Saliva was evaluated as a diagnostic fluid for screening individuals for evidence of previous hepatitis A virus (HAV) infection and for evidence of seroconversion after vaccination with inactivated ...hepatitis A vaccine. A new and simple saliva collection method and an assay for detection of HAV antibody were used; the assay used an antibody capture format. There was complete concordance between the results of saliva-based assays and those of serum-based assays, both of which were used for determining previous natural HAV exposure. However, for vaccine recipients, 100% concordance for saliva-based and serum-based assays occurred only at serum titers of >9,000 mlU/mL, which were determined with use of the modified HAVAB assay. Saliva provides adequate sensitivity and specificity for determining naturally acquired HAV infection, although it is not useful in clinical trials for determining seroconversion after HAV vaccination.
Although inactivated hepatitis A vaccine is known to be well tolerated and immunogenic in healthy children and adults, its efficacy has yet to be established.
To evaluate the efficacy of the ...hepatitis A vaccine in protecting against clinically apparent disease, we conducted a double-blind, placebo-controlled trial in an Hasidic Jewish community in upstate New York that has had recurrent outbreaks of hepatitis A. At the beginning of a summer outbreak, 1037 healthy seronegative children 2 to 16 years of age were randomly assigned to receive one intramuscular injection of a highly purified, formalin-inactivated hepatitis A vaccine or placebo. A case was defined by the presence of typical signs and symptoms, a diagnostic increase in IgM antibody to hepatitis A, and a serum concentration of alanine aminotransferase at least twice the upper limit of normal. Cases occurring greater than or equal to 50 days after the injection were included in the evaluation of efficacy. The children were followed for a mean of 103 days.
A total of 519 children received vaccine, and 518 received placebo. The vaccine was well tolerated, with no serious adverse reactions. From day 50 after the injection, 25 cases of clinically apparent hepatitis A occurred in the placebo group and none in the vaccine group (P less than 0.001), confirming that the vaccine had 100 percent protective efficacy. Before day 21, seven cases occurred in the vaccine group and three cases in the placebo group. After that time, there were no cases among vaccine recipients and 34 cases among placebo recipients.
The inactivated purified hepatitis A vaccine that we tested is well tolerated, and a single dose is highly protective against clinically apparent hepatitis A.
Formalin-inactivated, alum-adsorbed, hepatitis A vaccine was evaluated in 100 healthy adults who were stratified at enrollment into two age groups: 18–39 years: n=50; 40–65 years: n=50. All ...individuals received vaccine at 25 U of viral antigen. After stratification, both groups were randomized to receive either vaccination at 0 and 24 weeks or vaccination at 0, 2 and 24 weeks. Subjects were bled for serology at 0, 2, 4, 24, 28 weeks and 1 year. The seroconversion rate and geometric mean titer (GMT=mIU ml−1) after one dose of vaccine was lower for older subjects second week: <40 years: 1525 (60%) (GMT: 12.9), >40 years: 522 (23%) (GMT: 6.1); fourth week: <40 years: 2022 (91%) (GMT: 29.0), >40 years: 1623 (70%) (GMT: 14.3). After a second dose at 2 weeks the seroresponse improved so that there were no longer differences between age groups 24 weeks: <40: 2122 (95%) (GMT: 123.9), >40: 2223 (96%) (GMT: 106.1). A third dose at 24 weeks resulted in a 20–40-fold increase in GMT in both age groups. As a separate evaluation height, weight, skin fold thickness, and body mass index (BMI) were assessed by logistic regression for their ability to predict serologic response. Serologic response was significantly associated with lower weight (P=0.032) and BMI (P=0.024) but not with height or skin fold thickness. Hepatitis A vaccine was well tolerated, with no serious adverse experiences. Adults older than 40 years appear to respond less well than younger adults to a single dose of 25 U of hepatitis A vaccine but equally well after two doses of vaccine. The slower antibody response to hepatitis A vaccine in overweight individuals was not attributable to skin adipose tissue.
301 healthy adult volunteers were randomized to one of three treatment groups: inactivated hepatitis A vaccine alone; inactivated hepatitis A vaccine with immune globulin (Ig) concurrently; or Ig ...alone. The first two treatment groups received a second dose of hepatitis A vaccine at week 24. Anti-HAV was measured 4, 8, 12, 24 and 28 weeks after the primary immunization. When comparing subjects receiving inactivated hepatitis A vaccine alone to those receiving vaccine and Ig, the seropositivity rates were not significantly different at 4, 8, 12 and 28 weeks, but at week 24 the seropositivity rate was lower in the group receiving both vaccine and Ig compared to the group receiving vaccine alone (92.0% compared to 97.0%). At weeks 8, 12 and 24 the geometric mean titers (GMTs) were significantly lower for subjects receiving both vaccine and Ig. The GMTs were not significantly different after the second dose of vaccine. At all time points, the lower serum antibody concentrations observed in subjects receiving both inactivated hepatitis A vaccine and Ig were nevertheless substantially higher than the cutoff for assay seropositivity and much higher than after Ig alone; these differences are therefore clinically insignificant.
