Therapeutic Vaccination for Chronic Hepatitis B

A Systematic Review and Meta-analysis

Seng Gee Lim; Jennielyn Agcaoili; Nurun Nisa Amatullah De Souza; Edwin Chan


J Viral Hepat. 2019;26(7):803-817. 

In This Article

Abstract and Introduction


Therapeutic vaccines may be promising treatments for chronic hepatitis B (CHB), but their clinical efficacy and safety are unclear. We conducted a systematic review of the evidence for the efficacy and safety of therapeutic vaccines in CHB patients. We searched PubMed, EMBASE and Google Scholar from 1990 until present and abstracts from EASL, APASL and AASLD from 2012 to 2017 and selected randomized controlled trials of CHB patients, comparing therapeutic vaccines with no treatment or standard of care. The Cochrane Risk of Bias tool v2.0 and GRADE method were used. Analyses were stratified by hepatitis B e antigen (HBeAg) status and the comparator (therapeutic vaccines vs no treatment, or therapeutic vaccines + standard of care vs standard of care). Efficacy outcomes were HBeAg seroconversion, hepatitis B virus DNA reduction and hepatitis B virus surface antigen (HBsAg) loss, measured at the end of treatment or end of follow-up. Effects were reported as risk differences with 95% confidence intervals using a random effects model. Fifteen studies were included. A wide variety of therapeutic vaccines were tested. For HBeAg clearance at the end of follow-up, when comparing therapeutic vaccines vs no therapy, RD = 0.01, 95% CI −0.05 to 0.07, and when comparing therapeutic vaccines + standard of care vs standard of care, RD = 0.03, 95% CI −0.03 to 0.09. For HBVDNA reduction at the end of follow-up, when comparing therapeutic vaccines vs no therapy, RD = −0.03, 95% CI −0.08 to 0.02, and when comparing therapeutic vaccines + standard of care, RD = 0.15, 95% CI 0.02-0.28. There were only a few studies on HBsAg loss, and hence, the findings were inconclusive. The only efficacy finding was HBVDNA reduction at the end of follow-up for therapeutic vaccines + standard of care vs standard of care; otherwise, therapeutic vaccines do not appear to be efficacious for the treatment of CHB, but were limited by few RCTs, suboptimal therapeutic vaccines and patient selection.


Chronic hepatitis B (CHB) is an increasingly serious global health problem. The report issued by the World Health Organization in 2017[1] estimates 1.34 million viral hepatitis deaths worldwide in 2015, a 22% increase from that reported in 2000. CHB is readily preventable by inexpensive prophylactic vaccination,[2] but for those chronically infected, there is the spectre of progression to cirrhosis and hepatocellular carcinoma (HCC).[3] Consequently, many guidelines recommend treatment[4–6] for those who are at high risk of progression.

Recently, there has been renewed interest in functional cure as a meaningful surrogate goal of hepatitis B virus (HBV) therapy. This has been defined as loss of hepatitis B virus surface antigen (HBsAg) 24 weeks after the end of therapy.[7] Those achieving HBsAg loss have been shown to have significantly improved clinical outcomes such as better overall survival, reduced risk of HCC and liver-related mortality.[8] Current widely prescribed therapies such as nucleos(t)ide analogues (NAs) and immunomodulators (pegylated interferon) are limited in their ability to achieve functional cure. Another meaningful surrogate outcome is hepatitis B e antigen (HBeAg) seroconversion defined as loss of serum HBeAg coupled with the appearance of anti-HBe antibodies. This event is usually associated with resolution of liver inflammation, significant reduction in HBV viral load and lower rates of progression to cirrhosis and HCC.[9] In a long-term study from Taiwan, up to 45% of such HBeAg seroconverters achieved functional cure (HBsAg loss) over a 25-year period.[10] Consequently, the definition of success in CHB trials might be defined differently depending on the patient's HBeAg status. For HBeAg-positive patients, success could be considered as achieving HBeAg seroconversion, while for those who are HBeAg negative, success could be considered as a reduction in or loss of HBV DNA and/or HBsAg loss.

Hepatitis B virus persistence is dependent upon a complex interaction between virus and host with suboptimal immune responses, notably defective cell-mediated immunity (CD4, CD8 and NK cells, cytolytic responses), defective dendritic cell functions and imbalance of cytokine production.[11] A recent workshop examined various therapeutic strategies that could lead to improved functional cure rates.[12] Of the immunotherapy options available, other than interferon-based therapy, only therapeutic vaccines (TVs) have regulatory approval. Various strategies for stimulating T-cell responses with TVs have been explored,[13] such as altering the vaccine antigen composition by using combinations of core, X and polymerase antigens in addition to HBsAg; using a DNA vaccine instead of a protein/peptide vaccine; using vaccine vectors; using altered vaccine adjuvants; and using different TV doses, vaccination frequencies and prime-boost methods. The first clinical study of a HBV TV in 1995 showed promising results with 53% achieving undetectable HBV DNA.[14] Almost a quarter of a century has since passed, but has the promise of therapeutic vaccination been met? A number of review articles[13,15,16] have assessed this, but a systematic evidence-based approach is much needed to consolidate the evidence. Consequently, it is timely to assess the clinical efficacy of TVs in light of the renewed interest in functional cure. The aim of our review was to systematically appraise the evidence for the efficacy and safety of TVs compared to no treatment, placebo or standard care in the treatment of CHB.