Barbara J. Kuter

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.

Safety and Immunogenicity of an Inactivated Hepatitis A Vaccine among HIV-Infected Subjects

BACKGROUND Hepatitis A is a major health risk for many human immunodeficiency virus (HIV)-infected individuals. Vaccination is a potentially attractive measure to reduce the incidence of hepatitis A among this population, but data on its safety and immunogenicity are incomplete. METHODS Ninety HIV-uninfected adults received an inactivated hepatitis A vaccine (VAQTA; Merck), and 90 HIV-infected subjects were randomized, in double-blind fashion, to receive either the vaccine or placebo. The HIV-infected subjects were stratified by CD4 cell count, with 45 subjects having CD4 cell counts of > or =300 cells/mm3 and 45 subjects having CD4 cell counts of <300 cells/mm3. Vaccine was given at weeks 0 and 24 of the study.Results. Seroconversion rates at week 28 of the study were 94% among the HIV-infected subjects and 100% among the HIV-uninfected control subjects. HIV-infected subjects with CD4 cell counts of <300 cells/mm3 had a seroconversion rate of 87%, and HIV-infected subjects with CD4 cell counts of > or =300 cells/mm3 had a seroconversion rate of 100%. The vaccine was generally well tolerated, and no adverse effect on either HIV load or CD4 cell count was found. CONCLUSION Hepatitis A vaccine was both immunogenic and safe among HIV-infected subjects.

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.

Safety, tolerability, and immunogenicity of two regimens of Oka/Merck varicella vaccine (Varivax®) in healthy adolescents and adults

A multicenter clinical trial was conducted among 757 healthy adolescents and adults, 13-54 years, to compare two regimens of Oka/Merck varicella vaccine with respect to safety, tolerability, and immunogenicity. Participants were randomized to receive two injections of vaccine either four or eight weeks apart and were followed for clinical reactions and serologic response. The two vaccine regimens were equally well tolerated. The seroconversion rates (gpELISA) four weeks after injection 1 and 2 were 72 and 99%, respectively, for those who received vaccine four weeks apart and 78 and 99%, respectively, for those who received vaccine eight weeks apart. The differences in seroconversion rates were not statistically significant. However, delaying the second dose to eight weeks resulted in a higher antibody titer one month after the second injection. Administration of a two-dose regimen of varicella vaccine to susceptible adolescents and adults is well tolerated and highly immunogenic.

Effectiveness of hepatitis A vaccine in a former frequently affected community: 9 years’ followup after the Monroe field trial of VAQTA®

The Kiryas Joel community in Monroe, N.Y. was the site of the first clinical trial which proved the protective efficacy of hepatitis A vaccine. The vaccine used was VAQTA J. Med. Virol (hepatitis A vaccine, inactivated). In the 9 years since the trial ended vaccination of infants reaching 2 years of age has continued along with monitoring for hepatitis A cases. The prevaccine pattern of frequent outbreaks has converted to a sustained pattern of no outbreaks, despite sporadic introduction of hepatitis A into the community in nonvaccinees. Community use of VAQTA in children 2 years of age and older has proven capable of providing long-term prevention of hepatitis A outbreaks in a formerly frequently affected community despite prolonged sporadic introduction of the virus.

Evaluating the safety of a rotavirus vaccine: the REST of the story

The Rotavirus Efficacy and Safety Trial (REST) was a blinded, placebo-controlled study of the live pentavalent human-bovine vaccine, RotaTeq® (Merck & Co. Inc., West Point, PA). REST was noteworthy because its primary objective was to evaluate the safety of RotaTeq® with regard to intussusception, a rare intestinal illness that occurs with a background incidence of approximately 50 cases per 100 000 infant years. The study involved approximately 70 000 infants at over 500 study sites in 11 countries. The study demonstrated that the risk of intussusception was similar in vaccine and placebo recipients and that the vaccine prevented rotavirus gastroenteritis, ameliorated the severity of disease in those who had any disease, and substantially reduced rotavirus-associated hospitalizations and other health care contacts. This report provides an in-depth review of the background, statistical and regulatory considerations, and execution of REST. We describe the rationale and methods used for sample size, continuous safety monitoring, group sequential design, and detailed study execution. The results of the study have been reported elsewhere. The design and conduct of this study may serve as a useful model for planning other future large-scale clinical trials, especially those evaluating uncommon adverse events. Clinical Trials 2008; 5: 131—139. http:// ctj.sagepub.com

Randomized, Double-Blind Study in Healthy Adults to Assess the Boosting Effect of Vaqta or Havrix after a Single Dose of Havrix

A randomized, double-blind, multicenter study was conducted to investigate the boosting effect of Vaqta or Havrix in 537 healthy adults 18-53 years of age who had received a single dose of Havrix either 24 or 52 weeks earlier. Subjects were randomized in a 2 : 1 ratio to receive either Vaqta or Havrix for their second dose of vaccine and followed for clinical reactions for 14 days after dose 2 was administered. Serum samples were collected immediately before dose 2 was administered and again 4 weeks later and evaluated for hepatitis A antibody (modified hepatitis A virus antibody assay). The booster response rate after administration of the second dose of either vaccine was similar (86.1% for Vaqta vs. 80.1% for Havrix). The geometric mean titers were also similar: 3274 mIU/mL (95% confidence interval [CI], 2776-3858) for Vaqta versus 2423 mIU/mL (95% CI, 1911-3074) for Havrix. The proportion of subjects who reported > or =1 injection-site adverse experiences was lower in the patients receiving Vaqta than in those receiving Havrix (36.6% vs. 59.7%; P<.001). The results of this study indicate that a regimen of Havrix followed by Vaqta is generally well tolerated and highly immunogenic.

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.

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.

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 ...