The Hepatitis B Vaccine Protects Re-Exposed Health Care Workers, But Does Not Provide Sterilizing Immunity

doi:10.1053/j.gastro.2013.07.044

Gastroenterology

Volume 145, Issue 5, November 2013, Pages 1026-1034

https://doi.org/10.1053/j.gastro.2013.07.044 Get rights and content

Background & Aims

Infection with hepatitis B virus (HBV) can be prevented by vaccination with HB surface (HBs) antigen, which induces HBs-specific antibodies and T cells. However, the duration of vaccine-induced protective immunity is poorly defined for health care workers who were vaccinated as adults.

Methods

We investigated the immune mechanisms (antibody and T-cell responses) of long-term protection by the HBV vaccine in 90 health care workers with or without occupational exposure to HBV, 10−28 years after vaccination.

Results

Fifty-nine of 90 health care workers (65%) had levels of antibodies to HBs antigen above the cut-off (>12 mIU/mL) and 30 of 90 (33%) had HBs-specific T cells that produced interferon-gamma. Titers of antibodies to HBs antigen correlated with numbers of HBs-specific interferon-gamma−producing T cells, but not with time after vaccination. Although occupational exposure to HBV after vaccination did not induce antibodies to the HBV core protein (HBcore), the standard biomarker for HBV infection, CD4⁺ and CD8⁺ T cells against HBcore and polymerase antigens were detected. Similar numbers of HBcore- and polymerase-specific CD4⁺ and CD8⁺ T cells were detected in health care workers with occupational exposure to HBV and in patients who acquired immunity via HBV infection. Most of the HBcore- and polymerase-specific T cells were CD45RO⁺CCR7⁻CD127⁻ effector memory cells in exposed health care workers and in patients with acquired immunity. In contrast, most of the vaccine-induced HBs-specific T cells were CD45RO⁻CCR7⁻CD127⁻ terminally differentiated cells.

Conclusions

HBs antigen vaccine-induced immunity protects against future infection but does not provide sterilizing immunity, as evidenced by HBcore- and polymerase-specific CD8⁺ T cells in vaccinated health care workers with occupational exposure to HBV. The presence of HBcore- and HBV polymerase-specific T-cell responses is a more sensitive indicator of HBV exposure than detection of HBcore-specific antibodies.

Section snippets

Study Cohort

Ninety health care workers were studied for humoral and cellular immune responses 10−28 years after a documented complete course of HBsAg vaccination. Seventy-one health care workers had received recombinant HBs vaccine (Engerix B or Recombivax), and 14 health care workers had received a plasma-derived HBs vaccine (Heptavax). For 5 health care workers the vaccine type was unknown. This immunological analysis was part of a larger recall study of HBsAg vaccinees conducted in the Liver Diseases

HBsAg-Induced Antibody Responses Correlate With HBs-Specific T-Cell Responses But Not With Time After Vaccination

Ninety health care workers were studied 10−28 years after a documented full course of HBsAg vaccination. Anti-HBs levels were determined by enzyme immunoassay (EIA) and HBs-specific T-cell responses by ELISpot. Fifty-nine of 90 (65%) health care workers displayed anti-HBs levels above the clinical cut-off of 12 mIU/mL. About one third of both the anti-HBs−positive and the anti-HBs−negative groups tested positive for HBs-specific IFN-γ−producing T cells (Figure 1A). The anti-HBs titer correlated

Discussion

In this cross-sectional study, we showed that 65% of health care workers who had received a full course of HBsAg vaccination during adulthood maintained anti-HBs titers above the clinical cut-off of 12 mIU/mL 10−28 years after primary vaccination. We assessed the impact of occupational HBV exposure with an exposure score, and by quantitating exposure-induced T-cell responses against HBcore and HBVpol, which are not part of the HBsAg vaccine. This allowed us to draw 3 main conclusions.

First,

Acknowledgments

The authors thank Elenita Rivera for excellent study support as well as all patients and healthy volunteers for participating in this study. The authors also thank James Schmitt, Occupational Medical Service, National Institutes of Health, for discussion and information on the HBs vaccine.

