV DNA < LLOQ during screening. 8. Anti-HBs < 2 IU / L during screening. 9. Serum ALT and AST ≤ ULN during screening. 10. Female participants must have a negative pregnancy test or be confirmed to be postmenopausal. 11. Male participants with fertile female partners must agree to meet one of the following contraceptive requirements from the time of study drug administration until 48 weeks after the last study drug administration. 12. I agree not to donate blood during the research period. 13. Willing and able to comply with the study procedures and requirements, including discontinuing PEG-IFNα and NRTI treatment according to the protocol.

[0168] Researchers believe that screening laboratory test values ​​that are problematic and have been approved by medical monitors can be repeated once. Exclusion criteria

[0169] Participants will be excluded from the study if any of the following evidence exists at the time of screening or before randomization (if applicable): Medical condition 1. Any clinically significant chronic medical condition (excluding chronic HBV infection) would, in the investigator's judgment, render the participant unsuitable for this study. 2. Any clinically significant acute condition, such as fever (>38°C) or acute respiratory illness, within 7 days prior to the first study drug administration. 3. Based on the liver stiffness test results at the time of screening, a result > 9 kPa indicates significant liver fibrosis or cirrhosis. 4. A history of clinically significant chronic liver disease from any cause other than chronic HBV infection. 5. History of liver decompensation, including but not limited to ascites, hepatic encephalopathy and / or esophageal or gastric varices. 6. Confirmed or suspected hepatocellular carcinoma. Participants with an alpha-fetoprotein (AFP) concentration ≥200 ng / mL at screening should be excluded. If the AFP concentration at screening is ≥50 ng / mL and <200 ng / mL, no liver lesions must be recorded by imaging examination at screening. 7. Within 12 months prior to screening, the researcher must have a history or evidence of drug or alcohol abuse. 8. Current or past history of human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis D virus (HDV) infection. 9. A history of thyroid disease that is not adequately controlled with prescription medication, or clinically significant signs of thyroid dysfunction as determined by the investigators at the time of screening. 10. Known history of impaired immune function, including but not limited to: a) Autoimmune diseases (e.g., rheumatoid arthritis, immune thrombocytopenic purpura, autoimmune hepatitis, etc.); or b) Primary immunodeficiency diseases (e.g., common variant immunodeficiency diseases, phagocytic dysfunction and neutropenia syndrome, and complement deficiency); or c) Secondary immunodeficiency diseases (e.g., acquired immunodeficiency syndrome caused by human immunodeficiency virus (HIV) infection, solid organ transplantation, and splenectomy). 11. The researcher judges the patient to have uncontrolled diabetes or uncontrolled hypertension; or to have been diagnosed with advanced heart failure (New York Heart Association Class III or IV) or unstable angina. 12. Previous or current mental condition that prevents adherence to the protocol. Individuals who, according to the researcher's judgment, have a serious mental disorder, including but not limited to schizophrenia, psychosis, major depressive disorder, bipolar disorder, major anxiety disorder, persistent suicide risk, or a history of suicide attempts or postures within the past 5 years are specifically excluded. 13. A history of cancer requiring local or systemic treatment within the 5 years prior to randomization, or current cancer. Participants who have undergone complete surgical removal of the tumor and have been free of disease for more than 3 years are eligible, or participants with a history of low-risk basal cell carcinoma (low-risk is defined as: 1) located on the trunk, arm, leg, cheek, forehead, temple, scalp, neck, or chin; 2) <2 cm in size; 3) nodular or superficial; 4) primary cancer that has not recurred after treatment; 5) well-defined and smooth margins of the cancerous area; and 6) not within or around nerves). Previous / Concomitant Medication 14. Have received any HBV vaccine (marketed or experimental) within the 5 years prior to screening. 15. Have received any of the following treatments within the 12 months prior to screening: a) Small interfering RNA or antisense oligonucleotides b) Interferon-based therapy 16. Have received any of the following treatments within 6 months prior to screening: a) Telbivudine b) Granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), recombinant human interleukin-11 (Aoprui interleukin), or erythropoietin (EPO). 17. Day 1 visit: Received blood products or immunoglobulins within 90 days prior to administration of the study drug, or may require blood products during the study. 18. During the first day of the study, the patient received any of the following treatments within 30 days prior to drug administration: a) Myelotoxic drugs, such as systemic cytotoxic agents (i.e., chemotherapy drugs for cancer). b) Systemic immunosuppressants (including but not limited to corticosteroids with a prednisone equivalent dose > 40 mg / day) c) Attenuated vaccines (e.g., mumps, measles, rubella). 19. Participant has participated in another clinical trial involving the investigational drug or biologic within 30 days or 5 drug half-lives (whichever is longer) prior to Day 1 visit administration. Participants must agree not to participate in any other studies during the duration of this study (including follow-up and NRTI discontinuation monitoring). Discontinuation of NRTI treatment

