倍尔来福TM甲、乙型肝炎联合疫苗安全性和免疫原性研究

目的 观察倍尔来福~(TM)甲、乙型肝炎(甲、乙肝)联合疫苗的安全性和免疫原性。方法以高中一年级(成人组)和小学1～5年级(儿童组)学生为研究对象,按对甲、乙肝病毒均易感、只对甲肝病毒易感和只对乙肝病毒易感分为AB组、A组和B组,按0、1和6个月三剂程序分别接种甲、乙肝联合疫苗、灭活甲肝疫苗和重组乙肝疫苗。疫苗剂量成人组每剂含甲肝病毒抗原500U和(或)HBsAg10μg,儿童组减半。疫苗接种后72h内观察副反应,免疫后2、7个月采集血清标本检测抗-HAV和抗-HBs。结果 儿童AB组和成人AB组局部副反应发生率分别为0.58％(2/344)和2.56％(8/312),全身副反应发生率分别为9.88％(34/344)和5.45％(17/212),与对照组相比差异无显著性。局部反应主要是轻度疼痛,全身反应主要是低热。免疫后7个月,两组抗-HAV阳转率均为100％,与A组相同;抗体滴度(GMT)分别为33 910mIU/ml和23 435 mIU/ml,显著高于A组;两组抗-HBs阳转率分别为97.30％和96.63％;GMT为103 mIU/ml和102 mIU/ml,抗-HBs阳转率及GMT均与B组差异无显著性。结论 倍尔来福~(TM)甲、乙肝联合疫苗与单价甲肝灭活疫苗和单价重组乙肝疫苗具有相同的安全性和免疫原性。     

Safety and immunogenicity of a modified process hepatitis B vaccine in healthy neonates

Background

A manufacturing process using a modified adjuvant was developed to optimize the consistency and immunogenicity for recombinant hepatitis B vaccine (control: RECOMBIVAX-HB™). This modified process hepatitis B vaccine (mpHBV), which was previously shown to have an acceptable safety and immunogenicity profile in young adults, has now been studied in newborn infants.

Methods

Healthy 1–10-day-old neonates (N = 566) received 3 intramuscular doses (5 μg hepatitis B surface antigen [HBsAg] per dose) of either mpHBV or control at Day 1, and Months 1 and 6. Serum antibody to HBsAg (anti-HBs) was assayed at Month 7 (1 month Postdose 3). Anti-HBs geometric mean titers (GMTs) and seroprotection rates (SPRs) (% of subjects with an anti-HBs titer ≥10 mIU/mL) were compared at Month 7. After each dose, injection-site adverse experiences (AEs) and axillary temperatures were recorded for 5 days; systemic AEs were recorded for Days 1–14.

Results

Month 7 SPR was 97.9% for the mpHBV group and 98.9% for the control. The GMT was 843.7 mIU/mL for the mpHBV group and 670.1 mIU/mL for the control. The GMT ratio (mpHBV/control) was 1.26 (95% confidence interval [CI]: 0.94, 1.69), meeting the prespecified non-inferiority criteria. The percentages of subjects reporting any AE, injection-site AEs, or systemic AEs were similar across the 2 vaccination groups. There were no serious AEs.

Conclusions

The safety profile of mpHBV was comparable to that of the control vaccine. The geometric mean antibody titer for mpHBV was higher than control vaccine in this infant population, but the difference did not meet the predefined statistical criterion for superiority.     