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Millions of people worldwide are infected chronically with HBV, which results in significant morbidity and mortality. Therapeutic vaccination is a strategy that aims to induce functional cure by restoring cellular immunity to HBV. Previously we have shown the candidate HBV immunotherapeutic vaccine ChAdOx1-HBV, encoding all major HBV antigens and a genetic adjuvant (shark invariant chain), is highly immunogenic in mice.
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ChAdOx1-HBV is safe and immunogenic in healthy volunteers and patients with CHB. In further studies, ChAdOx1-HBV will be used in combination with other therapeutic strategies with an aim to overcome the attenuated immunogenicity in patients with CHB.
Therapeutic vaccine ChAdOx1-HBV, a novel treatment for chronic hepatitis B infection (CHB), has been shown to be immunogenic in preclinical studies. In HBV001, a first-in-human phase I study, we show vaccination with ChAdOx1-HBV is safe and generates high magnitude T cell responses in healthy volunteers and lower levels of responses in patients with CHB. This is an important first step in the development of ChAdOx1-HBV as part of a wider therapeutic strategy to induce hepatitis B functional cure, and is of great interest to patients CHB and clinicians treating the condition.
This study is registered at ClinicalTrials.gov (NCT04297917).
Humoral immunity in hepatitis B virus infection: Rehabilitating the B in HBV
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Insights into the immunopathogenesis of chronic HBV infections are fundamental in the quest for novel treatment approaches aimed at a functional cure. While much is known about the ineffective HBV-specific T-cell responses that characterise persistent HBV replication, B cells have been left largely understudied. However, an important role for humoral immunity during the natural history of HBV infections, as well as after functional cure, has been inadvertently revealed by the occurrence of HBV flares following B cell-depleting treatments. Herein, we review our current understanding of the role of the humoral immune response in chronic HBV, both at the level of HBV-specific antibody production and at the phenotypic and broader functional level of B cells. The recent development of fluorescently labelled HBV proteins has given us unprecedented insights into the phenotype and function of HBsAg- and HBcAg-specific B cells. This should fuel novel research into the mechanisms behind dysfunctional HBsAg-specific and fluctuating, possibly pathogenic, HBcAg-specific B-cell responses in chronic HBV. Finally, novel immunomodulatory treatments that partly target B cells are currently in clinical development, but a detailed assessment of their impact on HBV-specific B-cell responses is lacking. We plead for a rehabilitation of B-cell studies related to both the natural history of HBV and treatment development programmes.
Hepatitis B and Health Care Workers
2021, Clinics in Liver Disease
Citation Excerpt :
Guidelines for some European countries use a cutoff of 100 mIU/mL, rationalizing this cutoff based on the fact that it is higher than the levels usually seen in the rare situation of an HBV carrier with concurrent positive HBsAg and anti-HBs.25 The evidence-based data supporting an anti-HBs cutoff of 10 mIU/mL or more seems to be more reasonable, particularly in settings in which HBV prevalence is low.25,26 CDC recommendations for postexposure management of HCW based on HBV vaccination status is presented in Table 2.3
European survey of hepatitis B vaccination policies for healthcare workers: An updated overview
2020, Vaccine
Citation Excerpt :
In our study most countries (12 out of 18) had adopted 10 IU/l as a threshold, compared to 13 in our previous study, while 6 preferred 100 IU/l. Working with a 100 IU/l threshold has the advantage of being usually above the levels measured in HBV carriers with concurrent serum HBsAg and anti-HBs [3,25] and a meta-analysis concluded that available data did not allow to exclude an increased risk for infection with time since vaccination [27]. But recent research has confirmed previous studies that a level of ≥10 IU/l confers a long-term (10–28 years) immunity in immunocompetent individuals that have adequately responded to a primary HBV vaccination course, even in the absence of HBV exposure [28,29]. Therefore, current recommendations state that no boosters are necessary in immunocompetent individuals that have adequately responded to a primary HBV vaccination course [25].
The risk of transmission of bloodborne pathogens, including hepatitis B virus (HBV) to healthcare workers (HCWs) is well known. In 2005 we performed a survey on HBV prevention in HCWs in the European Union (EU). An update of the 2005 survey deemed necessary as an EU Council Directive (2010/32/EU) on sharps injuries was to be implemented into national legislation by 11 May 2013 and more countries were starting universal HBV vaccination.
We performed an electronic survey in 2016, among national representatives from the Occupational Medicine section of the European Union of Medical Specialists (UEMS), to find out how policies have been put into practice in the European Union countries (plus Norway and Switzerland). The data were updated in 2019.
Answers were received from 21 countries (among them 19 EU Member States), representing 78% of the population and 60% of HCWs in the EU-28. HBV vaccination was mandatory for medical and nursing staff in 10 countries; for other paramedical staff, medical and nursing students in 9 countries; for paramedical students in 8 countries; for cleaning staff in 7 countries; and for technical staff in 5 countries; it was recommended in all but one of other countries. Serotesting before vaccination was done in 7 countries. The vaccination schedule most often used was 0, 1, 6 months (18countries), monovalent HBV vaccine was used in 14 countries, and combined (HAV + HBV) vaccine in 11 countries. Serotesting after vaccination was done in 18 countries and boosters were recommended in 14 countries. A non-responder policy was present in 18 countries. HBV vaccination coverage (5 countries) was 70–95%. Sharps injuries were reported in 13 countries, nationwide in 7 of them; European-wide reporting was not mentioned by respondents.
These results show the variation in the implementation of EU legislation in the participating countries. More consultation between actors at EU level, including enhancing medical surveillance in occupational medicine could help to optimise policies in European countries in order to further reduce HBV transmission to HCWs.
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While the cellular immune response associated with acute and chronic HBV infection has been thoroughly studied, the B cell response in chronic hepatitis B and the role of antibodies raised against the HBV envelope antigens in controlling and prevention of infection requires further investigation. The detection of anti-HBs antibodies is considered as one of the biomarkers for functional cure of chronic hepatitis B virus infection, as well as for protective immunity. Indeed, vaccine-induced neutralizing anti-HBs antibodies have been shown to protect against HBV challenge. Yet, the therapeutic potential of viral envelope-specific antibodies and the mechanism involved in protection and prevention of cell-to-cell transmission warrants additional investigative efforts. In this review, we will provide a critical overview of the available preclinical and clinical literature supporting the putative role of active and passive vaccination and neutralizing envelope-specific antibodies for therapeutic intervention in combination regimens intended to cure persistent HBV infection.
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: Conflicts of interest The authors disclose no conflicts.