[0170] After participants complete their 88-week visit, investigators will assess their eligibility to discontinue NRTI treatment based on the following NrtI discontinuation criteria: — HBsAg < LLOQ and — HBV DNA < LLOQ and — HBeAg undetectable and — ALT ≤ 2x ULN.

[0171] Participants who meet all the above criteria at at least two consecutive visits at week 88 are eligible to discontinue NrtI treatment. Investigators should confirm participant eligibility as early as possible within two weeks of the week 88 visit. Participants who discontinue NrtI will enter the study's NrtI discontinuation monitoring period within one week of investigator confirmation of eligibility. Participants will stop taking their NRTI medication on the first day of the NrtI discontinuation monitoring period and will undergo an additional 24 weeks of follow-up. ***

[0172] Although the foregoing embodiments have been described in detail by way of illustration and example for the purpose of clarity, those skilled in the art will readily understand that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. Only the limitations appearing in the appended claims shall be applied to any claimed invention.

[0173] All publications, patents and patent applications cited in this specification are incorporated herein by reference as if each publication, patent or patent application were specifically and individually indicated as incorporated by reference.

Claims

1. A method for treating a hepatitis B virus (HBV) infection in a subject having chronic hepatitis B, the method comprising: a) administering to the subject an HBV surface antigen (HBsAg); and b) administering to the subject an HBV therapy other than the HBsAg at least 4 weeks after the initial dose of the HBsAg.

2. The method of claim 1, wherein the initial dose of the HBV therapy is administered after at least 2 doses of the HBsAg, or after at least 3, 4, or 5 doses of the HBsAg.

3. The method of claim 2, wherein the initial dose of the HBV therapy is administered at least 8 weeks after the initial dose of the HBsAg, or at least 9, 10, 11, 12, 13, 14, or 15 weeks after the initial dose of the HBsAg.

4. The method of any one of claims 1-3, wherein the subject has not received treatment with the HBV therapy prior to administration of the HBsAg.

5. The method of claim 4, wherein the subject has not received treatment with an interferon prior to administration of the HBsAg.

6. The method of claim 4 or 5, wherein the subject has not received treatment for the HBV infection prior to administration of the HBsAg.

7. The method of claim 6 or 7, wherein the HBsAg is administered at 20 pg to 100 pg per dose once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W).

8. The method of any preceding claim, wherein the HBV therapy is selected from the group consisting of an anti-HBsAg siRNA, interferon alpha (IFNa), pegylated interferon alpha (PEG-IFNa), an HBV neutralizing mAb, and combinations thereof.

9. The method of claim 9, wherein the HBV therapy comprises an anti-HBsAg siRNA.

10. The method of claim 10, wherein the anti-HBsAg siRNA is administered at 100 mg to 400 mg per dose once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), or once every six weeks (Q6W).

11. The method of claim 10 or 11, wherein the HBV therapy further comprises pegylated interferon alpha (PEG-IFNa).

12. The method of claim 12, wherein the PEG-IFNa is administered at 50 to 500 pg once per week, 100 to 300 pg once per week, or 180 pg once per week. ​ 13. A method for treating a hepatitis B virus (HBV) infection in a subject having chronic hepatitis B, the method comprising: administering to the subject 20 pg to 100 pg of HBV surface antigen (HBsAg) per dose once every two weeks (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W); and 100 mg to 400 mg of an anti-HBsAg siRNA per dose once every two weeks (Q2W), once every three weeks (Q3W), once every four weeks (Q4W), once every five weeks (Q5W), or once every six weeks (Q6W); wherein the treatment comprises at least four doses of each of the HBsAg and the siRNA.

