Immunogenicity and reactogenicity of two regimens of diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio and Haemophilus influenzae type b vaccines administered to infants primed at birth with hepatitis B vaccine.

An open, randomized study evaluated the immune response and safety of two different regimens of diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus-Haemophilus influenzae type b (DTPa-HBV-IPV-Hib) immunization in infants primed at birth with hepatitis B vaccine. One-half of the 150 healthy, full-term infants received a DTPa HBV-IPV-Hib vaccine at 1 1/2, 3 and 5 months of age; the other received a DTPa-IPV-Hib vaccine at 1 1/2, 3 and 5 months of age with separate HBV vaccine at 1 and 5 months of age. Immune response was similar following the two regimens with 100% of the vaccinees seroprotected for HBV, diphtheria, tetanus, Hib and poliovirus types 2 and 3 diseases after the full vaccination course. One vaccinee in the DTPa HBV-HPV- Hib group failed to respond to the poliovirus type 1 antigen. Response to the three pertussis antigens ranged from 92-97% in the DTPa-IPV-Hib plus separate HBV group and 100% in the DTPa HBV-IPV-Hib group. The most frequently reported post-vaccination symptoms were irritability in the DTPa-IPV-Hib plus separate HBV group (49% of vaccinees) and fever, defined as axillary temperature > or =37.5 degrees C, in the DTPa HBV- IPV-Hib group (50% of vaccinees).

Vaccination against hepatitis A in children aged 12 to 24 months [corrected].

BACKGROUND: Current hepatitis A vaccines are either licensed for children >2 years of age, as in the U.S. or Chile, or >1 year of age, as in Europe and other parts of the world. Recent recommendations for immunization against hepatitis A have included routine vaccination of children in areas or regions of higher endemicity. However, data on hepatitis A vaccination in toddlers aged between 1 and 2 years are scarce. METHODS: This open clinical study investigated the reactogenicity and immunogenicity of two doses (0, 6-month schedule) of an inactivated hepatitis A vaccine (Havrix pediatric, Glaxco SmithKline Biologicals, Rixensart, Belgium) in 120 seronegative children aged 12-24 months. RESULTS: Pain at the injection site and irritability were the most frequently reported local and general symptoms, respectively. No serious adverse events related to the study vaccine were reported. One month after the first dose, all but one subject had antibodies against hepatitis A with a GMT of 159 mIU/mL. After the booster dose, all had antibodies with a GMT of 2,939 mIU/mL. CONCLUSIONS: Our data show that the inactivated hepatitis A vaccine was well tolerated by these toddlers and that the vaccine elicits a good immune response.

Perspectives of vaccination against hepatitis E.

Hepatitis E, an important cause of morbidity and mortality in humans, accounts for more than 50% of acute viral hepatitis in young adults in developing countries with a 20-30% mortality rate among infected pregnant women primarily those in their third trimester. The development of inactivated or live attenuated virus vaccine has been hampered because this virus does not replicate efficiently in cell culture. A vaccine has been developed by an alternative approach through recombinant technology. Preliminary results of the first administration in man conducted in the US at Walter Reed Army Institute of Research indicate the vaccine to be safe and immunogenic and have led to the decision to further evaluate the vaccine in an endemic setting.

A comparison of two commercial recombinant vaccines for hepatitis B in adolescents.

The immunogenicity and reactogenicity profiles of three doses each of Engerix-B(R) (10 microg hepatitis B surface antigen) and Recombivax(R) (5 microg hepatitis B surface antigen), given on a 0, 1, 6 month schedule to healthy adolescents were compared in a single-blind, randomized clinical trial. One month following the third dose, seroprotection rates after Engerix-B and Recombivax were similar (99 and 98%, respectively). The geometric mean titre (GMT) was statistically significantly higher following vaccination with Engerix-B (3961 vs. 1001 mIU/ml; P=0.0001, Fisher's exact test). Most of the symptoms reported were mild or moderate in intensity and transient. There were no vaccine-related serious adverse events.

Immunization against hepatitis A in the first year of life: priming despite the presence of maternal antibody.

