Resolution of chronic hepatitis B and anti-HBs seroconversion in humans by adoptive transfer of immunity to hepatitis B core antigen

doi:10.1053/gast.2002.31887

Gastroenterology

Volume 122, Issue 3, March 2002, Pages 614-624

https://doi.org/10.1053/gast.2002.31887 Get rights and content

Abstract

Background & Aims: Impaired T-cell reactivity is believed to be the dominant cause of chronic hepatitis B virus (HBV) infection. We characterized HBV-specific T-cell responses in chronic hepatitis B surface antigen carriers who received bone marrow from HLA-identical donors with natural immunity to HBV and seroconverted to antibody to hepatitis B surface antigen. Methods: T-cell reactivity to HBV antigens and peptides was assessed in a proliferation assay, the frequency of HBV core- and surface-specific T cells was quantified directly by ELISPOT assays, and T-cell subsets were analyzed by flow cytometry. Results: CD4⁺ T-cell reactivity to HBV core was common in bone marrow donors and the corresponding recipients after hepatitis B surface antigen clearance, whereas none reacted to surface, pre-S1, or pre-S2 antigens. Furthermore, CD4⁺ T cells from donor/recipient pairs recognized similar epitopes on hepatitis B core antigen; using polymerase chain reaction for the Y chromosome, the recipients' CD4⁺ T lymphocytes were confirmed to be of donor origin. The frequency of core-specific CD4⁺ and CD8⁺ T cells was several-fold higher than those specific for surface antigen. Conclusions: This study provides the first evidence in humans that transfer of hepatitis B core antigen–reactive T cells is associated with resolution of chronic HBV infection. Therapeutic immunization with HBV core gene or protein deserves further investigation in patients with chronic hepatitis B.

GASTROENTEROLOGY 2002;122:614-624

Section snippets

Patients

Eight patients with chronic HBV infection (serum HBsAg positive for more than 12 months) who underwent BMT because of hematologic malignancy and received marrow from an HLA-matched sibling with natural immunity to HBV (antibody to hepatitis B surface antigen [anti-HBs] and antibody to hepatitis B core antigen [anti-HBc] positive) were studied (Table 1).Before BMT, the 3 patients with acute leukemia were in complete remission, induced by an appropriate chemotherapy regimen: cytarabine,

Results

After engraftment of the bone marrow, all 8 HBsAg-positive recipients developed a hepatitis flare (defined as elevation of serum alanine aminotransferase level >3-fold above the upper level of normal) at a median of 3.3 months (range, 1.6–13.3 months). Between 0.5 and 6 months later, all 8 BMT recipients cleared serum HBsAg (Table 1). In 6 cases, the seroconversion to anti-HBs was sustained at the last follow-up visit (between 1.7 and 7.9 years after BMT) (Table 1). The other 2 patients lost

Discussion

The phenomenon of HBsAg clearance and seroconversion to anti-HBs after adoptive transfer of immunity in patients with chronic hepatitis B provides a unique model to understand virus-specific T-cell reactivity associated with resolution of chronic HBV infection. By studying the largest series of patients, who cleared HBsAg after the engraftment of HLA-identical bone marrow from a donor with past exposure to HBV, we found that resolution of chronic HBV infection is associated with a transfer of

References (35)

M Kane
Global programme for control of hepatitis B infection
Vaccine
(1995)
D Shouval et al.
Transplantation of hepatitis B immune lymphocytes as means for adoptive transfer of immunity to hepatitis B virus
J Hepatol
(1995)
Y Ilan et al.
Ablation of persistent hepatitis B by bone marrow transplantation from a hepatitis B-immune donor
Gastroenterology
(1993)
JF Bishop et al.
Etoposide in acute nonlymphocytic leukemia. Australian Leukemia Study Group
Blood
(1990)
MC Jung et al.
Virus-specific lymphokine production differs quantitatively but not qualitatively in acute and chronic hepatitis B infection
Virology
(1999)
S Iwarson et al.
Protection against hepatitis B virus infection by immunization with hepatitis B core antigen
Gastroenterology
(1985)
F Schodel et al.
Immunization with recombinant woodchuck hepatitis virus nucleocapsid antigen or hepatitis B virus nucleocapsid antigen protects woodchucks from woodchuck hepatitis virus infection
Vaccine
(1993)
MK Maini et al.
Direct ex vivo analysis of hepatitis B virus-specific CD8(+) T cells associated with the control of infection
Gastroenterology
(1999)
MC Jung et al.
Hepatitis B virus antigen-specific T cell activation in patients with acute and chronic hepatitis B
J Hepatol
(1991)
G Marinos et al.
Induction of T-helper cell response to hepatitis B core antigen in chronic hepatitis B: a major factor in activation of the host immune response to the hepatitis B virus
Hepatology
(1995)

S Pol et al.