14. The method of any one of claims 1-14, wherein the HBsAg comprises virus-like particles (VLPs) comprising HBV surface envelope proteins Pre-Sl, Pre-S2, or S.

15. The method of claim 15, wherein the VLPs comprise HBV surface envelope proteins Pre-Sl, Pre-S2, and S.

16. The method of any one of claims 8-16, wherein the siRNA is elebsiran.

17. The method of any one of claims 1 to 17, wherein the subject is also administered a nucleos(t)ide reverse transcriptase inhibitor (NrtI).

18. The method of claim 18, further comprising stopping administration of the NrtI if the subject meets one or more of the off-drug criteria.

19. The method of claim 19, wherein the off-drug criteria comprise (a) HBsAg < LLOQ (lower limit of quantification), (b) HBV DNA < LLOQ, (c) no HBeAg detected, and (d) ALT (alanine aminotransferase) < 2x ULN (upper limit of normal).

20. A method for excluding a subject having chronic hepatitis B (CHB) from a clinical study, the method comprising: (a) screening a group of CHB subjects by administering to the CHB subjects HBV surface antigen (HBsAg), wherein each CHB subject has a predetermined baseline HBV antibody concentration prior to administration of HBsAg, and wherein each CHB subject that does not have a response to the HBsAg administration of a post-baseline HBV antibody concentration that is greater than its baseline HBV antibody concentration is excluded from the clinical study; and (b) conducting the clinical study, wherein the CHB subjects that are not excluded from the clinical study are administered an HBV therapy.

21. The method of claim 21, wherein each CHB subject that does not have a response to the HBsAg administration of a post-baseline HBV antibody concentration that is greater than 5 times its baseline HBV antibody concentration is excluded from the clinical study.

22. The method of claim 21, wherein (i) for each CHB subject having a predetermined baseline HBV antibody concentration at or below the lower limit of detection (e.g., < 2 IU / L), the CHB subject is excluded from the clinical trial unless the CHB subject has a post-baseline HBV antibody concentration above the lower limit of detection (e.g., > 2 IU / L), and (ii) for each CHB subject having a predetermined baseline HBV antibody concentration above the lower limit of detection (e.g., > 2 IU / L), the CHB subject is excluded from the clinical trial unless the subject has a post-baseline HBV antibody concentration that is at least 2-fold greater than the subject’s predetermined baseline HBV antibody concentration.

23. The method of any one of claims 21-23, wherein the CHB subject achieved viral suppression by a nucleos(t)ide reverse transcriptase inhibitor (NrtI) prior to administration of the HBsAg.

24. The method of any one of claims 21-24, wherein the HBV antibody concentration is a serum anti-HBs concentration.

25. The method of any one of claims 21-25, wherein the HBV therapy does not include the HBsAg.

26. A method for selecting a subject having chronic hepatitis B (CHB) for hepatitis B virus (HBV) therapy, comprising: a) determining a baseline HBV antibody concentration of a subject having CHB prior to administration of a HBV surface antigen (HBsAg) to the subject; b) administering the HBsAg to the subject; c) determining a post-baseline HBV antibody concentration of the subject after the subject is administered the HBsAg, wherein the subject is selected for the HBV therapy if the post-baseline HBV antibody concentration is greater than the baseline HBV antibody concentration, and the subject is excluded from the HBV therapy otherwise; and d) administering the HBV therapy to the selected subject.

27. The method of claim 27, wherein the subject is selected for the HBV therapy if the post-baseline HBV antibody concentration is greater than 5-fold the baseline HBV antibody concentration, and the subject is excluded from the HBV therapy otherwise.

