Box 2 Risk factors associated with poor antiHBs response to hepatitis B vaccine

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Immunocompromised from chronic disease nonresponders mounted an appreciable anti-HBs titer. When nine of the 12 refractory nonresponders were sampled, six of them carried at least one of two extended major histocompatibility complex (MHC) HLA haplotypes B44-DR7-FC31 or B8-DR3-SC01. In contrast, only two of the 11 revaccinees sampled who responded to the second vaccine series carried these haplotypes, suggesting a genetic contribution to immuno-genicity [52]. In a large series of nearly 600 subjects who received a full course of hepatitis B vaccine, an analysis of HLA haplotypes among the 20 vaccinees with the lowest anti-HBs titer responses indicated a disproportionately higher number of HLA-B8-DR3-SC01 [53]. When nine of the haplotype carriers were given three additional doses of vaccine, four of the five homozygotes but none of the nine heterozygotes remained hyporesponders. These findings implicate a recessive MHC-linked trait as a cause of hyporesponse to hepatitis B vaccination [53].

Efficacy of hepatitis B vaccines

Seroprotective rate up to 95% or above has been demonstrated in multiple placebo-controlled, randomized double-blind trials involving health care workers [29] and homosexual males [54-56]. This is defined as percentage of vacinees achieving an anti-HBs titer > 10 mlU/mL. Infection rates in reported studies were <4% among the vaccinees, in contrast with rates of 10% to 27% in the placebo arms. A significant reduction of hepatitis B cases within 75 days after randomization of subjects suggested the effectiveness of vaccine even when given shortly after exposure to the virus [55].

Patients who develop seroprotective titers will continue to maintain high levels of protection from clinical disease for at least a decade. In a large cohort of Yupik Eskimos who had a 94% rate of anti-HBs seroconversion, 76% maintained titers > 10 mlU/mL after 10 years of follow-up. None became chronically infected despite development of anti-HBc in 10 vaccine re-sponders, implicating subclinical exposure to HBV among vaccinees with durable protection against the virus [57,58]. Long-term follow-up in similar series have noted boosts in anti-HBs titers despite no interim booster vaccine injection, probably attributable to immunologic protection against viral exposure [59]. The maximal anti-HBs response postvaccination is strongly predictive of titer persistence and inversely correlated with the risk of viral infection, as demonstrated by a longitudinal follow-up of nearly 800 homosexual males for 5 years after vaccination [60].

A two-dose vaccine regimen over a 6-month period may suffice in producing a comparable long-term protection against HBV in immunocompetent hosts. In a group of young healthy adults who received Recombivax HB doses of 10 mcg or 20 mcg, anti-HBs seroconversion rates of 46% to 67% were observed after the first dose, but increased to 97% to 99% after the second dose with booster responses in GMT. Furthermore, a sizable proportion (75% to 89%) of vaccinees maintained titers > 10 mlU/mL 2 years after the regimen was given, with 79% to 87% demonstrating rapid and vigorous anamnestic response after another booster dose [61]. Nevertheless, if immediate short-term immunologic protection is also desired, a three-dose regimen remains the preferred choice for individuals who are at high risk for infection during the initial 6-month period.

A few investigators have reported that the interval between the second and third vaccine doses is important in determining the ultimate anti-HBs titer. The CDC observed a significant rise in anti-HBs titers in those who received the third vaccine dose late (>7 months after the first dose) among the 1000 Yucpa Indian vaccinees [46]. Similar conclusion was drawn by an interesting study comparing the efficacies of three vaccine regimens, given at 0,1,2, 12 months; 0, 1, 6 months; and 0, 1, 12 months [62]. Booster anti-HBs responses were seen after the third dose for each of the last two regimens but were not observed until after the fourth dose in the first regimen. Furthermore, the ultimate titers achieved by the first and third regimens were comparable but 20 fold higher than that achieved by the second regimen with the third and last dose administered at 6 months. Hence, the anti-HBs response after a typical three-dose hepatitis B vaccine series depends on the time interval between the last two doses [62].

