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Hep B Booster Shot Unnecessary: Study
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-- Robert Preidt
FRIDAY, Oct. 14 (HealthDay News) -- A booster shot against hepatitis B may not be necessary because infants and teens who are vaccinated against hepatitis B are protected for 10 years after the vaccination, according to Italian researchers.
Viral hepatitis B is the leading cause of acute and chronic liver disease worldwide. About 2 billion people around the world have been infected with hepatitis B, says the World Health Organization. Currently, 168 countries have universal infant or adolescent hepatitis B vaccination programs.
Until now, it wasn't clear if vaccinated children needed booster shots to sustain their immunity to hepatitis B infection.
Reporting in this week's issue of The Lancet, the researchers studied whether concentrations of antibodies against hepatitis B were still present in 1,212 children and 446 Italian Air Force recruits who received hepatitis B vaccinations as infants and adolescents, respectively.
The study found that 64 percent of the children and 89 percent of the recruits still had protective concentrations of antibodies. The results indicate that infant and adolescents immune systems can recall responding to hepatitis B more than 10 years after immunization.
"In light of our findings, the use of routine booster doses of hepatitis B vaccine does not seem necessary to maintain long-term protection in immunocompetent individuals vaccinated as infants and teenagers," researcher Alessandro Remo Zanetti of the Institute of Virology in Milan, said in a prepared statement.
The Lancet 2005; 366:1379-1384
Long-term immunogenicity of hepatitis B vaccination and policy for booster: an Italian multicentre study
Alessandro Remo Zanetti a , Andrea Mariano b, Luisa Roman˜ a, Raffaele D'Amelio c, Maria Chironna d, Rosa Cristina Coppola e, Mario Cuccia f, Rossana Mangione g, Fosca Marrone h, Francesco Saverio Negrone i, Antonino Parlato j, Emanuela Zamparo k, Carla Zotti l, Tommaso Stroffolini b m and Alfonso Mele b, The Study Group
Summary
Background
Universal anti-hepatitis-B vaccination of infants and adolescents was implemented in Italy in 1991. We undertook a multicentre study in previously vaccinated individuals to assess the duration of immunity and need for booster, over 10 years after vaccination.
Methods
In 1212 children and 446 Italian Air Force recruits vaccinated as infants and adolescents, respectively, we measured the concentrations of antibodies to hepatitis-B surface antigen (anti-HBs) and the presence of antibodies to hepatitis-B core antigen (anti-HBc) at enrolment; postimmunisation values were not available. Individuals positive for anti-HBc were tested for hepatitis B surface antigen (HBsAg) and hepatitis B viral DNA. Individuals with anti-HBs concentrations at 10 IU/L or more were regarded as protected; those with antibody less than 10 IU/L were given a booster dose and retested 2 weeks later. Individuals showing postbooster anti-HBs concentrations of less than 10 IU/L were offered two additional vaccine doses and retested 1 month after the third dose.
Findings
Protective anti-HBs concentrations were retained in 779 (64%, 95% CI 61á6Ð67) children and 398 (89%, 86á4Ð92á1) recruits. We recorded antibody amounts of less than 10 IU/L in 433 children (36%, 33Ð38á4) and 48 (11%, 7á9Ð13á6) recruits. One child and four recruits were positive for anti-HBc, but negative for HBsAg and hepatitis B viral DNA. Antibody concentrations were higher in recruits than in children (geometric mean titre 234á8 IU/L vs 32á1 IU/L, p=0á0001). 332 (97%) of 342 children and 46 (96%) of 48 recruits who received a booster showed an anamnestic response, whereas ten (3%) children and two (4%) recruits remained negative for anti-HBs or had antibody concentrations of less than 10 IU/L. Prebooster and postbooster antibody titres were strongly correlated with each other in both groups. All individuals given two additional vaccine doses (eight children and two recruits) showed anti-HBs amounts of more than 10 IU/L at 1 month after vaccination.
Interpretation
Strong immunological memory persists more than 10 years after immunisation of infants and adolescents with a primary course of vaccination. Booster doses of vaccine do not seem necessary to ensure long-term protection.
