Since its widespread introduction in 1983, the hepatitis B vaccine has become an essential part of infant immunization programmes globally, and is the key component of the global hepatitis B control programme for the World Health Organization (WHO). (1) Infection with hepatitis B virus (HBV) can cause acute liver disease, as well as chronic infection that may lead to liver failure or hepatocellular carcinoma. The vaccine has been particularly important for countries where the incidence of HBV-related hepatocellular carcinoma is high. In effect, the hepatitis B vaccine was the world's first anticancer vaccine.
Effective treatment options for individuals with chronic hepatitis B infection were limited until 1998 when lamivudine, the first nucleoside analogue drug, was approved for treatment. Newer agents have been developed, but lamivudine remains the mainstay therapy in many countries with high HBV prevalence because of its safety, efficacy and low cost. As a single treatment agent, however, lamivudine has a significant drawback: monotherapy has resulted in the appearance of lamivudine-resistant HBV strains, a phenomenon that has been observed with single-drug regimens used to treat other infections such as tuberculosis and HIV infection. (2) The emergence of these drug-resistant strains limits therapeutic options for individuals chronically infected with HBV; moreover, the spread of these strains may pose a risk to the global hepatitis B immunization programme. Mutations associated with drug treatment can cause changes to the surface antigen protein, the precise portion of the virus that the hepatitis B vaccine mimics. This article examines the mechanism of antiviral drug-selected changes in the part of the viral genome that also affects the surface antigen, and explores their potential impact on current hepatitis B vaccine programmes (Box 1).
Features of the virus
HBV is an enveloped, partly double-stranded DNA virus containing a compact, circular genome of overlapping reading frames (Fig. 1). Human HBV causes both acute and long-term infections, including chronic and neoplastic liver disease. The virus exists as eight genotypes labelled A to H, with varied geographical distributions. Differences between genotypes involve approximately 8% of the genomic sequence. (3-5) HBV uses an encoded enzyme reverse transcriptase to replicate its viral genome. Reverse transcription is an error-prone process that generates a large number of nucleotide changes within the viral genome. This process results in new, closely-related viral species; as a result, at any given time in a particular host the viral population consists of a swarm of similar but discrete viruses. (6,7)
Vaccine escape mutants
The hepatitis B vaccine is an effective means of preventing HBV infection, producing protective levels of antibodies in up to 95% of recipients. (8) The envelope gene of HBV produces proteins of three different lengths: two larger proteins, preS1 and preS2, as well as the smaller S protein. The commercially available hepatitis B vaccine used in most programmes is a yeast-derived recombinant surface antigen of the small S protein alone. Antibodies elicited by the hepatitis B vaccine specifically target the "a" determinant of the surface antigen (Fig. 1).
It has been recognized that the administration of hepatitis B vaccine can increase the mutation rate of the virus. In high-prevalence countries such as China, Thailand as well as Province of Taiwan, China, monitoring for more than a decade has shown that hepatitis B immunization programmes have increased the incidence of HBV variants with mutations in the surface antigen protein (9,10) even as they reduce the overall burden of chronic hepatitis B infection. (11) Mutations in and around the "a" determinant may lead to an alteration in the antigenicity of the surface antigen protein so that antibodies directed against the surface antigen protein may fail to neutralize the virus. (12-20) Infection of immunized individuals with a vaccine escape mutant (VEM) (20) is therefore possible. VEMs are typically characterized by the presence of single-amino-acid changes in the S protein. (12,21) Some of these variants are associated with high levels of viraemia and have persisted in the host for more than 10 years, suggesting they are stable and transmissible variants. In addition, the antibody responses against the surface antigen protein elicited by the recombinant yeast-derived vaccine now in use are weaker and more specific than those achieved with the previous plasma-derived surface antigen vaccine. (22-24) In Province of Taiwan, China, up to 28% of children with chronic hepatitis B infection also harbour hepatitis B surface antigen mutants. So VEMs capable of causing infection in fully immunized individuals are not uncommon in countries with high rates of endemic HBV infection and universal hepatitis B infant immunization programmes. (12, 20) However, to date the emergence of VEMs has not had a known negative impact on any country's immunization programme. (25)
Treatment of infection
Five oral antiviral agents have been approved by the United States Food and Drug Administration for the treatment of chronic hepatitis B …