Anti-HBs seroconversion is appreciably lower with vaccination of immuno-compromised patients, such as those on hemodialysis, despite early reports of excellent results [63]. Suboptimal results with intramuscular double-dosing regimen prompt continued search for better solution. In a randomized double-blind placebo-controlled trial of double-dosed hepatitis B vaccine, only 63% of hemodialysis patients developed adequate antibody response [64]. This figure, however, decreased to 50% after correction for possible transfer of antibodies by blood transfusion. When compared with the placebo arm, there was no significant reduction in HBV infection within the first two years among the vaccinees (6.4% versus 5.4%) [64]. Similarly, the seroconversion rate with immunizing cirrhotic patients awaiting liver transplantation was dismal. Vaccinating these patients with standard doses produced seroconversion rate of 28%, compared with 97% achieved by healthy controls [65]. Even when a double dose was given to cirrhotic patients, the seroconversion rate was 44% and increased to only 62% with a repeat series [66].

Perinatal immunoprophylaxis with hepatitis B vaccine is now routinely given to newborn infants, with an additional early dose of HBIG for those who are born to HBV-infected mothers. The use of HBIG alone does not provide long-term protection against the infection [16]. The vaccine series should be initiated within the first 12 hours after birth for neonates born to HBsAg-positive mothers but may be administered by a relatively flexible schedule to those born to HBsAg-negative women [67]. With immunization, more than 95% of babies develop anti-HBs titer > 10 mlU/mL [68,69]. Vaccinated infants of HBsAg-positive mothers should then be tested for HBV status at 12 months of age. Without immunization, >90% would be chronically infected due to vertical transmission of HBV [7]. As for adult vaccinees, hepatitis B vaccine affords long-term protection for most infants when initiated soon after birth [16,70], Even if children lose detectable anti-HBs later on in life, which occurs in up to half of individuals, a booster vaccine injection will almost always lead to a robust anam-nestic response and resurgence of anti-HBs [71-73].

A delay in the initial dose of vaccine increases the risk to the child for HBV infection [74], In addition, infants may fail immunoprophylaxis due to in utero infection, genetically determined nonresponsiveness, or vaccine-breakthough mutations in mother or in infants [5]. In utero infection of the fetus is relatively uncommon [75] but may result from placental leakage [76,77]. Vaccine-breakthrough mutations are attributable to immune pressure from either hepatitis B vaccine or HBIG [78] and may involve point substitution from glycine to argi-nine at codon 145 (G145R), asparagine to threonine at codon 126 (N126T), or asparagine to isoleucine substitution at codon 126 (N1261) in the S gene [79], plus many others that were discovered subsequently [80]. In general, the S gene mutation causes decreased binding of anti-HBs to determinant "a," thus allowing the mutant virus to escape neutralization [2].

The global impact of hepatitis B vaccination, including a decreased prevalence of chronic infection and associated complications, is clearly demonstrated in recent studies. In July 1984, Taiwan became the first country to launch a universal newborn hepatitis B vaccination program. Over the subsequent 15 years, a serologic survey of the prevalence of HBsAg among youngsters of ages 15 years or less demonstrated a significant reduction from 9.8% to 0.7%. In addition, seropositivity for anti-HBc, which reflects HBV infection and not vaccination, dropped from 20.6% to 2.9% [81]. A retrospective review in 1997 showed a significant decline in the average annual incidence of HCC per 100,000 children of ages 6 to 14 years, with 0.70 between 1981 and 1986, 0.57 between 1986 and 1990, and 0.36 between 1990 and 1994 [82]. Furthermore, the incidence of HCC in children of ages 6 to 9 declined per 100,000 from 0.52 for those who were born between 1974 and 1984 to 0.13 for those who were born between 1984 and 1986 [82]. On the other hand, the prevalence of S gene mutations among HBsAg-positive children has been increasing, from 7.8% in 1984 immediately before implementation of the universal vaccination program, to 19.6% in 1989 and 28.1% in 1994 [83]. It was not until 1991 in the United States that the ACIP recommended universal hepatitis B vaccination of all infants [6]. Shortly afterward the American Academy of Pediatrics and the American Academy of Family Physicians published similar recommendations. Nevertheless, in 1999 the proportion of children <3 years of age who were immunized against HBV had not yet reached the target of 90% as originally proposed by the Childhood Immunization Initiative [84].

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