BACKGROUND: Maternal antibodies interfere with hepatitis A vaccination in young infants. We examined the response to a high dose hepatitis A vaccine administered concomitantly with a combination of diphtheria-tetanus toxoids-acellular pertussis-inactivated poliovirus vaccine/Haemophilus influenzae type b vaccine to initially seropositive vs. initially seronegative infants. METHODS: Three hundred subjects were originally planned to be enrolled at age 6 to 10 weeks and received hepatitis A vaccine (formalin-inactivated vaccine, SB-Bio, 720 enzyme-linked immunosorbent assay units) at 2, 4 and 6 months concomitantly with a diphtheria-tetanus toxoids-acellular pertussis-inactivated poliovirus vaccine/H. influenzae type b vaccine. Children initially seropositive received a booster dose at 12 months of age. An additional 100 twelve-month-old infants previously not vaccinated with hepatitis A vaccine were given 1 dose, to observe the primary response at that age. Reactogenicity was recorded on diary cards for the 3 subsequent days. Immunogenicity was measured at Months 2, 4, 5, 10 and 11 after administration of the first vaccine dose. For the subjects enrolled at 12 months, blood was drawn before and 1 month after the first vaccination. RESULTS: Of 297 initially enrolled infants 36% were seronegative before vaccination (Group A). The geometric mean concentration (GMC) (milli-International Units/ml) of the seropositive infants (Group B) before immunization was 2587. The GMCs of Group A infants 1 month after each dose and at 12 months of age were 93, 518, 1656 and 786, respectively. For Group B infants, the respective GMCs were 1165, 460, 508 and 167. One hundred subjects of Group B received a booster dose at age 12 months; at Month 13 all were seropositive with a GMC of 1902. For comparison, a third group of 100 not previously immunized 12-month-old infants (Group C) were enrolled and received 1 dose of hepatitis A vaccine with pre- and postimmunization GMCs of 52 and 120, respectively. CONCLUSIONS: Our results suggest that the initially seropositive infants were primed despite maternal antibody interference. The hepatitis A vaccine was well-tolerated in this population of young infants.

Immunogenicity and reactogenicity of the combined hepatitis A and B vaccine in young adults.

The combination of hepatitis A virus (HAV) and hepatitis B virus (HBV) vaccinations can offer convenience, increased compliance and cost saving. We have studied the immunogenicity, reactogenicity and safety of combined hepatitis A and B vaccination in young adults (16-35 years old). Eighty healthy young adults were divided into two random groups. One group received the combined hepatitis A and B vaccine (HAB) in one arm while the other group was administered concomitant hepatitis A and B vaccines (HAV + HBV) in the right and left arms, respectively. The immunogenicity, reactogenicity and safety were assessed after each dose in both the groups. In local symptoms, the percentage of the combined HAB group was lower than the HAV + HBV group, and the general symptoms were noted in approximately 30% of each group without any significant difference. No serious adverse effects were noted. All the subjects were seropositive for antibody to hepatitis A virus (anti-HAV) after one dose of vaccine, and remained seropositive after three doses in both groups. The seropositive rate for antibody to hepatitis B surface antigen (anti-HBs) was significantly higher (84%) in the combined HAB group than the concomitant HAV + HBV group (62%), (p<0.05) after dose two, and all the subjects were seropositive (100%) after the third dose. The GMTs of anti-HAV and anti-HBs were not significantly different between groups 1 and 2 (p>0.1) except in month 6 when the GMT of anti-HBs was higher in HAB group (p=0.0039). The combined HAB vaccine was found to be safe, well tolerated and had less local symptoms in young adults. The immunogenicity and reactogenicity were similar to the concomitant HAV + HBV vaccines.

Vaccination against hepatitis B: current challenges for Asian countries and future directions.

AIMS: To review the current status of hepatitis B immunization programmes as well as future issues concerning hepatitis B immunization in Asian countries. METHODS: Pertinent literature was identified via in-house and MEDLINE (1980-99) searches and references cited in published articles. Articles within the Proceedings of the IX Triennial International Symposium on Viral Hepatitis and Liver Disease provided valuable state-of-the-art resource data. RESULTS: Chronic hepatitis B infection is responsible for 75-90% of primary hepatocellular carcinoma, one of the 10 most common cancers worldwide. Hepatitis B and its chronic sequelae can potentially be eradicated through vaccines that have been shown to be 95-99% efficacious in preventing development of the disease or the carrier state in immunized infants. Approximately 75% of the world's hepatitis B carriers live in Asian countries wherein wide variations in immunization strategies exist. Vaccination programmes in hyperendemic Asian countries have elicited decreases in the incidence of acute and chronic infections as well as a decrease in chronic carriers in the unvaccinated population. Decreases in the incidence of hepatocellular carcinoma have been recorded in Taiwan and Singapore after at least 10 years of universal hepatitis B immunization programmes. CONCLUSIONS: In Asian countries currently without nationwide hepatitis B programmes, utilization of the existing vaccination infrastructure for administration of other World Health Organization Expanded Programme on Immunization vaccines will provide the most economical and efficient means of administration of the hepatitis B vaccine.

