Boosters for hepatitis B vaccination? Need for an evidence-based policy
Authors: Andrew J. Hall
Journal: Hepatology (2010)

Until recent years, the major modes of transmission of hepatitis B virus (HBV) globally were from child to child (by unclear routes) and perinatal transmission. This was critically important in determining the worldwide distribution of HBV carriage, and its chronic liver disease sequelae, because the risk of carriage is very high at birth and during the first 5 years of life. However, the successful implementation of HBV vaccination in infancy has changed all that. In July 2009, the World Health Organization1 reported that 177 of 192 member states had implemented national infant vaccination, with 138 countries achieving coverage of 80% or better with three doses. Thus, the pattern is moving toward that long seen in North America and Western Europe, with unsafe injection and sexual transmission as the predominant modes. This shift highlights the question of whether infant vaccination will continue to protect into late adolescence and early adult life, when sexual activity is maximal. Nevertheless, perinatal transmission will remain important in most countries (and particularly in Asia) because of the high risk of becoming a carrier. This has led the World Health Organization recently to recommend a birth dose of hepatitis B vaccine in all countries. HBIG, hepatitis B hyperimmune globulin; HBV, hepatitis B virus. A recent review2 found evidence of protection up to the age of 15 years. Some care needs to be taken in interpreting this data because the impact of vaccination is such that vaccinated individuals who are living in highly vaccinated populations may not be challenged by exposure to the virus. Even when core antibody conversion is studied to estimate exposure, very few studies have the statistical power to estimate risk of disease or viral persistence following core antibody conversion. In adults, the risk of carriage following infection is expected to be 10% or less, and acute hepatitis B has only been documented in one individual with a history of successful vaccination.3 This leaves tests of immunological memory as a measure of duration of protection. Surface antibody has been shown to be a correlate of immunity in a cohort study,4 both against infection and persistence. However, the concentration shows a steady decline in the successfully immunized individual, with around one-third to half of the individuals becoming negative 15 years after vaccination. This decline is remarkably similar whether in African children5 or German adults.6 Therefore, does loss of antibody indicate loss of immunity? The persistence of B cells committed to surface antibody production has been shown to persist beyond disappearance of antibody, and there has been considerable work on both B and T cell assays to assess ongoing immunity.7 However, this has not led to any clear answers, and the methods are difficult to transfer to highly endemic low-income countries where the question is most relevant. This has led to the use of a "test" dose of vaccine to ascertain whether the subject still has a secondary response to the vaccine, implying memory. The expectation is that a secondary response would be more rapid and therefore antibody is tested between 7 and 14 days after the test vaccination. Results from this approach have been reassuring until now. Populations have been studied at 13, 15, and 22 years of age. The proportion of individuals who had lost antibody was limited to 10% or less. However, in this issue of HEPATOLOGY,8 there is a report of a study in Taiwanese individuals at the age of around 20 years which suggest that around 80% of individuals may have lost immune memory by that age. This study differs from other studies because it measures early response at 7-10 days whereas others have measured at 10-14 days. This may explain some of the difference. In addition, there has been one study in the United Kingdom9 which examined loss of immunological memory in relation to whether the child received hepatitis B hyperimmune globulin (HBIG) with their initial dose of vaccine, which suggests that HBIG could lead to a more rapid loss of surface antibody. The study in this issue linked subjects to vaccine records and found that only two had received HBIG even though in the introduction to the article it is pointed out that all children before 1992 should have received it. Thus, some doubts linger as to whether this finding is truly dissimilar to others and importantly whether it can be generalized to populations where HBIG is not routinely used. Replication of the study is important to inform the policy decision on whether booster doses of hepatitis B vaccination will be required and at what age. There are few populations in which infant vaccination history and documentation of immune response to vaccination are still available at the age of 20 years and older. So, most studies will have to make assumptions about nonresponse rates in the young adults studied. Because duration of antibody response is clearly related to peak antibody level after immunization, it will be important to have some evidence of the background level of response in the populations studied. Even if these studies show a loss of immune memory by this method, this does not necessarily mean that booster doses will be required. There needs to be an attempt to gather evidence on the critical endpoints: protection against infection and protection against disease. Observational studies can help by showing rates of core antibody conversion in vaccinated populations by age, by estimating the incidence of acute hepatitis B in vaccinated populations and by conducting case-control studies of acute hepatitis B to estimate vaccine efficacy. The issue of lack of challenge to the vaccinated state can potentially be overcome by studying vaccinated individuals who have been married to infectious carriers; this both ensures that the vaccinated individual has been exposed and can even be used, by measuring the carrier's HBV DNA level, as an estimate of exposure dose. The best evidence to support policy would come from randomized trials. Given the evidence from Taiwan, trials of booster schedules with disease endpoints could be set up now that in 3-5 years could deliver the strongest evidence on whether boosting was necessary and what the best schedule might be. Such trials would best be done across the range of differing hepatitis B epidemiology, for example, in China, in sub-Saharan Africa, and perhaps in highly exposed populations in Europe or North America such as intravenous drug users. If this is not done, there will continue to be doubt about the implications of measures of immune memory and a danger that costly precautionary booster vaccination will be implemented for lack of evidence. Such a policy has major implications for low-income countries. Vaccine delivery systems are virtually limited to children in the first 2 years of life with only a few countries even attempting to deliver a preschool DPT (diphtheria-pertussis-tetanus) booster. The implementation of an adolescent or young adult program of hepatitis boosters would be a major undertaking because there is currently no mechanism for reaching these people. Attendance at secondary school in many countries is still far from universal, so if this were the location for vaccination there would therefore be a danger of introducing inequalities in health which vaccination programs have done so much to reduce. Mathematical modeling of the potential benefits coupled with careful economic costing would best be undertaken to ensure that this would be a cost-effective approach for countries with many other priorities.