Long-term Protection After Hepatitis B Vaccine

(See the major article by Bruce et al on pages 16–22.) Hepatitis B virus (HBV) infection is highly prevalent around the globe. An estimated 3.6% of the world's population (or 248 million persons) are positive for hepatitis B surface antigen (HBsAg) [1], and HBV causes significant morbidity and mortality. In 2013, approximately 686 000 HBV-infected persons died from causes related to acute infection (69 000 deaths), cirrhosis (317 000 deaths), and HBV-associated liver cancer (300 000 deaths) [2]. The age of acquisition of HBV infection is the main determining factor in the clinical expression of acute disease and the development of chronic infection. Genetic characteristics of HBV might also contribute to the outcome of infection [3, 4]. Safe and effective hepatitis B vaccines have been commercially available since 1982, and, over the years, recombinant DNA vaccines have replaced plasma-derived vaccines. Gaps in hepatitis B vaccination policy were first addressed in 1992, when the World Health Organization called for all countries to incorporate hepatitis B vaccination into their national childhood immunization services. In the following decade, hepatitis B vaccination coverage grew rapidly, and by the end of 2014, 184 countries had integrated hepatitis B vaccine into their national childhood immunization systems, and the global coverage with 3 doses of hepatitis B vaccines was estimated at 82% [5]. Elimination of HBV transmission is an achievable public health goal, particularly in light of the proven effectiveness and safety of hepatitis B vaccine. In general, studies conducted in areas with high HBV endemicity have demonstrated declines in the prevalence of chronic HBV among children to <2% after routine infant immunization [6]. After several decades of hepatitis B vaccination, the duration of protection is still unknown, and the question whether a booster dose is ever needed continues to challenge us. In fact, the hepatitis B vaccine was the first vaccine for which long-term protection was rigorously studied; this was perhaps because of the originally higher cost compared with other infant vaccines or—at least in industrialized countries—owing to the implementation at a younger age although risk exposure would start in adolescence or adulthood. Today, equal attention is given to long-term protection induced by other vaccines, not the least for HPV vaccines. An antibody to hepatitis B surface antigen (anti-HBs) concentration of ≥10 mIU/mL measured 1–3 months after administration of the last dose of the initial vaccination series is considered a reliable marker of protection against infection [7]. After primary hepatitis B immunization, anti-HBs concentrations decline rapidly within the first year and more slowly thereafter: among children who respond to a primary 3-dose vaccination series with anti-HBs concentrations of ≥10 mIU/mL, 15%–50% have low or undetectable concentrations of anti-HBs 5–15 years after vaccination; among adult vaccinees, anti-HBs concentrations decline to <10 mIU/mL in 7%–50% within 5 years after vaccination and in 30%–60% within 9–11 years [8]. The persistence of anti-HBs over time is correlated with the peak level of anti-HBs immediately achieved after primary immunization [9]. In other words, the higher the vaccine-induced anti-HBs concentration after the primary vaccination course, the longer the antibodies will persist. The issue of duration of protection can be addressed, as documented in by Bruce et al [10] in this issue of The Journal of Infectious Diseases, by long-term follow-up studies of immunized cohorts who continue to be exposed to HBV and by exploring anamnestic responses to HBsAg through challenge. Several observational studies have shown that a primary hepatitis B vaccination series can prevent infection for >20 years, despite decrease or loss of vaccine-induced anti-HBs over time [11–16]. Bruce et al [10] present for the first time results of a 30-year follow-up study and response to a booster dose in an Alaskan Native population. It is the longest cohort study on extended protection after hepatitis B vaccination to date. Their unique data add a new piece of evidence to the puzzle of long-term immunity: no significant breakthrough infections were diagnosed in the vaccinees during the 30-year period, and 51% (125 of 243) still had anti-HBs levels ≥10 mIU/mL 30 years after initial vaccine administration [10]. Initial anti-HBs level and age at vaccination seemed to play an important role in the persistence of antibodies. These results are similar to findings of other cohort studies in other parts of the world carried out through 20–25 years of follow-up [11–16]. Indeed, in immunocompetent individuals, the specific immunity to HBsAg outlasts the presence of vaccine-induced antibodies, conferring effective long-term protection against acute disease and development of HBsAg carriage, even in those showing waning or disappearing anti-HBs [17–18]. Thus, a negative anti-HBs result does not necessarily indicate lack of immunity in vaccinated persons; it is immune memory that matters [8]. The mechanism for continued vaccine-induced protection is thought to be preservation of immune memory through selective expansion and differentiation of clones of antigen-specific B and T lymphocytes [19]. To illustrate the prolonged duration of protection and immune memory against hepatitis B, Bruce and colleagues [10] offered participants with anti-HBs levels <10 mIU/mL a challenge hepatitis B vaccine dose 30 years after primary vaccination. An anamnestic response of 88% was measured 30 days after challenge. These results confirm and expand on earlier findings showing anamnestic responses of 62% to >90% among subjects vaccinated 15–23 years earlier, indicating that a high proportion of vaccine recipients retain immune memory and would develop an anti-HBs response on exposure to HBV [8]. There is, however, recent evidence suggesting that the immune memory may begin to wane after the second decade of vaccination, but this does not seem to imply increased susceptibility to clinically significant HBV disease. Absence of an anamnestic response after such challenge vaccination may not necessarily mean that individuals are susceptible to HBV infection, but further research is needed in this field. Some long-term follow-up studies have documented breakthrough HBV infections, illustrated by seroconversion to anti-HBc but, in this recent Alaskan study [10], virtually no clinical significant infections (acute diseases or carriage) were reported [8]. From a public health point of view, prevention of viral carriage remains of utmost importance; the hepatitis B vaccination program in Alaska is among the earliest and shows excellent efficacy in reducing rates of chronic HBV infection and hepatocellular carcinoma [20]. In a recent evaluation of the hepatitis B universal infant immunization program in the Gambia, 94% vaccine effectiveness was observed in fully vaccinated infants. Many of these fully vaccinated individuals had at some time been infected and experienced a nonsignificant breakthrough infection (anti-HBc positivity, 27%); chronic active hepatitis was not common and was probably a consequence of perinatal infection from the mother. The study concluded that full infant HBV vaccination protects strongly against chronic HBV infection but less strongly against ever having HBV infection [21]. Immunity against HBV provides protection against infection as well as against disease. Protection against infection is associated with presence of antibody, which is directly related to the peak concentration of anti-HBs after primary vaccination. Protection against disease is associated with immune memory, which persists beyond the time when anti-HBs disappears. The question that is nearly as old as hepatitis B vaccine itself—how long will immune memory last?—remains to be answered, but the current Alaskan study shows 30 years after initial vaccination that specific immune memory can outlast the persistence of vaccine-induced antibodies. The data presented by Bruce et al confirm statements from the World Health Organization, Centers for Disease Control and Prevention, and Viral Hepatitis Prevention Board that booster vaccination against hepatitis B for immunocompetent children and adults is not recommended [22–24]. The absence of anamnestic response requires further understanding, and long-term follow-up studies are still needed to show how long immune memory persists and whether, when and at what age booster doses may be needed to guarantee continued protection. Financial support. P. V. D. acts as investigator for vaccine trials conducted on behalf of the University of Antwerp, for which the university obtains research grants. Potential conflict of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.