|Year : 2005 | Volume
| Issue : 1 | Page : 56-73
|Hepatitis B immunization: Is a booster necessary?
Chun-Yi Lu1, Mei-Hwei Chang2
1 Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
2 Department of Pediatrics, National Taiwan University Hospital, No. 7, Chung-Shan South Road,Taipei, Taiwan
Click here for correspondence address and email
|How to cite this article:|
Lu CY, Chang MH. Hepatitis B immunization: Is a booster necessary?. Hep B Annual 2005;2:56-73
| Introduction|| |
In 1992, the World Health Assembly endorsed the recommendation issued by the Global Advisory Group of EPI (Expanded Programme on Immunization) that hepatitis B virus (HBV) vaccine be integrated into national immunization programs for countries with a hepatitis B carrier prevalence of 8% or greater by 1995 and in all countries by 1997. Tremendous progress has been made thereafter. The proportions of WHO member states having universal infant or childhood hepatitis B vaccination program were 126 (66%) of 191 in 2001 and 151 (79%) of 192 in 2003. An estimated 32% of children aged <1 year around the world were vaccinated fully with the 3-dose hepatitis B vaccination series in 2001.
Neonatal HBV vaccine has been proved to be highly effective in inducing protective anitibodies and preventing perinatal HBV transmissions.,, The prevalences of chronic HBV infections, fulminant hepatitis B, and hepatocellular carcinoma have all been shown to decrease significantly after mass HBV vaccination.,, HBV vaccine-induced hepatitis B surface antibody (anti-HBs) titers declined with time. Long-term protection against clinically significant breakthrough HBV virus infection and chronic carriage depends on immunological memory, which appears to last at least 10-15 years in immunocompetent individuals who respond adequately to the primary vaccination. However, instances of late infection, occasionally resulting in HBV carriage, were documented in some long-term follow-up studies.,, Currently, booster vaccination is not recommended for immunocompetent subjects up to 15 years after neonatal vaccination., Nonetheless, several countries and individuals currently have a policy of administering booster doses to certain risk groups. The real duration of protection conferred by HBV vaccination remained uncertain. The necessity of booster vaccination for HBV has been a subject of much debate.
Antibody response and efficacy of neonatal HBV vaccination
Typically, a neonatal HBV vaccination program consists of three to four doses. The primary series consisted of two doses given at intervals of about one month, with the first dose given right after birth. A booster dose was given approximately 6-12 months after the first. The first two or three doses prime the immune system, the last dose stimulates a secondary response, resulting in high anti-HBs titers. Several studies have shown that vaccine induced anti-HBs is protective at a serum concentration of 10 mIU/ml.
Typical antibody response was demonstrated by an early study, which demonstrated that the first dose (20-microrgram) of HBV vaccine stimulated the production of anti-HBs (>10 mIU/mL) within one month in 48% of the neonates. Anti-HBs was detectable in the serum of 91% of the vaccinees two months after the second dose. By the age of six months, 96% of vaccinees had detectable anti-HBs in their serum. All vaccinees developed anti-HBs one month after a third dose was administered at the age of seven months. A fair number of studies have shown similar results - that neonatal HBV vaccination program, composed of either plasma-derived or recombinant, are adequate in eliciting protective (>10 mIU/mL) anti-HBs antibodies in approximately 90 to 100% of the vaccinees.,, Except for very few non-responders, adequate immunogenicity was observed in the great majority of HBV vaccinees. Slight differences may exist between various products of HBV vaccines.
The protective efficacies of HBV vaccines are also well established. Without vaccination, an overall carrier rate in excess of 70% is expected in infants born to HBV carrier mothers., For infants born to HBeAg positive HBV carrier mothers, the carrier rate is even higher than 90% if no prophylactic measure is given., Early efficacy studies have shown that HBV vaccine had an overall 74-86% efficacy in preventing perinatal transmission of HBV.,,,, For example, in an early report from Taiwan, where HBsAg carrier rate in the general population was 15-20% at that time, the efficacy of HBV vaccine in preventing perinatal transmission in high risk infants was about 74%. Higher protection efficacies have also been reported. A study conducted in Thailand showed only 2 (3.6%) of the 55 vaccinated high-risk infants of women with positive HBsAg and HBeAg became chronically infected by the HBV at the age of 13 months, suggesting a protective efficacy of higher than 90%. Adding HBIG after birth increased the protective efficacy of HBV vaccine to greater than 90%.,,,
A successful story of universal HBV vaccination from Taiwan,,
Before the national hepatitis B vaccination program was implemented, HBV infection was highly endemic in Taiwan. In 1980, over 90% of the general population under the age of 40 years had serological evidence of HBV infection. About 15 to 20% of them were chronically infected by the virus. Perinatal mother-to-infant transmission was the main route of HBV transmission in Taiwan. Newborn babies contracting the infection in the perinatal period would have a 90% chance to become a chronic carrier. In 1981, a large scale follow-up study in Taiwan further showed that chronic HBV carriers had a 273-fold increased risk of getting hepatocellular carcinoma compared with non-carriers.