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.

Comparison study of combined DTPw-HB vaccines and separate administration of DTPw and HB vaccines in Thai children.

The safety, immunogenicity and tolerability of two different DTPw-HBV combination vaccines, containing 5 and 10 microg of HBsAg; were investigated in comparison with separate administration of DTPw and HBV (10 microg of HBsAg). A three dose primary vaccination course at 2, 4 and 6 months of age was followed by a booster dose at 18 months. All vaccines were safe and well tolerated. The DTPw-HBV combination vaccine containing 10 microg of HBsAg elicited significantly higher anti-HBs titres than the other two vaccines after the primary and booster vaccination course. All vaccines elicited a high response against the other components. Based on these results, DTPw-HBV (10 microg HBsAg) was the most effective vaccine at this schedule.

A two dose combined hepatitis A and B vaccine in Chinese youngsters.

This open, randomized study was conducted in healthy Chinese youngsters, aged between 10 and 19 years to compare the reactogenicity and immunogenicity of two vaccines: the combined vaccine against hepatitis A and B was administered in a two-dose schedule with the profile of the corresponding monovalent vaccines, while the concomitant vaccine was administered also on a two-dose schedule but simultaneously in opposite arms. All vaccinees had antibodies against hepatitis A (anti-HAV) after the 2-dose administration, whereas all but four in the first and two in the second group had protective titres against hepatitis B (anti-HBs). At month 7, the geometric mean titres for both antibodies were more than double for the group of subjects receiving the combined vaccine: 3,701 vs. 1,705 mIU/ml for the anti-HAV, and 1,524 vs. 720 mIU/ ml for the anti-HBs response. Injection site pain was the most commonly reported local symptom and headache was the most reported general symptom. It is concluded that this combined vaccine against hepatitis A and B, administered according to a two-dose schedule, is well-tolerated and highly immunogenic.

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.

Hepatite A: uma doença possível de prevenção com vacina / Hepatitis A can be prevented with a vaccine

A doença causada pelo virus da hepatite A (VHA) costuma ser considerada como benigna, afetando principalmente os pré-escolares. Contudo, nesta revisäo se discutem os vários grupos da populaçäo em geral, nos quais a infecçäo pelo VHA pode apresentar consequências mais graves. Em consequência da alteraçäo epidemiológica verificada na América Latina, um número cada vez maior de adolescentes e adultos jovens se mantêm suscetíveis à infecçäo pelo VHA. A infecçäo por esse vírus, neste grupo etário, irá representar grave impacto no futuro, ausência prolongada ao trabalho e/ou escola e custos maiores para os sistemas locais de saúde. Em estudos recentes na Argentina e Chile, o VHA foi, também, o agente etiológico mais prevalente nos casos de insuficiência hepática fulminante em pré-escolares. A hepatite A aguda em pacientes com doença hepática crônica subjacente, especialmente hepatite C crônica, tem sido associada à insuficiência hepática grave ou fulminante. A prevençäo da hepatite A através da vacinaçäo parece ser o meio mais potente de se conter o VHA. As vacinas inativadas contra a hepatite A comprovaram ser seguras, altamente imunogênicas e indutoras de proteçäo duradoura contra infecçöes pelo VHA

Safety and immunogenicity of hepatitis A vaccine in infants: a candidate for inclusion in the childhood vaccination programme.

Forty-eight infants received a single dose (720 ELISA units = 0.5 ml) of inactivated hepatitis A vaccine at the fifth month of age with booster at the 11th month of age, together with the second and third doses of the vaccines compulsory under Italian law (diphtheria, tetanus, oral polio and hepatitis B). Overall, the seroconversion rate was 100%. The anti-HAV geometric mean titre (GMT) reached 3,021 mIU/ml in infants born to anti-HAV-negative mothers, but only 399 mIU/ml in infants born to anti-HAV-positive mothers. Hepatitis A vaccine was immunogenic, safe and well tolerated without significant side-effects. There seems to be no reason for not including it in childhood vaccination programmes particularly in low endemic HAV areas.

Immunogenicity and reactogenicity of two recombinant hepatitis B vaccines in healthy adolescents on two-dose schedule.