Efficacy and limitations of a specific immunotherapy in chronic hepatitis B

J Hepatol

(2001)

FV Chisari et al.

Hepatitis B virus immunopathogenesis

Annu Rev Immunol

(1995)

B Rehermann et al.

The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response

Nat Med

(1996)

A Penna et al.

Long-lasting memory T cell responses following self-limited acute hepatitis B

J Clin Invest

(1996)

C Niederau et al.

Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B

N Engl J Med

(1996)

YF Liaw et al.

Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study

Hepatology

(1991)

DK Wong et al.

Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis

Ann Intern Med

(1993)

Cited by (156)

A novel therapeutic HBV vaccine candidate induces strong polyfunctional cytotoxic T cell responses in mice
2021, JHEP Reports
Current standard-of-care suppresses HBV replication, but does not lead to a functional cure. Treatment aiming to cure chronic hepatitis B (CHB) is believed to require the induction of strong cellular immune responses, such as by therapeutic vaccination.
We designed a therapeutic HBV vaccine candidate (YF17D/HBc-C) using yellow fever vaccine YF17D as a live-attenuated vector to express HBV core antigen (HBc). Its ability to induce potent cellular immune responses was assessed in a mouse model that supports flavivirus replication.
Following a HBc protein prime, a booster of YF17D/HBc-C was found to induce vigorous cytotoxic T cell responses. In a direct head-to-head comparison, these HBc-specific responses exceeded those elicited by adenovirus-vectored HBc. Target-specific T cells were not only more abundant, but also showed a higher degree of polyfunctionality, with HBc-specific CD8⁺ T cells producing interferon γ and tumour necrosis factor α in addition to granzyme B. This immune phenotype translated into a superior cytotoxic effector activity toward HBc-positive cells in YF17D/HBc-C vaccinated animals in vivo.
The results presented here show the potential of YF17D/HBc-C as a vaccine candidate to treat CHB, and warrant follow-up studies in preclinical animal models of HBV persistence in which other candidate vaccines have been unable to achieve a sustained virologic response.
Resolution of CHB requires the induction of strong cellular immune responses. We used the yellow fever vaccine as a vector for HBV antigens and show that it is capable of inducing high levels of HBV-specific T cells that produce multiple cytokines simultaneously and are cytotoxic in vivo.
Targeting Innate and Adaptive Immune Responses to Cure Chronic HBV Infection
2019, Gastroenterology
Fewer than 1% of chronic hepatitis B virus infections per year are cured with antiviral treatment. This creates a need for long-term treatment, which poses challenges for patients and health systems. Because cure is accompanied by recovery of antiviral immunity, a combination of direct-acting antiviral agents and immunotherapy are likely to be required. Extensive efforts have been made to identify determinants of the failed immune response to hepatitis B virus in patients with chronic infection. We review mechanisms of immune dysfunction in patients with chronic hepatitis B virus infection, immunotherapy strategies in development, and the challenges associated with successful implementation of immunotherapy.
A mouse model with age-dependent immune response and immune-tolerance for HBV infection
2018, Vaccine
Citation Excerpt :
The identity of the types of cells and molecules that mediate age-related tolerance in this mouse model warrants further investigation. The treatment instructions regarding CHB during bone marrow transplantation strongly recommend that repriming an invalid immune response may resolve chronic HBV infection [36]. However, the efficacy of the therapeutic vaccination for CHB is limited [29,37].
Viral clearance of human HBV infection largely depends on the age of exposure. Thus, a mouse model with age-dependent immune response and immune-tolerance for HBV infection was established.
HBVRag1 mice were generated by crossing Rag1^−/− mice with HBV-Tg mice. Following adoptive transfer of splenocytes adult (8–9 weeks old) and young (3 weeks old) HBVRag1 mice were named as HBVRag-ReA and HBVRag-ReY mice respectively. The biochemical parameters that were associated with viral load and immune function, as well as the histological evaluation of the liver tissues between the two mouse models were detected. The immune tolerance of HBVRag-ReY mice that were reconstituted at the early stages of life was evaluated by quantitative hepatitis B core antibody assay, adoptive transfer, and modulation of gut microbiota with the addition of antibiotics.
HBVRag-ReA mice indicated apparent hepatocytes damage, clearance of HBsAg and production of HBsAb and HBcAb. HBVRag-ReY mice did not develop ALT elevation, and produced HBcAb and HBsAg. A higher number of hepatic CD8⁺ T and B cells promoted clearance of HBsAg in HBVRag-ReA mice following 30 days of lymphocyte transfer. In contrast to HBVRag-ReA mice, HBVRag-ReY mice exhibited higher levels of Th1/Th2 cytokines. HBVRag-ReY mice exhibited significantly higher (P < .01, approximately 10-fold) serum quantitative anti-HBc levels than HBV-Tg mice, which might be similar to the phase of immune clearance and immune tolerance in human HBV infection. Furthermore, the age-related tolerance in HBVRag-ReY mice that were sensitive to antibiotic treatment was different from that noted in HBV-Tg mice. GS-9620 could inhibit the production of HBsAg, whereas HBV vaccination could induce sustained seroconversion in HBVRag-ReY mice with low levels of HBsAg.
The present study described a mouse model with age-dependent immunity and immune-tolerance for HBV infection in vivo, which may mimic chronic HBV infection in humans.
New treatments to reach functional cure: Rationale and challenges for emerging immune-based therapies
2017, Best Practice and Research: Clinical Gastroenterology
The landscape for chronic HBV therapy is rapidly evolving. The latest generation of antiviral drugs provide robust virus suppression with a high barrier to resistance that facilitates long-term treatment. However, low rates of HBsAg loss demonstrate that additional strategies are needed to consistency achieve a functional cure. The immune system can clear HBV and establish long-term control over the virus. Sufficiently boosting HBV immunity in chronic patients has been very difficult due to immune exhaustion, immune dysregulation, and inhibitory pathways suppressing the immune response. Therapeutic vaccines employing new technology, vectors and new immunomodulatory drugs that can elicit direct antiviral effects and cancel inhibitory mechanism may be able to overcome exhaustion. This review will discuss the justification for immunotherapy, lessons from previous trials and new vaccines/drugs in early stage clinical trials. The challenges of correlating immune responses induced by these drugs to clinical efficacy will also be addressed.
Management of viral hepatitis in patients with haematological malignancy and in patients undergoing haemopoietic stem cell transplantation: Recommendations of the 5th European Conference on Infections in Leukaemia (ECIL-5)
2016, The Lancet Infectious Diseases
Viral hepatitis affects millions of people worldwide, and host immunity is the key determinant of patient outcome. Viral hepatitis can be life threatening in patients with haematological malignancy, including haemopoietic stem cell transplant recipients, because of the virus itself, or through a need to decrease the dose of chemotherapy. A past or currently infected haemopoietic stem cell donor could also transmit viral hepatitis. The burden of viral hepatitis in patients with haematological malignancies and the weak evidence on which previous guidelines are based has prompted the European Conference on Infection in Leukaemia (ECIL-5) to convene a group of experts in the fields of viral hepatitis and of haematological malignancy to specifically address previously unconsidered issues and grade the available quality of evidence according to the Infectious Diseases Society of America grading system. The group recommends that all patients should be screened for hepatotropic viruses before haematological treatment and that patients or haemopoietic stem cell donors with markers of past or current viral hepatitis should be assessed by an expert. Screening, vaccination, and treatment rules are reported in this Review.
Adaptive immunity in HBV infection
2016, Journal of Hepatology
During hepatitis B virus (HBV) infection, the presence of HBV-specific antibody producing B cells and functional HBV-specific T cells (with helper or cytotoxic effects) ultimately determines HBV infection outcome. In this review, in addition to summarizing the present state of knowledge of HBV-adaptive immunity, we will highlight controversies and uncertainties concerning the HBV-specific B and T lymphocyte response, and propose future directions for research aimed at the generation of more efficient immunotherapeutic strategies.