To combat HBV infection in Taiwan, a mass vaccination program was launched on July 1, 1984, aiming primarily at preventing chronic HBV carriage from perinatal transmission. In the initial two years, only infants born to HBsAg carrier mothers were vaccinated. The program was expanded to cover all newborn infants from 1986. In the first eight years, the infants were vaccinated with plasma-derived vaccines at 0, 1, 2, 12 months of ages. Newborns of highly infectious carrier mothers, which was defined by presence of HBeAg or high titers of anti-HBs (1:2560 or higher), were also given 100 IU of HBIG at birth. Plasma-derived vaccine was replaced later by recombinant yeast vaccine with a three-dose regimen at ages 0, 1, 6 months.
Vaccination coverage rates in infants were 92 to 98% for different doses. The program has reduced perinatal transmission rates from 86-96% to 12-14% in babies born to highly infectious HBsAg carrier mothers and from 10-12% to 2-4% in babies of less infectious carrier mothers. The protective efficacy was estimated to be about 85%. The overall prevalence rate of hepatitis B surface antigenemia decreased from 9.8% in 1984 to 1.3% in 1994 in children younger than 12 years of age. The overall prevalence rate of hepatitis B core antibody was 26% in 1984, 15% in 1989, and 4% in 1994.
HBV vaccination not only protected infants from becoming HBV carriers, it also prevented complications of HBV infections. Since the institution of a program of universal hepatitis B vaccination in Taiwan, the mortality associated with fulminant hepatitis in infants has declined significantly and the incidence of hepatocellular carcinoma has been reduced in children, especially in boys. HBV vaccine has been proved, for the first time in human medical history, to be effective in preventing a malignant disease. Twenty years have lapsed after implementation of the universal HB vaccination program in Taiwan. The reliability of the long-term protection conferred by HBV vaccines is one of the key points in maintaining the achievement of HBV control in Taiwan. Currently, no routine booster vaccination is recommended for immunocompetent subjects in Taiwan.
Decline of anti-HBs titers after HB vaccination
Declining of anti-HBs titers with time after the primary vaccination is the rule. The geometric mean titers of serum anti-HBs antigen rapidly decreased during the first few years. However, studies have shown that the anti-HBs titers remained protective 2 to 4 years, or even 10 years after the primary vaccination in virtually all infants who had responded to the primary course of vaccination.
It is not uncommon to see anti-HBs levels decline to low or undetectable levels during follow-up.,,, In follow-up studies conducted in Taiwan, where HBV was highly endemic, the overall seropositive rate of anti-HBs dropped from 99% at 1 year of age to 83% at 5 years of age. The percentage of protective anti-HBs in 951 children without booster vaccination gradually decreased from 71.1% at age 7 years to 37.4% at age 12 years. Most follow-up studies showed similar pattern of antibody decline. However some studies showed higher percentages of children losing their anti-HBs. In a study done in Alaska, 88% (182 of 208) of children who were vaccinated with recombinant hepatitis B vaccine after birth lost their anti-HBs at the age of 5 years.
Immune memory and the question of booster
Even if the anti-HBs levels waned with time to non-protective or undetectable levels, evidence showed that the protection was still maintained among vaccinees. This mainly depends on immunologic memory, which allows a protective anamnestic antibody response to HBsAg challenge. Numerous studies have shown anamnestic antibody responses to booster doses in vaccinees up to 15 years post neonatal vaccination, even when they have lost their circulating antibodies.,,,
In addition to the anamnestic anti-HBs responses, persistence of B-cell memory has also been proved by an in vitro enzyme-linked immunospot assay (ELISPOT). In Netherlands, a study of hospital employees who were followed up for up to 15 years revealed that although 30% had no detectable anti-HBs, all had B-cell memory documented either by anamnestic antibody response or positive ELISPOT results. These data suggest that immune memory for HBV lasts for at least 15 years after HBV vaccination.
However, some doubts regarding this aspect emerged when the evidence was further dissected. Anamnestic antibody responses to HBV boosters were actually demonstrated in the majority, but not all the HBV vaccinees. It is not unusual to see a small proportion of vaccinees having no detectable antibody response to HBV vaccine booster years after the primary vaccination. In the previously-mentioned follow-up study done in Alaska, among those who had responded initially to HBV vaccination in infancy and did not have protective antibody titers at the age of 13 years, 33% (4 of 12) did not respond to a booster dose. In another long-term follow up study of 78 children whose initial antibody response to neonatal HB vaccination had been documented in infancy, two children had no antibody response to a booster dose of HBV vaccine at the age of 15 years.