This is an open, randomized study to compare the immunogenicity and reactogenicity of two recombinant hepatitis B virus (HBV) vaccines. The HBV-NF is a new formulation with a new adjuvant phenoxyethanol which replaced the conventional adjuvant of a commercially available recombinant HBV vaccine (Engerix-B). These two vaccines had the same 20 micrograms hepatitis B surface antigen (HBsAg). They were administered to the deltoid muscle of 116 healthy adolescents, aged between twelve and eighteen years, according to the 0, 6-month schedule. Serum was taken at month 0, 1, 6, and 7. Antibody to HBsAg was tested by radioimmunoassay. Geometric mean titers of both vaccines displayed no significant difference at month 1, 6, and 7. Following the second dose of vaccine, the seroprotection titer (10 mIU/ml) rates at month 7 were 90.9% in HBV-NF and 93.4% in Engerix-B, respectively (p = 0.43). The incidences of local and general adverse reactions were from 3% to 7% without significant difference between the two vaccines and the reactions were all mild and tolerable. Based on this study, regimens of this two-dose schedule proved to be safe and immunogenic, which may provide a cost-effective alternative for HBV mass vaccination program in adolescents.

Production of antibody to hepatitis A virus and hepatitis B surface antigen measured after combined hepatitis A/hepatitis B vaccination in 242 adult volunteers.

Two batches of a new hepatitis A/hepatitis B combined vaccine were tested in 242 healthy students. Three injections, given at 0, 1 and 6 months, produced seroconversion rates and hepatitis A virus (HAV) and hepatitis B surface antigen (HBsAg) antibody levels comparable to those reported after administration of separate monocomponent vaccines. The vaccine proved to be safe and well-tolerated. Influence of host factors, such as elevated body mass index or gender, were investigated and proven to be of little influence on the immunoresponse.

Follow-up immunogenicity of an inactivated hepatitis A virus vaccine in healthy children: results after 5 years.

Long-term persistence of hepatitis A virus (HAV) serum antibody in vaccinated children has not been demonstrated in previous studies. To study the long-term immunogenicity to HAV vaccine, three doses of strain HM 175 HAV vaccine with 360 enzyme-linked immunosorbent assay units were administered to 107 children, aged from 1.0 to 6.8 years, at 0, 1, and 6 months. The administration of one vaccine dose induced seropositivity (anti-HAV titer > or = 20 mIU ml-1) in 95% of all vaccinees at month 1. All subjects remained seropositive until month 6. The titers of HAV antibody remained above 20 mIU ml-1 in all subjects followed up to 60 months. The geometric mean titer (GMT) reached its peak (3802 mIU ml-1) at month 7, i.e. 1 month after the booster dose, and then declined until the end of follow-up at month 60 (661 mIU ml-1). A trend of higher GMT in female subjects persisted up to month 60. The changes of the GMT over time were best described by the regression equation: log (GMT) = 3.26-0.08 x (age in years) (r = -0.95, P = 0.014). According to this equation, the geometric mean concentration would reach 20 mIU ml-1 at around 24.5 years after the beginning of vaccination. In conclusion, those who completed the recommended three-dose inactivated HAV vaccination series remained seroprotective for at least 5 years. Theoretically, such a vaccination program can provide a protective period of over 20 years in children. This paper may be the first to describe at least 5-year immunogenicity of inactivated HAV vaccination in healthy children.

Safety and immunogenicity of a hepatitis B vaccine formulated with a novel adjuvant system.

A formulation of recombinant hepatitis B surface antigen (HBsAg) combined with a novel adjuvant system, SBAS4--a combination of aluminium salt and monophosphoryl lipid A (MPL), was assessed in 27 healthy adult volunteers with a commercial vaccine (Engerix-B) as control. After three doses (0, 1, 6 months schedule), reactogenicity profiles were similar. Local reactions were essentially mild, the most frequent being soreness at the injection site. Seroprotection was achieved after two doses in all subjects given the candidate vaccine, all Engerix-B vaccines being seroprotected after the third dose. After the second and third doses, higher anti-HBs Geometric Mean Titres (GMTs) were observed in the group which received the formulation with the novel adjuvant system, and cellular immunity, measured as HBsAg-specific lymphoproliferation was stronger than with Engerix-B. These results indicate that the new formulation is safe, well-tolerated and immunogenic and may promote more rapid protection against hepatitis B infection.

Diphtheria, tetanus and whole cell pertussis vaccine combined with hepatitis B vaccines: a comparison of two doses (10 microg and 5 microg).