甲、乙型肝炎联合疫苗在儿童中0、6月程序接种的安全性和免疫原性研究

目的 观察和评价在儿童中接种2剂倍尔来福~(TM)甲、乙型肝炎(分别简称为甲肝、乙肝)联合疫苗的安全性及免疫原性.方法 本研究以江苏省常州市116名1～10岁完成乙肝疫苗全程免疫同时无甲肝疫苗接种史的抗甲肝病毒抗体(anti-hepatitis A virus,抗-HAV)阴性儿童为研究对象,按0、6个月程序接种甲、乙肝联合疫苗(倍尔来福~(TM)).每剂疫苗0.5 ml,含HAV抗原250 U和乙肝表面抗原5μg.观察接种疫苗后72 h内局部反应和全身反应,检测免疫后1、6、7个月的血清抗-HAV阳转率、乙肝病毒表面抗体(抗-HBs)保护率及抗体滴度.结果 倍尔来福~(TM)接种后局部和全身不良反应发生率分别为12.1%(14/116)和6.0%(7/116),其中局部不良反应以注射部位红、肿、硬结为主,占6.9%(8/116)～11.2%(13/116),全身不良反应发生率为6.0%(7/116),以发热为主.免疫后1、6、7个月,抗.HAV阳转率为92.9%(92/99)～100.0%(101/101),抗体几何平均滴度(GMT)为47.0～2762.3 mIU/ml;疫苗免疫前抗-HBs阳性保护率为86.1%(87/101),免疫后1个月达到100.0%(101/101),免疫后1、6、7个月抗-HBs GMT为894.3～3314.3 mlU/ml.结论 倍尔来福~(TM)甲、乙肝联合疫苗2剂接种程序在乙肝基础免疫儿童中应用具有良好的安全性和免疫原性.     

Safety and immunogenicity profile of an experimental hepatitis B vaccine adjuvanted with AS04

The reactogenicity and safety of an experimental hepatitis B (HB) vaccine containing adjuvant system (AS04) was compared with a licensed vaccine in a phase III, single-blind, randomised study in healthy volunteers ≥15 years of age. A total of 1303 subjects were enrolled to receive either two doses of HB-AS04 (0, 6 months) or three doses of the comparator vaccine (0, 1, 6 months). Two doses of HB-AS04 elicited seroprotection rates close to 100% and two-fold higher GMTs than the comparator vaccine. Results showed that both vaccines were well tolerated and the general safety profile of HB-AS04 was similar to that of the comparator vaccine.     

Safety and immunogenicity profile of an experimental hepatitis B vaccine adjuvanted with AS04

The reactogenicity and safety of an experimental hepatitis B (HB) vaccine containing adjuvant system (AS04) was compared with a licensed vaccine in a phase III, single-blind, randomised study in healthy volunteers >or=15 years of age. A total of 1303 subjects were enrolled to receive either two doses of HB-AS04 (0, 6 months) or three doses of the comparator vaccine (0, 1, 6 months). Two doses of HB-AS04 elicited seroprotection rates close to 100% and two-fold higher GMTs than the comparator vaccine. Results showed that both vaccines were well tolerated and the general safety profile of HB-AS04 was similar to that of the comparator vaccine.     

A controlled clinical trial comparing the safety and immunogenicity of a new adjuvanted hepatitis B vaccine with a standard hepatitis B vaccine

A randomised trial was conducted in 285 adults not immune to hepatitis B (HB) to compare the safety and immunogenicity of a commercial aluminium-adjuvanted HB vaccine with and without an additional new adjuvant (AgB/RC-210-04 or AgB study groups, respectively). The additional adjuvant RC-529 is a fully synthetic monosaccharide mimetic of monophosphoryl lipid A. Subjects in the AgB/RC-210-04 (n=136) and AgB (n=149) groups were vaccinated intramuscularly on days 0, 30, and 180, according to the standard vaccination schedule for hepatitis B vaccines. Serum levels of anti-HBs were measured on days 30, 60, 90, 180, and 210. Standard safety assessments were made throughout the study period. The rates of seroprotection (anti-HBs > or =10.0 mIU/ml) were significantly greater for the AgB/RC-210-04 group at all time points: at day 90, the seroprotection rate, the primary endpoint of the trial, was 99% for AgB/RC-210-04 compared with 84% for AgB (p<0.0001). Similarly, geometric mean anti-HBs titres were significantly higher at all time points for the AgB/RC-210-04 group. There were more local reactions in the AgB/RC-210-04 group, however they were transient and this double-adjuvanted formulation was well tolerated. We conclude that the addition of a synthetic adjuvant to the AgB vaccine significantly enhanced the immunogenicity of the commercial vaccine AgB. The results indicate furthermore that a two-dose regime of the double-adjuvanted vaccine (schedule: 0-1 month) may be sufficient to achieve seroprotection in nearly 100% of individuals.     

Safety and immunogenicity of a recombinant hepatitis B vaccine manufactured by a modified process in renal pre-dialysis and dialysis patients

Background

Patients with renal insufficiency are hyporesponsive to vaccination, including to hepatitis B vaccines. A manufacturing process modification for a hepatitis B vaccine (mpHBV) was studied in renal pre-dialysis and dialysis patients.