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Introduction
Viral hepatitis B is a leading cause of acute and chronic liver disease worldwide, including cirrhosis and hepatocellular carcinoma. WHO estimates that, globally, about 2 billion people have been infected with hepatitis B virus, more than 350 million are chronically infected, and nearly 1 million die every year from acute or chronic sequelae of primary infection of the disease.1,2
Safe and effective vaccines have been available since the early 1980s, offering the opportunity to exert substantial prevention and control of the disease on a global scale.3 For almost a decade, vaccination strategies focused largely on the protection of individuals at increased professional or behavioural risk of exposure to hepatitis B virus.4 The failure of such policies to reduce the incidence of the disease in the general population5 led to the WHO recommendation that all countries should have universal infant or adolescent hepatitis B vaccination (or both) integrated into their national immunisation programmes by 1997.6,7 By the end of 2004, 168 countries implemented these immunisation programmes. Italy was one of the first countries to do so,8,9 and selective immunisation targeted to high-risk groups was implemented in 1983. In 1991, mandatory universal vaccination of infants, hepatitis-B-surface-antigen (HBsAg) screening of pregnant women, and vaccination of 12-year-old adolescents (restricted to the first 12 years of application of the vaccination law) was introduced. As a result of this policy, more than 12 million children had been immunised against hepatitis B (coverage rate of about 95%) by 2003, with an outstanding record of safety and effectiveness.10 By the end of 2003, the first infant cohort vaccinated in 1991 reached the age (12 years) when adolescents' vaccination takes place. In 2004, vaccination of 12-year-old adolescents was stopped, and that of infants was maintained.
A substantial reduction of newly acquired infections of hepatitis B, carrier rate, and hepatitis-B-related mortality has been reported in countries where universal vaccination has been implemented.11Ð17 Long-term protection of 10 years or more seems to occur in children vaccinated during infancy in hyperendemic areas.18Ð22 However, data are scarce for the duration of immunity in vaccinated infants and teenagers in countries at low endemicity,23,24 and needs to be further corroborated. Therefore it is urgent to assess whether vaccinated infants maintain protection until the time when risk of infection (either by lifestyle or professional exposure) may be expected, or whether they need booster vaccination to sustain immunity into adolescence and adulthood.
We undertook an extensive study to assess the anamnestic response to a booster injection of vaccine in children vaccinated as infants and in Italian Air Force recruits vaccinated as adolescents who showed antibodies to hepatitis B surface antigen (anti-HBs) below the protective concentration (10 IU/L) more than 10 years after the primary course of vaccination.
DISCUSSION
This study, designed to determine the duration of immunity and the need for booster vaccinations, showed that more than 60% of children and nearly 90% of recruits maintained anti-HBs amounts that were regarded as protective (? 10 IU/L) more than 10 years after vaccination. We recorded undetectable concentrations in about 9% of children and 4% of recruits and detectable amounts lower than 10 IU/L in 27% and 7%, respectively. However, all recruits and all but six children responded to a booster dose of vaccine. Prebooster and postbooster antibody titres were strongly correlated with each other. Overall, the booster dose elicited a rapid and vigorous anamnestic response. Increase of anti-HBs titres was greater in children and adolescents with preboosting anti-HBs positivity, even if at low amounts (<10 IU/L), than in those with preboosting undetectable antibody.
1 month after receiving a second full course of vaccination, seven of ten vaccinated individuals (including five children who were non-responsive to one booster dose of vaccine, and three children and two recruits who developed antibody amounts less than 10 IU/L) had poor anti-HBs responses with antibody concentrations increased to less than 100 IU/L. We can infer that these vaccinated individuals were hyporesponsive to the immunisation and that their antibodies may rapidly wane over time. However, even in these instances, loss of antibody does not necessarily imply loss of protection, since the long incubation period of hepatitis B virus could allow time for the immunological memory to protect them against acute disease or the development of chronic carriage.
During the past 20 years, the frequency of hepatitis B infection has declined greatly in Italy, as a result of social, behavioural, and demographic changes; the general improvement in standard of living and hygiene; and the introduction of public-health measures including refinement in blood screening, use of universal precautions in medical settings, and implementation of universal vaccination policies.25,26
Evidence shows that in healthy vaccinated individuals, immunological memory for HBsAg may outlast the presence of antibody, providing effective protection even in those showing waning (<10 IU/L) or absent concentrations of anti-HBs after vaccination.29 Hence, booster doses of vaccine may not be necessary to sustain long-term immunity in healthy vaccinated individuals.30
Although this study was not specifically designed to compare the duration of immunity between the two study groups, our findings have indicated that both anti-HBs amounts and percentage of individuals with protective antibody titres were higher in recruits than in children. Previous findings have shown that male sex was associated with extended persistence of anti-HBs.20 However, we could not detect any difference between male and female individuals vaccinated as infants. Hence, the difference between the two vaccinated groups could be attributed to a different response to the primary course of vaccination due to different age and vaccine doses (three paediatric doses vs three adult doses), or to a different degree of exposure to natural boosters, conceivably higher in adolescence than in childhood. Four (nearly 1%) recruits had markers of hepatitis B infection (anti-HBc). Since serological data were not obtained either before or after vaccination, it is impossible to conclude whether these individuals were already infected at the time of vaccination or whether they were infected with hepatitis B virus subsequently.