28. The method of claim 27, wherein the subject is selected for the HBV therapy if (i) the subject has a baseline HBV antibody concentration at or below the lower limit of detection (e.g., < 2 IU / L) and the subject has a post-baseline HBV antibody concentration above the lower limit of detection (e.g., > 2 IU / L), or (ii) the subject has a baseline HBV antibody concentration above the lower limit of detection (e.g., > 2 IU / L) and the subject has a post-baseline HBV antibody concentration that is at least 2-fold greater than the subject’s baseline HBV antibody concentration, and the subject is excluded from the HBV therapy otherwise.

29. The method of any one of claims 27-29, wherein the subject achieved viral suppression by a nucleos(t)ide reverse transcriptase inhibitor (NrtI) prior to administration of the HBsAg. ​ 30. The method of any one of claims 27-31, wherein the baseline and post-baseline HBV antibody concentrations are anti-HBs concentrations determined from serum samples collected from the subject.

31. The method of any one of claims 27-31, wherein the HBV therapy does not include the HBsAg.

32. The method of any one of claims 27-32, wherein the HBV therapy is an siRNA, an interferon alpha (IFNa), a pegylated interferon alpha (PEG-IFNa), an HBV neutralizing mAb, or a combination thereof.

33. A method for treating an HBV infection in a subject having chronic hepatitis B, the method comprising: a) administering to the subject an HBV therapy, wherein the subject has been determined to have a post-baseline HBV antibody concentration following administration of an HBsAg that is greater than a baseline HBV antibody concentration of the subject prior to administration of the HBsAg.

34. The method of claim 34, wherein the HBV therapy is administered when the subject has been determined to have a post-baseline HBV antibody concentration following administration of an HBsAg that is greater than 5 times the baseline HBV antibody concentration of the subject prior to administration of the HBsAg.

35. The method of claim 34, wherein the HBV therapy is administered to the subject if (i) the subject has a baseline HBV antibody concentration that is less than or equal to the lower limit of detection (e.g., < 2 IU / L) and the subject has a post-baseline HBV antibody concentration that is greater than the lower limit of detection (e.g., > 2 IU / L); or (ii) the subject has a baseline HBV antibody concentration that is greater than the lower limit of detection (e.g., > 2 IU / L) and the subject has a post-baseline HBV antibody concentration that is at least 2 times the baseline HBV antibody concentration of the subject.

36. The method of any one of claims 34-36, wherein the baseline and post-baseline HBV antibody concentrations are anti-HBs concentrations determined from serum samples collected from the subject.

37. The method of any one of claims 34-37, wherein the HBV therapy does not include the HBsAg.

38. The method of any one of claims 34-38, wherein the HBV therapy is an siRNA, an interferon alpha (IFNa), a pegylated interferon alpha (PEG-IFNa), an HBV neutralizing mAb, or a combination thereof.

39. A method for treating an HBV infection in a subject diagnosed with or suspected of having an HBV infection, the method comprising: a) administering to the subject an HBsAg; b) determining a post-baseline HBV antibody concentration in a serum sample collected from the subject following administration of the HBsAg; and c) administering to the subject an HBV therapy if the post-baseline HBV antibody concentration is greater than a baseline HBV antibody concentration in a serum sample collected from the subject prior to administration of the HBsAg.

40. The method of claim 40, wherein the HBV therapy is administered in step (c) if the post-baseline HBV antibody concentration is greater than 5-fold from the baseline HBV antibody concentration in a serum sample collected from the subject prior to administration of HBsAg.

41. The method of claim 40, wherein the HBV therapy is administered to the subject if (i) the subject’s baseline HBV antibody concentration is less than or equal to the lower limit of detection (e.g., < 2 IU / L) and the subject’s post-baseline HBV antibody concentration is greater than the lower limit of detection (e.g., > 2 IU / L); or (ii) the subject’s baseline HBV antibody concentration is greater than the lower limit of detection (e.g., > 2 IU / L) and the subject’s post-baseline HBV antibody concentration is at least 2-fold the subject’s baseline HBV antibody concentration.

42. The method of any one of claims 40-42, wherein the baseline and post-baseline HBV antibody concentrations are anti-HBs concentrations.

43. The method of any one of claims 40-43, wherein the subject achieved viral suppression by NrtI prior to administration of HBsAg.