Methods

This randomized, open-label, multicenter, estimation study enrolled previously unvaccinated, HBV-seronegative adult dialysis and pre-dialysis patients (N = 276, median age 72.0 years). At 0, 1, 6, and 8 months, group 1 received a 1 mL intramuscular dose of mpHBV (containing 40 μg HBsAg) as a single injection, while group 2 received a 1 mL intramuscular dose of a licensed hepatitis B vaccine as two injections (each containing 20 μg HBsAg; 40 μg HBsAg total). Serum antibody to HBsAg (anti-HBs) was measured predose 1, and 1 month postdose 3 and 4. Anti-HBs geometric mean concentration (GMC) and seroprotection rate (SPR, % of subjects with anti-HBs titer ≥10 mIU/mL) were estimated at months 7 and 9.

Results

For group 1, month 7 SPR was 48.5% (49/101, 95% CI: 38.4%, 58.7%); with an additional dose, month 9 SPR increased to 66.7% (66/99, 95% CI: 56.5%, 75.8%). For group 2, month 7 SPR was 57.7% (64/111, 95% CI: 47.9%, 67.0%); with an additional dose, month 9 SPR increased to 69.2% (72/104, 95% CI: 59.4%, 77.9%). group 1 GMCs at months 7 and 9 were 27.5 mIU/mL (95% CI: 15.7, 48.0) and 61.7 mIU/mL (95% CI: 34.2, 111.5), respectively. group 2 GMCs at months 7 and 9 were 48.7 mIU/mL (95% CI: 28.7, 82.7) and 115.8 mIU/mL (95% CI: 65.2, 205.5), respectively. There were 22 serious adverse events; none were considered related to study vaccine.

Conclusions

Both formulations were immunogenic in this population but required more vaccinations to reach seroprotective levels than comparable regimens in healthy individuals, as expected. The relatively reduced SPRs seen in this population support the need for routine screening and re-dosing in this population.     

国产甲型肝炎灭活疫苗的安全性与免疫原性初步观察

目的 评价国产甲型肝炎灭活疫苗的安全性和免疫原性。方法 对健康易感儿童1％名和成人206名随机分为4组，107名儿童(A组)和131名成人(B组)接种国产甲肝灭活疫苗，另69名儿童(c组)和75名成人(D组)作为对照接种史克必成公司生产的甲肝灭活疫苗。国产疫苗剂量为儿童640EIU／1．0ml。成人1440EIU／1．0ml，对照疫苗剂量儿童720EIU／1．0ml，成人1440EIU／1．0ml，均采用0、6程序。观察72小时内局部和全身反应及免后1、6、7月的免疫应答水平。结果 所有接种对象均未出现明显局部和全身副反应，亦未发现免后ALT升高。初免后一个月A组和B组抗体阳性率分别为94．8％和96．7％，几何平均滴度为758．6mIU／ml和3630．8mIU／ml。全程免疫后一个月4组抗体阳性率均为100％，A组和B组抗体几何平均滴度上升至10471．2mIU／ml和12302．7mIU／m1，略高于对照的C组和D组(分别为3090．3mIU／d和3388．4mIU／ml)。结论 国产甲肝灭活疫苗具有良好安全性和免疫原性。     

Safety and immunogenicity of a new formulation of an inactivated hepatitis A vaccine

The safety and immunogenicity of a new formulation of the inactivated hepatitis A vaccine, Avaxim, was evaluated in 189 children, aged 18 months to 15 years in a monocentric, open trial. Two vaccinations were given six months apart. Enrollment was balanced within three age groups: 18 months to 3 years, 4-8 years and 9-15 years. Antibody titers were measured blindly by an independent laboratory using a modified radioimmunoassay. Two weeks after the first dose, seroconversion was achieved by 94.6, 94.3 and 96.4% of initially HAV-seronegative subjects (antibody titre <20 mIU/ml) in each age group (youngest to oldest, respectively), with corresponding geometric mean titre concentrations (GMC) of 72.2, 54.3 and 47.1 mIU/ml. Just before the booster dose, the seroconversion rate was 100% in all groups, and the corresponding GMC values were 163, 169 and 111 mIU/ml. All groups included, a 22.6-fold rise in GMC from prebooster levels was observed four weeks after the booster dose. An explanatory analysis suggested a tendency for higher antibody levels in younger children at all vaccination time points. Local reactions were noted in 18.2% of the vaccinees after the first dose and in 8.5% after the booster dose. The rates of systemic reactions were 23.8% after the first dose and 11.4% after the booster dose. Overall, this trial demonstrated the good safety and immunogenicity profile of this vaccine in children aged 18 months to 15 years of age.     