The final end point of evaluating the efficacy of HBV vaccines should be the percentage of vaccinees getting clinically significant HBV infection and chronic carriage of HBV. Presence of anti-HBc provides evidence for natural infections in vaccinees. Most of the follow-up series revealed that no subject had clinically significant HBV infection or became chronic carrier of HBV even though natural infections in vaccinees did occur. During 5 to 10 years period after the neonatal vaccination, subclinical infections revealed by the presence of anti-HBc occurred in 1-9% of subjects, but none developed clinical infection or a persistent HBsAg carrier state. Even though natural infections kept on occurring around 10-15 years after the primary immunization, protection against chronic infections with hepatitis B virus was maintained. Subclinical HBV infections among individuals who have been previously vaccinated left no sequelae associated with chronic HBV infection. Subclinical HBV infections might even act as natural boosters to enhance immunity to future HBV infections in vaccinees.
Taken together, the above mentioned data provided evidence that loss of detectable circulating antibodies did not necessarily result in lost of protection against clinically significant HBV infection. The majority of vaccinees reacted to HBV infections by rapid antibody response, which effectively prevented clinically significant HBV infections and chronic carriage of the virus. Booster vaccination before 15 years postvaccination is thus not recommended by most authorities.
Nevertheless, exceptions have been reported. In a report from Netherlands, a child who had responded to HBV vaccination with a peak anti-HBs of 50-60 mIU/mL at the age of about 1 year, lost protective anti-HBs at 2 years of age and became a HBsAg carrier in the fifth year of follow-up. In the long-term follow-up study from Taiwan, a cohort of 78 children, whose postvaccination anti-HBs had been documented right after the neonatal vaccination, was followed up to 15 years of age. These children were born to HBsAg and HBeAg doubly positive mothers. One-third (26/78) of them had evidence of natural HBV infections (having positive ant-HBc) at the age of 15 years. One child became HBsAg carrier at the age of 15 years. In that unusual case, infection by escape mutants was ruled out.
These results reveal evidence arguing that protection provided by HBV vaccine might not be as reliable as generally believed. Even if boosters are unnecessary in the first 15 years after the neonatal HB vaccination, as the vaccinees get older, the immunity may decay to a level at which breakthrough infections can take place. The real duration of protection conferred by HBV vaccination in infancy remained uncertain. Furthermore, as children grow up into their teen ages and engage in sexual activities, the chance of getting HBV infection increases. The importance of maintaining a reliable immunity to HBV is crucial in the control of HBV infections. From the perspective of public health, if a booster vaccination program is to be implemented, it is imperative to set booster vaccination at an age when all the children are still easily accessible and one-dose regimen is effective in inducing a protective antibody. Therefore, a booster HB vaccine given to high school students who are at the age of about 15 years is an option worth consideration. Yet, evidence needs to be provided to prove its benefit. Rapid decline of anti-HBs titer after boosting in those who tend to lose their anti-HBs is another concern.
Factors affecting anti-HBs persistence
Different regimen, dosing or timing of the primary vaccination might also influence the persistence of the anti-HBs titer. As a general concept, higher vaccine antigen dose is related to a more vigorous initial T-cell response and consequently influences the strength of the anamnestic response and immune memory. A meta-analysis showed that the seroprotection rates of two recombinant HBV vaccines differed slightly (95.8% vs 88.5% in infants less than 1 year of age). This difference probably resulted from the differences in the quantities of HBsAg contained in the vaccines rather than the difference in quality of the vaccines. Some recombinant HBV vaccines for infants contain 10 micro-grams of recombinant HBsAg, while the others contain 5 micro-grams only. Besides, there is less long-term immunogenicity associated with the 2-dose regimen when compared with the 3-dose regimens of HBV vaccination. In another study, it was found that after 5 years of follow-up, the group that started active immunization at birth had significantly more infants with loss of protective anti-HBs than the corresponding group starting at 3 months of age. Vaccinees achieving a higher concentration of antibody will retain circulating antibodies for a longer period of time,, and infants who receive the vaccine alone reach significantly higher anti-HBs titers than those who are also given HBIG.,,, In a long-term follow-up study, most children who did not demonstrate immune memory had been given HBIG at birth, suggesting that passive antibody may interfere with the induction of immunological memory. Higher maternal HBV loads might be a confounding factor because most of the newborns who had received HBIG were born to mothers with positive HBeAg.