44. The method of any one of claims 40-44, wherein the HBV therapy does not include the HBsAg.

45. The method of any one of claims 40-45, wherein the HBV therapy is an siRNA, an interferon alpha (IFNa), a pegylated interferon alpha (PEG-IFNa), an HBV neutralizing mAb, or a combination thereof.

46. A method for treating an HBV infection in a subject having chronic hepatitis B, wherein the subject has an HBV antibody concentration of less than 2 IU / L, the method comprising: a) administering HBsAg to the subject; b) administering an HBV therapy to the subject, wherein it has been determined that the subject has an HBV antibody concentration of at least 2 IU / L, at least 5 IU / L, at least 10 IU / L, at least 15 IU / L, at least 20 IU / L, at least 25 IU / L, at least 30 IU / L, at least 40 IU / L, at least 50 IU / L, at least 60 IU / L, at least 70 IU / L, at least 80 IU / L, at least 90 IU / L, at least 100 IU / L, at least 200 IU / L, at least 300 IU / L, at least 400 IU / L, at least 500 IU / L, at least 600 IU / L, at least 700 IU / L, at least 800 IU / L, at least 900 IU / L, or at least 1000 IU / L after administration of HBsAg.

47. The method of claim 47, wherein the subject achieved viral suppression by NrtI prior to administration of HBsAg.

48. The method of claim 47 or 48, wherein the HBV antibody is anti-HBs.

49. The method of any one of claims 47-49, wherein the HBV therapy does not comprise the HBsAg.

50. The method of any one of claims 47-50, wherein the HBV therapy is an siRNA, an interferon alpha (IFNa), a pegylated interferon alpha (PEG-IFNa), an HBV neutralizing mAb, or a combination thereof.

51. A method for treating HBV infection in a subject having chronic hepatitis B, the method comprising administering to a subject having chronic hepatitis B a therapeutically effective amount of an HBV therapy, wherein, The subject has been determined to have an HBV antibody concentration of at least 10 IU / L, at least 15 IU / L, at least 20 IU / L, at least 25 IU / L, at least 30 IU / L, at least 40 IU / L, at least 50 IU / L, at least 60 IU / L, at least 70 IU / L, at least 80 IU / L, at least 90 IU / L, at least 100 IU / L, at least 200 IU / L, at least 300 IU / L, at least 400 IU / L, at least 500 IU / L, at least 600 IU / L, at least 700 IU / L, at least 800 IU / L, at least 900 IU / L, or at least 1000 IU / L prior to administration of the HBV therapy.

52. The method of claim 52, wherein the subject’s HBV antibody concentration is an anti-HBs concentration.

53. The method of claim 52 or 53, wherein the HBV therapy does not comprise an HBsAg.

54. The method of any one of claims 52-54, wherein the HBV therapy is an siRNA, an interferon alpha (IFNa), a pegylated interferon alpha (PEG-IFNa), an HBV neutralizing mAb, or a combination thereof.

55. An HBV surface antigen (HBsAg) for use in a method of any one of claims 1-35.

56. Use of an HBV surface antigen (HBsAg) and an HBV therapy that does not comprise the HBsAg in the manufacture of a kit for treating a subject having chronic hepatitis B, the subject producing a response of an increase in HBV antibody concentration following administration of the HBsAg relative to the subject’s HBV antibody concentration prior to administration of the HBsAg to the subject.

57. The use of claim 57, wherein (i) the subject has an HBV antibody concentration of less than 2 IU / L prior to administration of the HBsAg to the subject; or (ii) the subject produces a response of an increase in HBV antibody concentration that is greater than 2-fold the HBV antibody concentration prior to administration of the HBsAg.

58. The use of claim 57 or 58, wherein the subject achieved viral suppression by NrtI prior to administration of the HBsAg.

59. The use of any one of claims 57-59, wherein the HBV antibody is an anti-HBs.

60. The use of any one of claims 57-60, wherein the HBV therapy is siRNA, interferon alpha (IFNa), pegylated interferon alpha (PEG-IFNa), an HBV neutralizing mAb, or a combination thereof.

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