Safety and immunogenicity of a candidate parvovirus B19 vaccine

Parvovirus B19 is an important human pathogen causing erythema infectiosum, transient aplastic crisis in individuals with underlying hemolytic disorders and hydropsfetalis. We therefore evaluated a parvovirus B19 virus like particle (VLP) vaccine. The safety and immunogenicity of a 25 μg dose of parvovirus B19 recombinant capsid; 2.5 and 25 μg doses of the recombinant capsid given with MF59; and saline placebo were assessed in healthy adults. Because of 3 unexplained cutaneous events the study was halted after enrollment of 43 subjects and before any subject received their third scheduled dose. The rashes developed 5-9 days after the first or second injection and were seen in one placebo recipient (without an injection site lesion) and two vaccine recipients (with injection site reactions). No clear cause was established. Other safety evaluations revealed mostly injection site reactions that were mild to moderate with an increase in pain in subjects receiving vaccine and MF59. After dose 2 the majority of vaccine recipients developed ELISA and neutralizing antibody to parvovirus B19. Given the possible severe consequences of parvovirus B19 infection, further development of a safe and effective vaccine continues to be important.     

The first combined vaccine against hepatitis A and B: an overview

Hepatitis A and B infections are prevalent world-wide and are a significant cause of morbidity and mortality. A vaccine providing dual protection against hepatitis A and B is now available (Twinrix, SmithKline Beecham Biologicals). Six pivotal vaccine trials, involving 843 healthy adults, aged between 17 and 60 years and vaccinated following a 0, 1, 6 month schedule are discussed. At month 2 more than 99% of the vaccinees were seropositive for anti-HAV and 84% were protected against hepatitis B. The third dose induced a 12-fold increase in geometric mean titres (GMTs) to 5404 mIU/ml. One month after completion of the vaccination course nearly all vaccinees had protective titres against hepatitis B with a GMT of 4818 mIU/ml. Long term follow-up data until month 48 is available for two studies. At month 48 all 129 vaccinees sampled were still positive for anti-HAV antibodies and > 95% were still protected against hepatitis B. The combined hepatitis A and B vaccine Twinrix proves to be consistently safe, well tolerated and highly immunogenic and compares well with serological responses reached with monovalent vaccines. This combined hepatitis A and B vaccine offers more convenience, potentially better compliance and lower administration costs.     

Reactogenicity and immunogenicity profile of a two-dose combined hepatitis A and B vaccine in 1-11-year-old children

This study was conducted to compare the reactogenicity, immunogenicity and safety of a combined two-dose (0, 6 months) hepatitis A and B vaccine (720ELU HAV, 20 mcg HBsAg) with the established three-dose (0, 1 and 6 months) hepatitis A and B vaccine (360ELU HAV, 10 mcg HBsAg). A total of 511 children aged 1-11 years who had not previously received a hepatitis A or B vaccine were enrolled in the study. Both vaccines were well tolerated, and were shown to be safe and immunogenic. The analysis, stratified according to two age groups (1-5 year and 6-11-year-old children) demonstrated that the reactogenicity profile of the two-dose schedule was at least as good as that of the established schedule. Both vaccines and schedules provided at least 98% seroprotection against hepatitis B and 100% seroconversion against hepatitis A, 1 month after the end of the vaccination course (Month 7).     

Combined vaccine against hepatitis A and B

Among the infectious virus hepatitis diseases, types A and B can be successfully prevented with vaccinations. WHO recommend effective control of hepatitis A through immunisation, especially among populations with indirect or high endemicity. Since 1991 WHO has been recommending vaccinations against hepatitis B. It is planned to introduce it in all countries by the year 2007. Vaccinations against hepatitis A & B are recommended for people travelling to the regions endemic for these infections or for those with high professional risk of HAV and HBV. Presented here are the characteristic features of the vaccine, the analysis concerning the evaluation of its effectiveness, comparison of this effectiveness with monovalent vaccine effectiveness, as well as evaluation of the tolerance and safety.     