The first HBV vaccine was licensed in 1981 and was plasma-derived. Nowadays, plasma-derived HB vaccines have mostly been replaced by recombinant ones which were introduced in 1986. Qualitative differences may exist between plasma-derived and recombinant HB vaccines. The post-vaccination geometric mean titres in children who received 10-micrograms plasma-derived vaccine (179.55 mIU/ml) was significantly higher than those in children who received 5-micrograms recombinant vaccine (42.2 mIU/ml), but the anti-HBs titre was still above protective level (10 mIU/ml) in most of the infants. However, there were no differences in geometric mean titer of anti-HBs and the proportion having protective anti-HBs titers during a 18 years follow-up between the subjects receiving the 3-dose recombinant and the subjects receiving the 3-dose plasma-derived vaccines.
The usefulness of HBV booster vaccination
A few studies on the effects of HBV booster vaccinations have been done. At the end of the 9-12 years period of follow-up, anti-HBs were detected in 81% of children who received a booster dose at school age and in 68% of those who did not. No difference in antibody responses to boosters was present at the 10th year between the group of children who had received the booster dose at 5 years of age and the group who did not. No chronic carrier was found in the vaccinees, no matter whether they were boosted or not. Boosters did increase the proportion of children with protective antibodies. However, those children without detectable antibodies very likely retained immune memory for HBV. The long-term protection against HBsAg carriage by HBV vaccination was already adequate enough, so that the additional benefit of a booster dose at school age was minimal.
However, it is important to emphasize that these studies were done no later than 10-12 years after primary vaccination. The value of a booster vaccination depends on the degree to which the immune memory in vaccinees will decay. Additional protection conferred by a booster dose may be critical if the immune memory is eventually lost with time. A prospective, large-scale, long-term follow-up study is needed to elucidate this issue.
Current recommendations [Table - 1]
Currently most authorities recommend not boosting HBV vaccinees 9-15 years after the neonatal immunization. In the recommendations issued by US Immunization Practices Advisory Committee in 1991, it is stated: "For children and adults whose immune status is normal, booster doses of vaccine are not recommended, nor is serologic testing to assess antibody levels necessary." This recommendation was based on the data from vaccinees 9 years after the primary vaccination. They stated "the possible need for booster doses will be assessed as additional information becomes available", and actually 14 years have lapsed after that recommendation was published.
However, for certain high-risk groups, they do recommend boosters. For instance, they recommend booster vaccinations for hemodialysis patients when their antiHBs antibody levels are less than 10 mIU/mL. For hemodialysis patients, vaccine-induced protection may be less complete and may persist only as long as antibody levels are not less than 10 mIU/mL. They further pointed out that antibody levels should be assessed annually for these patients. A booster dose should be administered when antibody levels decline to <10 mIU/mL.
Similarly, the European Consensus Group on Hepatitis B Immunity do not recommend booster vaccination for HBV because there was no data supporting boosters in immunocompetent individuals responding to a primary course. Again, the recommendations do not apply to immunocompromised persons, e.g., patients requiring hemodialysis and those who are infected with HIV.
Local HBV endemicity should be taken into account when considering booster vaccination for HBV. High endemicity, such as that in most Asian countries, results in an increased risk of getting infected by the virus. With this concern, the Steering Committee for the Prevention and Control of Infectious Diseases in Asia has made a more conservative recommendation that whether to boost 10 years after primary vaccination should be judged by physicians on a case-by-case basis. The committee has put forward guidelines for physicians in highly endemic areas who choose to administer HBV vaccine booster: timing booster administration at approximately 10-15 years after primary vaccination. It recommended boosting rather than not when monitoring antibody levels is not feasible. They also recommended boosting immunocompromised patients when anti-HBs is below 10 mIU/ml, but not healthcare workers when the local endemicity is high.
| Conclusions|| |
Efficacy of HBV vaccination has been well-established. In fact, prevention of HBV infections and its complications by universal HBV vaccination is one of the most remarkable achievements in the medical history. Anti-HBs antibodies wane with time after the vaccination in infancy. Due to the presence of anamnestic antibody responses to boosters 10-15 years after vaccinations given in infancy, it is generally believed that routine booster doses are not required before 15 years of age,,, at least in immunocompetent subjects. Boosters may be used to enhance immune memory and provide reassurance of protective immunity against breakthrough infection. For immunocompromised patients, regular testing for anti-HBs and a booster injection when the titer falls below 10 mIU/mL are advised.,, Theoretically, booster vaccination, especially for vaccinees who have lost their anti-HBs, should also be considered for selected high-risk groups such as persons living in or traveling to highly endemic areas, vaccinees whose response to primary vaccination is weak, persons with occupational risk, household contacts and sex partners of HBV carriers. However, to date, sufficient data is not available to formally recommend so. As the vaccinees get older, the immune memory conferred by the HBV vaccine may decay further. The question of whether booster doses are eventually needed to maintain protection through adulthood demands further studies.
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Department of Pediatrics, National Taiwan University Hospital, No. 7, Chung-Shan South Road,Taipei
Source of Support: None, Conflict of Interest: None
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