View all citing articles on Scopus

^☆: Address requests for reprints to: Nikolai V. Naoumov, M.D., Institute of Hepatology, University College London, 69-75 Chenies Mews, London WC1E 6HX, England. e-mail: [email protected]; fax: (44) 20-7380 0405.

^☆☆: Dr. Lau's work at University College London was supported by a fellowship from The Royal Society, United Kingdom. Dr. Mullerova is a recipient of an EASL Training Fellowship.

View full text

Clinical ResearchResolution of chronic hepatitis B and anti-HBs seroconversion in humans by adoptive transfer of immunity to hepatitis B core antigen☆,☆☆

Abstract

Section snippets

Patients

Results

Discussion

Vaccine

J Hepatol

Gastroenterology

Blood

Virology

Gastroenterology

Vaccine

Gastroenterology

J Hepatol

Hepatology

J Hepatol

Hepatitis B virus immunopathogenesis

Annu Rev Immunol

The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response

Nat Med

Long-lasting memory T cell responses following self-limited acute hepatitis B

J Clin Invest

Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B

N Engl J Med

Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study

Hepatology

Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis

Ann Intern Med

Clinical Research
Resolution of chronic hepatitis B and anti-HBs seroconversion in humans by adoptive transfer of immunity to hepatitis B core antigen☆,☆☆