Comparison of the reactogenicity and immunogenicity of a two injection combined high-dose hepatitis A and hepatitis B vaccine to those of Twinrix

Twinrix (SmithKline Beecham Biologicals) is a combined hepatitis A and B vaccine licensed with a three-dose schedule. A two-dose combined hepatitis A and B vaccine would facilitate immunisation programs. In this prospective study, 100 healthy adults, aged between 18 and 40, were enrolled. A first group of 50 was given a high-dose vaccine at month 0 and 6. A second group of 50 received Twinrix at month 0, 1 and 6.The reactogenicity was assessed after each vaccine dose. There were no severe local adverse events. Seven severe systemic reactions occurred, of which five were fatigue, one was headache and one consist in gastrointestinal symptoms. They all resolved during the 4-day follow-up period. One serious general adverse event was reported, but was clearly unrelated to the vaccine. Thus, both vaccines were well tolerated.The immunogenicity was evaluated by testing for anti-HBs and anti-HAV antibodies. Seroconversion rates and geometric mean titres (GMTs) were compared. At month 7, the anti-HAV GMTs were higher in the high-dose group than in the Twinrix group and, inversely, the anti-HBs GMTs were slightly higher in the Twinrix group than in the high-dose group. At month 7, all subjects in both groups were positive for anti-HAV. All subjects in the high-dose group and 97.6% subjects in the Twinrix group had seroconverted for anti-HBs. Therefore, it can be concluded that with two injections of the high-dose hepatitis A and B vaccine, 6 months apart, a similar immune response can be obtained as induced with three doses of Twinrix at months 0, 1 and 6.     

Comparative immunogenicity in children of mammalian cell-derived recombinant hepatitis B vaccine and plasma-derived hepatitis B vaccine.

Three doses of hepatitis B vaccine were given at 2, 4 and 9 months of age to 220 Senegalese infants living in the Dakar area of Senegal. Half of the infants received 5 micrograms plasma-derived hepatitis B vaccine (Hevac B) and the remainder 20 micrograms mammalian cell-derived recombinant hepatitis B vaccine (GenHevac B). Both vaccines contain S and pre-S2 encoded proteins; however, the recombinant vaccine had a much higher pre-S2 content than the plasma-derived vaccine. Adverse reactions to both vaccines were limited to mild and transient soreness at the injection site. Fever was reported in 14-21% of the infants and was likely to be related to DTP-polio vaccine which was given simultaneously. After the two first doses, seroconversion rates and geometric mean titres of anti-HBs were higher in infants receiving the recombinant vaccine than in infants receiving the plasma-derived vaccine. After completion of vaccination, all infants in both groups had protective levels of anti-HBs antibodies. The recombinant vaccine induced more rapidly antibodies directed against S and pre-S2 epitopes. Anti-pre-S2 antibodies were detected after the first injection of GenHevac B and only after the third injection of Hevac B. From the data, GenHevac B vaccine is expected to be as effective as Hevac B vaccine for controlling hepatitis B infection.     

Lifelong protection against hepatitis B: the role of vaccine immunogenicity in immune memory

Long-term protection against hepatitis B (HB) disease is dependent on persistence of a strong immune memory. This paper presents and discusses new knowledge that allows a better understanding of the mechanisms of long-term protection following hepatitis B vaccination. Studies have revealed links between specific lymphoproliferation, the in vivo humoral response and immune memory. The strength of immune memory and of a subsequent secondary immune response can therefore be predicted by the antibody response following primary vaccination. Vaccine antigen dose and structure have been identified as important influences in the primary antibody response and development of immune memory. The data and considerations presented support the use of highly immunogenic HB vaccines in order to provide long-lasting protection against HB disease.     