The worldwide experience to date with VAQTA, a highly purified formalin-inactivated hepatitis A vaccine containing alum-adjuvant, is reviewed. No serious adverse experience related to vaccination has ...been reported. The vaccine has proven highly immunogenic, with seroconversion detectable after a single dose in 90-99% of children 2-16 years old, and of adults under 77 kg (170 lb) body weight. There is a trend toward lower one-dose seroconversion rates with increasing age and with weight > 77 kg. Early seroconversion in the latter groups may require two 25-unit doses given 2, 4 or 8 weeks apart, or a higher priming dose. Seroconversion induced by this vaccine has been shown to signify protection from clinical hepatitis A disease. The few vaccines whose titers have waned to borderline levels responded anamnestically to a booster, suggesting that the vaccine induces an immune memory response and should provide long-term protection.
The dose response relationship of 25-, 50-, and 100-U doses of an inactivated hepatitis A vaccine was examined in 358-seronegative volunteers in a 2-dose schedule. The 50-U and 100-U groups had ...statistically significantly higher seroconversion rates than the 25-U group at weeks 2, 4, 8, and 24. Seroconversion was statistically significantly greater for the 100-U compared with the 25- and 50-U doses 2 weeks after the first injection but was not significantly different by 4 weeks after the first injection in the 50- and 100-U dose groups. After 2 injections, all subjects in all groups seroconverted. The vaccine was well tolerated at all dosage levels.
Hepatitis A virus (HAV) infection in adults is often symptomatic and disabling. The present article summarizes our experience with phase 2 studies of an inactivated hepatitis A virus vaccine. Pre- ...and post-exposure prophylaxis with immune globulin (IG) is only effective for 4-6 months. We compared the safety, tolerability, and immunogenicity of a single i.m. injection of IG with single and booster doses of an inactivated hepatitis A virus vaccine (iHAV) in adults. A total of 75 healthy volunteers (aged 18-50 years) were evaluated in two separate studies. The first included 15 volunteers who received 25 units iHAV i.m. at 0 and 24 weeks. The second, a randomly controlled study, consisted of three groups receiving 25 units iHAV i.m. at 0, 1, and 6 months, or at 0, 2, and 6 months, or 0.06 ml/kg IG i.m. given once. Anti-HAV seroconversion was measured by radioimmunoassay (RIA). After IG injection, anti-HAV seroconversion occurred in 100% of recipients at week 1, declining to 10% at week 12, and 0% by week 20. In contrast, after a single 25-unit dose, RIA seropositivity in iHAV vaccines was 73% by week 2, reaching 100% by week 5, and persisted in all up to week 24, at which time anti-HAV geometric mean titers (GMT) were 2-fold higher than those seen at week 1 after IG. Administration of a booster dose given 1 or 2 months after primary immunization did not significantly improve the quantitative anti-HAV response at 6 months as compared to the effect of the primary dose.
The Navajo are known to be at high risk for hepatitis A virus (HAV) infection. This study investigated the safety and immunogenicity of an investigational, alum-adjuvanted, formalin-inactivated HAV ...vaccine (VAQTA) developed by Merck Research Laboratories in Navajo children. One hundred two of 212 children, ages 4 to 12 years, were HAV-seronegative (< 10 mIU/ml by an enhanced sensitivity modification of the HAVAB; Abbott). Ninety of these children received the HAV vaccine. Study participants were given vaccines containing various viral protein concentrations: Group A (n = 18), 6 units; Group B (n = 36), 13 units; and Group C (n = 36), 25 units HAV protein (1 unit approximately 1 ng viral protein antigen). Three-dose (0, 8, 24 weeks) and two-dose (0, 24 weeks) regimens were compared in subgroups within B and C. The vaccine was well-tolerated and there were no serious adverse reactions; no vaccinee developed hepatitis A. After 1 dose 82 to 100% of children seroconverted (> or = 10 mIU/ml, modified HAVAB; Abbott) and 100% seroconverted after 2 doses. After 1 dose the geometric mean titer for antibody was: Group A, 22 mIU/ml; Group B, 18 mIU/ml; and Group C, 38 mIU/ml. After 3 doses geometric mean titers increased to 10,106 mIU/ml in Group A, 7258 mIU/ml in Group B and 11,856 mIU/ml in Group C. Further field studies are indicated to evaluate its use in high risk populations, such as the Navajo.
The performance of vaccine protective efficacy trials is often more complex than reports of final results suggest. The current article reviews the background, planning and preparations for the ...Monroe, NY, protective efficacy trial of a formalin-inactivated, alum-adjuvanted hepatitis A vaccine (VAQTA, manufactured by Merck Research Laboratories). The vaccine trial was carried out at Kiryas Joel, a Hasidic Jewish community which had experienced numerous annual outbreaks in a local environment with similarities to day-care centers. Careful communication, and cooperation of community leadership, a flexible technical resource team, and knowledge of an epidemic already ongoing in a sister community whose members were due to arrive for summer holidays, permitted rapid and efficient completion of the trial with a striking demonstration of protection after a single vaccine dose.
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