BACKGROUND: A combined diphtheria-tetanus-whole cell pertussis-hepatitis B (DTPwHB) vaccine might facilitate the achievement of universal vaccination of infants against hepatitis B. METHODS: A double blind, randomized, two-armed, single center study was undertaken to evaluate the immunogenicity and reactogenicity of combined tetravalent DTPwHB vaccine, with two dosages of hepatitis B component (10 microg and 5 microg). The combined vaccine was tested in the context of a simplified vaccination schedule at 1.5, 3.5 and 6 months of age, to 120 healthy infants born to hepatitis B surface antigen-negative mothers after priming with one dose of hepatitis B vaccine (10 microg) at birth. Antibodies to each antigenic component were measured from blood samples collected immediately after birth, pre- and postvaccination blood samples. RESULTS: The reactogenicity profiles were similar in the two groups. No serious adverse events were reported. One month after completion of the four-dose vaccination schedule, all subjects except one in Group 1 (10 microg) had protective titers of anti-HBs (10 mIU/ml). At this time the geometric mean titer in Group 1 (10 microg) was higher than that observed in Group 2 (5 microg), 696 vs. 488 mIU/ml (P = 0.19). One month after three doses all subjects in both groups had protective antidiphtheria titers and antitetanus titers. The vaccine response rate to the Bordetella pertussis component of the vaccine was 88.0% in Group 1 and 96.2% in Group 2 (P = 0.86). CONCLUSION: Both combined tetravalent vaccines are safe and immunogenic when administered to infants born to a hepatitis B surface antigen-negative mother, with a 10-microg dose of priming hepatitis B vaccine at birth. This combined tetravalent DTPwHB vaccine may play an important role to promote integration of HB vaccine into the Expanded Program of Immunization in hepatitis B-endemic areas.

Safety and immunogenicity of hepatitis A vaccine in patients with chronic liver disease.

Acute hepatitis A superimposed on chronic liver disease (CLD) has been associated with severe or fulminant hepatitis. An open, multicenter study was performed to compare the safety and immunogenicity of an inactivated hepatitis A vaccine in patients with CLD with that in healthy subjects. A secondary objective was to compare the safety of the hepatitis A vaccine with that of a commercial hepatitis B vaccine in subjects with chronic hepatitis C. A total of 475 subjects over the age of 18 years were enrolled into 1 of 5 groups according to history, serological data, and previous diagnosis. Patients in groups 1 (healthy adults), 2 (chronic hepatitis B), 3 (chronic hepatitis C), and 5 (other CLD not caused by viral hepatitis) were vaccinated with two doses of inactivated hepatitis A vaccine, 6 months apart. Patients in group 4 (chronic hepatitis C) received 3 doses of a recombinant hepatitis B vaccine, according to a 0-, 1-, and 6-month schedule. Local injection-site symptoms were the most common reactions reported following vaccination in all groups (35.5% of all doses), with the hepatitis B vaccine eliciting fewer injection-site symptoms than the hepatitis A vaccine (19.8% compared with 37.5%). Although a higher percentage of healthy subjects (93%) seroconverted after a single dose of the hepatitis A vaccine than did subjects with chronic hepatitis C (73.7%) or CLD of nonviral etiologies (83.1%), more than 94% of all vaccinees were seropositive for anti-HAV after the complete vaccination course. At each time point, a lower geometric mean concentration of anti-HAV was observed for each group of CLD patients compared with the healthy control subjects. In conclusion, hepatitis A vaccine was well tolerated and induced a satisfactory immune response in patients with chronic hepatitis B, chronic hepatitis C, and miscellaneous CLD.

The new DTPw-HBV-Hib combination vaccine can be used at the who schedule with a monovalent dose of hepatitis B vaccine at birth.

An open, randomized, clinical trial was conducted in order to assess the reactogenicity and immunogenicity of DTPw-HBV and Haemophilus influenzae type b (Hib) vaccines when given either as a mixed administration or as separate concomitant injections using the WHO schedule at 6, 10 and 14 weeks of age, following a dose of HBV at birth. There were no clinically relevant differences in the immune response to any component between the mixed and separate administrations. In fact the anti-tetanus GMTs were significantly higher (p=0.002) in mixed administration (3.9 IU/ml) compared with the separate administration (1.9 IU/ml). However although all subjects achieved anti-PRP titers > or = 0.15 microg/ml, higher anti-PRP GMTs were seen in the group receiving the separate administration. Importantly, the addition of Hib did not adversely alter the reactogenicity profile of DTPw-HBV. This report which demonstrates that this novel combination can be used in WHO recommended schedule.