Design and immunogenicity analysis of the combined vaccine against zoonotic hepatitis E and foot-and-mouth disease

AimDesign and immunogenicity assessment of the combined vaccine candidate against zoonotic hepatitis E virus (HEV) and foot-and-mouth disease virus (FMDV).MethodsUsing the molecular cloning technology, we produced and purified 9 HEV ORF2-truncated proteins (HEV genotype 4). Then, we compared their thermal stability, antigenicity, and immunogenicity to select the best HEV immunogen. Next, we used the adjuvant Montanide ISA-206 to prepare different formulations of HEV vaccine alone, FMDV vaccine alone and HEV-FMDV combined vaccine. The formulations were injected into mice and the induced humoral immune responses were monitored up 12 weeks post-immunization.ResultsThe HEV p222 protein could self-assemble into VLPs (∼34 nm) and showed higher stability and better antigenicity/immunogenicity than the other HEV antigens, thus it was selected as the best HEV immunogen. Mice immunization with the FMDV vaccine alone induced high FMDV-specific antibody titers in a dose-dependent manner; the HEV p222 protein also induced high levels of anti-HEV antibodies but in a dose-independent manner. The HEV-FMDV combination induced anti-FMDV antibody titers 7–16-fold higher than the titers induced by the FMDV vaccine alone, and HEV-specific antibody titers 2.4-fold higher than those induced by the HEV p222 antigen alone.ConclusionHerein, we proposed a new approach for the control of zoonotic HEV infection through its control in its main host (pig). We also designed the first HEV-FMDV combined vaccine and the preliminary analyses revealed a synergistic effect on the immunogenicity of both HEV and FMDV antigens.     

关于乙型肝炎疫苗免疫原性的评价

乙型肝炎(乙肝)是经血传播的危害严重的病毒性传染病。我国是高发地区之一,乙肝表面抗原(HBsAg)阳性率约10％,乙肝病毒(HBV)感染率达60％～70％。乙肝除爆发性肝炎以外主要危害在于感染后变为慢性病毒携带者,并进一步发展成为慢性肝炎、肝硬化甚至肝癌,根据WHO 2001年的指南指出,90％慢性携带者为围产期感染HBV,但随着年龄增长,感染后慢性携带率逐渐降低;1～4岁     

Safety and immunogenicity of a recombinant vaccine against Trypanosoma cruzi in Rhesus macaques

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi is one of the most important neglected parasitic diseases in the Americas. Vaccines represent an attractive complementary strategy for the control of T. cruzi infection and pre-clinical studies in mice demonstrated that trypomastigote surface antigen (TSA-1) and the flagellar calcium-binding (Tc24) parasite antigens are promising candidates for vaccine development. We performed here the first evaluation of the safety and immunogenicity of two recombinant vaccine antigens (named TSA1-C4 and Tc24-C4) in naïve non-human primates. Three rhesus macaques received 3 doses of each recombinant protein, formulated with E6020 (Eisai Co., Ltd.), a novel Toll-like receptor-4 agonist, in a stable emulsion. All parameters from blood chemistry and blood cell counts were stable over the course of the study and unaffected by the vaccine. A specific IgG response against both antigens was detectable after the first vaccine dose, and increased with the second dose. After three vaccine doses, stimulation of PBMCs with a peptide pool derived from TSA1-C4 resulted in the induction of TSA1-C4-specific TNFα-, IL-2- and IFNγ-producing CD4⁺ in one or two animals while stimulation with a peptide pool derived from Tc24-C4 only activated IFNγ-producing CD4⁺T cells in one animal. In two animals there was also activation of TSA1-C4-specific IL2-producing CD8⁺ T cells. This is the first report of the immunogenicity of T. cruzi-derived recombinant antigens formulated as an emulsion with a TLR4 agonist in a non-human primate model. Our results strongly support the need for further evaluation of the preventive efficacy of this type of vaccine in non-human primates and explore the effect of the vaccine in a therapeutic model of naturally-infected Chagasic non-human primates, which would strengthen the rationale for the clinical development as a human vaccine against Chagas disease.     

Safety and immunogenicity of an inactivated hepatitis A candidate vaccine in healthy adult volunteers

The reactogenicity and immunogenicity of a formaldehyde-inactivated hepatitis A vaccine have been investigated. Three different dose levels of vaccine (180, 360 and 720 ELISA units) were administered to healthy volunteers according to a 0, 1, 2 and 12 month schedule. The vaccine was safe and well tolerated. Reactions observed following vaccination were essentially mild and were not dependent upon the quantity of antigen administered. All subjects had measurable titres of anti-HAV antibodies after the full vaccination course; the immune response to the vaccine was dose-related. Antibody titres in vaccinees at month 13 were between 60- and 190-fold higher than those observed in a group of subjects given anti-HAV immunoglobulin.