Leora Brown

A Controlled Trial of a Formalin-Inactivated Hepatitis A Vaccine in Healthy Children

BACKGROUNDnAlthough inactivated hepatitis A vaccine is known to be well tolerated and immunogenic in healthy children and adults, its efficacy has yet to be established.nnnMETHODSnTo 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.nnnRESULTSnA 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.nnnCONCLUSIONSnThe inactivated purified hepatitis A vaccine that we tested is well tolerated, and a single dose is highly protective against clinically apparent hepatitis A.

Duration of protection from clinical hepatitis A disease after vaccination with VAQTA

Recent papers examining the expected persistence of anti‐hepatitis A virus antibody following vaccination with inactivated hepatitis A vaccine have estimated that geometric mean antibody levels will remain above cut‐off levels for 10–30 years. However, the methodology used in these papers did not take into account any estimates of variability between subjects. In this paper data from the persistence of antibody after the administration of another vaccine, VAQTA® (hepatitis A vaccine, inactivated; MSD), were used to develop further models of antibody decay. Using individual subject estimates instead of group means allowed the estimation of time to negativity for various percentiles of the population (including the median), and the construction of confidence intervals on estimates of time to negativity. Data from studies of subjects who seroreverted to negativity, and subsequently received a booster dose, were also considered to show that subjects who lose detectable antibody are likely to remain protected from hepatitis A disease by persistent immune memory and rapid anamnestic response soon after exposure to hepatitis A virus. The estimates of duration of protection suggest that VAQTA® will provide protection for many years, first through presence of antibody and further through an anamnestic response based on persistent immune memory.

Worldwide experience with the CR326F-derived inactivated hepatitis A virus vaccine in pediatric and adult populations: an overview.

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 effect of age and weight on the response to formalin inactivated, alum-adjuvanted hepatitis A vaccine in healthy adults

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: 15/25 (60%) (GMT: 12.9). > 40 years: 5/22 (23%) (GMT: 6.1): fourth week: < 40 years: 20/22 (91%) (GMT: 29.0), > 40 years: 16/23 (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: 21/22 (95%) (GMT: 123.9), > 40: 22/23 (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.

Concurrent administration of inactivated hepatitis A vaccine with immune globulin in healthy adults

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.

Inactivated hepatitis A vaccine in childhood: implications for disease control

The experience to date with the Merck inactivated hepatitis A vaccine in healthy children 2-16 years old is reviewed. Comparison of response to increasing doses indicates that an intramuscular dose of 25 units results in seroconversion of 99% of children by week 4 following a single dose. Antibody persistence rate is nearly 100% six months later, whether or not a second priming dose is given at week 8. This vaccine has proven highly immunogenic in children and has a favourable safety/tolerability profile. It should be useful for pre-exposure prophylaxis and control of hepatitis A, and should eventually replace immune globulin (Ig) for this indication.

Immunogenicity, safety and tolerability of varying doses and regimens of inactivated hepatitis A virus vaccine in Navajo children.

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.

Anatomy of a trial: a historical view of the Monroe inactivated hepatitis A protective efficacy trial

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.

A Dose Response Study of Hepatitis A Vaccine in Healthy Adults Who Are ≥30 Years Old and Weigh ≥77 kg

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.

Monthly Update: Anti-infectives: VAQTA: Merck's hepatitis A vaccine, purified, inactivated

The safety/tolerability profile, immunogenicity and protective efficacy of VAQTA, Mercks hepatitis A vaccine, purified, inactivated, are based on studies of 18,239 vaccinees; 12,000 2–17 years and 6239 18 years and older. To date, no vaccinee has had any serious vaccine-related adverse experience. In placebo-controlled studies, the local and systemic adverse experience profile has been indistinguishable from that of placebo alum diluent. The goal of ≥ 95% seropositivity was achieved within 4 weeks after one im dose of 25 units (2–17 year olds, 1 U ≥1 ng of purified viral protein; 18 –76 year olds, 50 U). Anamnestic responses to a booster given at 6,12 or 18 months revealed that the priming dose conferred immune memory in > 99% of vaccinees, regardless of pre-booster antibody level.Protective efficacy of 100% starting at least as early as day 21 after a single dose was proven in a randomised, double-blinded field trial among 2–16 year olds in Monroe, NY. Although prior to the vaccine trial cases occurred ...