In conclusion, Italy's programme of hepatitis B vaccination has resulted in substantial progress towards the prevention and control of hepatitis B infection. 12 years after the implementation of universal vaccination of both infants and adolescents, the Italian population under 25 years of age is protected against infection with the hepatitis B virus. The immunisation programme targeting 12-year-old adolescents was withdrawn at the beginning of 2004 since all children at this age are already covered.
The importance of vaccination against hepatitis B in infancy is universally accepted. However, the duration of protection in children born to HBsAg-negative mothers and vaccinated during the first year of life in countries at low or moderate endemicity is not yet clearly established. In other words, will vaccinated babies maintain immunity into adulthood or are additional boosters necessary? Our data provide evidence that a strong immunological memory persists for more than 10 years after immunisation of healthy infants and adolescents with a primary course of hepatitis B vaccination. The selection criteria adopted in this study (random sampling procedure for children) and the wide geographical distribution of both groups ensure the validity and representativity of the observed findings.
The rate of anti-HBs persistence recorded in Italian children and recruits compare favourably with results reported elsewhere.14,15,18Ð22 However, unlike previous studies, our study was undertaken in a lower endemicity country, in which the presence of natural boosters is conceivably scarce, which suggests that the protective effect against hepatitis B infection could be due to the sole administration of vaccine.
In light of our findings, the use of routine booster doses of hepatitis B vaccine does not seem necessary to maintain long-term protection in immunocompetent individuals vaccinated as infants and teenagers. Clearly, this observation is specific to the 10-year checkpoint. Additional follow-up is warranted to establish whether a primary course of vaccination in infancy or adolescence may confer life-long protection or whether boosters may be needed at a later point in life.
RESULTS
Table 1 shows the main characteristics of the two study groups. 64% of the children examined had protective concentrations of anti-HBs (?10 IU/L) over 10 years after the primary course of vaccination, including one child who was positive for anti-HBc but negative for HBsAg and hepatitis B viral DNA (table 2). 27% of children had antibody titres of less than 10 IU/L, and 9% had undetectable amounts. Of the 446 recruits, 89% had protective concentrations of antibodies (including four individuals who tested positive for anti-HBc but negative for HBsAg and hepatitis B viral DNA), 7% had anti-HBs concentrations less than 10 IU/L, and 4% had undetectable antibodies. Antibody concentrations were significantly higher in recruits than in children (geometric mean titre 234á8 IU/L vs 32á1 IU/L, p=0á0001).
Socioeconomic factors such as residential location, family size, fathers' level of education, year of initial vaccination, and sex (in the children group) did not affect the probability of protective antibody concentrations in either group (data not shown).
We gave a booster dose of vaccine to the 342 (79%) children and all 48 recruits who had anti-HBs concentrations that were lower than 10 IU/L or were undetectable at enrolment. The proportion of children who refused the booster vaccination did not differ significantly between those with undetectable concentrations and those with concentrations less than 10 IU/L (18 [17%] of 106 vs 73 [22%] of 327, p=0á241).
2 weeks after the booster was given, ten children (3%, 95% CI 1á1Ð4á7) still had antibody concentrations of less than 10 IU/L (including six with undetectable amounts), whereas the remaining 332 (97%, 95á3Ð98á9) showed an anamnestic increase in concentration (table 3). Anti-HBs titres after booster were higher in children whose prebooster antibody was positive (but less than 10 IU/L) than in those with undetectable prebooster antibody (table 3, p=0á0001).
46 of 48 recruits (96%, 90á2Ð100) showed a postbooster increase of anti-HBs to more than 10 IU/L (table 4). The remaining two recruits (4%, 0Ð9á8) who were initially antibody-negative seroconverted to anti-HBs but had concentrations less than 10 IU/L. Similar to our findings in children, antibody amounts were higher in those with prebooster anti-HBs positivity of less than 10 IU/L than in those with undetectable prebooster antibody (table 4, p=0á0001).
Ten children and two recruits who had postbooster anti-HBs concentrations of less than 10 IU/L were offered to complete a second course of vaccination with two additional vaccine doses given at 1 and 6 months after the first booster injection. Eight of these ten children (including five of the six who remained anti-HBs-negative at the postbooster check) and both recruits accepted. All vaccinated individuals presented antibody concentrations of more than 10 IU/L at 1 month after the third immunisation (table 5). In particular, the five children who did not respond to the first booster injection (Child 1 to Child 5) showed a poor rise in antibody titres (median 61á6 IU/L, IQR 24Ð96á2 IU/L) after the second course of vaccination was completed. After the third vaccination dose, two children (Child 6 and Child 7) had antibody amounts of more than 100 IU/L, whereas the remaining child (Child 8) and both recruits had increased antibody concentrations to values less than 100 IU/L.
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