: Funding This study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health intramural research program. JMW was supported by grant We-4675/1-1 from the Deutsche Forschungsgemeinschaft (DFG), Bonn, Germany.

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Original ResearchFull Report: Clinical—LiverThe Hepatitis B Vaccine Protects Re-Exposed Health Care Workers, But Does Not Provide Sterilizing Immunity

Background & Aims

Methods

Results

Conclusions

Section snippets

Study Cohort

HBsAg-Induced Antibody Responses Correlate With HBs-Specific T-Cell Responses But Not With Time After Vaccination

Discussion

Acknowledgments

Lancet

Lancet

Vaccine

New insight in the pathobiology of hepatitis B virus infection

Gut

Yeast-recombinant hepatitis B vaccine. Efficacy with hepatitis B immune globulin in prevention of perinatal hepatitis B virus transmission

JAMA

Hepatitis B vaccine in medical staff of hemodialysis units: efficacy and subtype cross-protection

N Engl J Med

Characterization of antibodies to the structural polypeptides of HGSAg: evidence for subtype-specific determinants

J Immunol

Recombivax-HB: perspectives past, present and future

Expert Rev Vaccines

Vaccination against hepatitis B: comparison of three different vaccination schedules

J Infect Dis

Antibody levels and protection after hepatitis B vaccination: results of a 15-year follow-up

Ann Intern Med

Original Research
Full Report: Clinical—Liver
The Hepatitis B Vaccine Protects Re-Exposed Health Care Workers, But Does Not Provide Sterilizing Immunity