Anti-HAV Geometric Mean Concentrations Research Articles

A randomized phase 3 trial of the immunogenicity and safety of coadministration of a live-attenuated tetravalent dengue vaccine (TAK-003) and an inactivated hepatitis a (HAV) virus vaccine in a dengue non-endemic country

BackgroundVaccination against hepatitis A virus (HAV) is largely recommended for travelers worldwide. Concurrent dengue and HAV vaccination may be desired in parallel for travelers to countries where both diseases are endemic. This randomized, observer-blind, phase 3 trial evaluated coadministration of HAV vaccine with tetravalent dengue vaccine (TAK-003) in healthy adults aged 18–60 years living in the UK. MethodsParticipants were randomized (1:1:1) to receive HAV vaccine and placebo on Day 1, and placebo on Day 90 (Group 1), TAK-003 and placebo on Day 1, and TAK-003 on Day 90 (Group 2), or TAK-003 and HAV vaccine on Day 1, and TAK-003 on Day 90 (Group 3). The primary objective was non-inferiority of HAV seroprotection rate (anti-HAV ≥ 12.5 mIU/mL) in Group 3 versus Group 1, one month post-first vaccination (Day 30) in HAV-naïve and dengue-naïve participants. Sensitivity analyses were performed on combinations of baseline HAV and dengue serostatus. Secondary objectives included dengue seropositivity one month post-second vaccination (Day 120), HAV geometric mean concentrations (GMCs), and safety. Results900 participants were randomized. On Day 30, HAV seroprotection rates were non-inferior following coadministration of HAV and TAK-003 (Group 3: 98.7 %) to HAV administration alone (Group 1: 97.1 %; difference: −1.68, 95 % CI: −8.91 to 4.28). Sensitivity analyses including participants who were neither HAV-naïve nor DENV-naïve at baseline supported this finding. Anti-HAV GMCs on Day 30 were 82.1 (95 % CI: 62.9–107.1) mIU/mL in Group 1 and 93.0 (76.1–113.6) mIU/mL in Group 3. By Day 120, 90.9–96.8 % of TAK-003 recipients were seropositive (neutralizing antibody titer > 10) to all four dengue serotypes. Coadministration of HAV vaccine and TAK-003 was well tolerated, with no important safety risks identified. ConclusionImmune responses following coadministration of HAV vaccine and TAK-003 were non-inferior to administration of HAV vaccine alone. The results support the coadministration of HAV vaccine and TAK-003 with no adverse impact on immunogenicity, safety, and reactogenicity of either vaccine.ClinicalTrials.gov registration: NCT03525119.

Comparison of the immunogenicity and safety of 3 inactivated hepatitis A vaccines in Korean children aged 12 to 18 months: An open-label, randomized, prospective, multicenter study.

Several approved inactivated hepatitis A (HA) vaccines are available in Korea. These have been shown to be immunogenic and safe in European children; however, their immunogenicity and safety have not been investigated among Korean children. We aimed to compare the immunogenicity and safety of the most commonly used HA vaccines in ethnic Korean children aged 12 to 18 months.In this open-label, randomized, prospective, multicenter study, 108 children were enrolled and randomized to receive a pediatric form of Avaxim, Epaxal, or Havrix. The 2nd dose was administered after an interval of 6 months. Anti-HA virus (HAV) immunoglobulin (Ig) G was measured to assess geometric mean concentrations (GMCs) and seropositvity rates (≥20 mIU/mL anti-HAV IgG). To assess safety, local solicited adverse events (AEs), systemic solicited AEs, unsolicited AEs, and serious AEs (SAEs) were graded.Among the 108 participants enrolled, 37, 34, and 37 received Avaxim, Epaxal, and Havrix, respectively. After administration of 2 doses, the seropositivity rates in the Avaxim, Epaxal, and Havrix groups were all 100% (95% confidence intervals [CIs]: 99.0–100, 98.9–100, and 99.0–100, respectively; P < .001). The anti-HAV GMCs in the Avaxim, Epaxal, and Havrix groups were 5868.4 (95% CI: 4237.2–8126.6), 1962.1 (95% CI: 1298.0–2965.9), and 2232.9 mIU/mL (95% CI: 1428.4–3490.4), respectively, after administration of 2 doses (P < .001). There were no significant differences in the proportions of participants reporting local solicited AEs, systemic solicited AEs, unsolicited AEs, and SAEs among the 3 vaccine groups after the 1st and 2nd doses. All local solicited and unsolicited AEs were grade 1 or 2. Grade 3 systemic solicited AE occurred in 5.4% and 2.9% of the participants in the Havrix group after the 1st and 2nd doses, respectively. SAEs after the 1st and 2nd doses were reported in 2 participants and 1 participant, respectively, but none was assessed as being related to vaccination.The results indicate that these vaccines were safe and immunogenic in ethnic Korean children. The results have contributed to the establishing of an HA vaccination policy in Korea and will be informative to countries that plan to initiate vaccination programs against HAV.

Long-term Serologic Follow-up of Children Vaccinated with a Pediatric Formulation of Virosomal Hepatitis A Vaccine Administered With Routine Childhood Vaccines at 12-15 Months of Age.

The aim of this open-label, active-controlled, parallel group, phase 2 follow-up study was to assess the long-term immunogenicity of Epaxal Junior, the pediatric dose of an aluminum-free virosomal inactivated hepatitis A virus (HAV) vaccine, in children receiving routine childhood vaccines (RCV). Healthy children (12-15 months old, ≥8 kg weight) were randomized (1:1:1) to group A: Epaxal Junior + RCV (day 1); group B: Epaxal Junior (day 1) + RCV (day 29) and group C: Havrix 720 + RCV (day 1). All 3 groups received 2 doses of HAV vaccines 6 months apart. Children who completed the primary study were followed up from 18 months to 7.5 years post booster. Of 291/327 randomized children who had completed the primary study, 157 were followed for the 7.5-year analysis (group A: 50; group B: 54; and group C: 53). Of these, 152 children had protective levels of anti-HAV antibodies [≥10 mIU/mL; 98% (group A); 96.3% (group B); 96.2% (group C)]. Anti-HAV geometric mean concentrations were similar in groups A and B at all the time points (1.5-, 2.5-, 3.5-, 5.25- and 7.5-year time point) but slightly lower in group C. Predictions of the median duration of persistence of seroprotective antibody levels, using the linear mixed model were similar in all groups: (group A: 19.1 years, group B: 18.7 years, group C: 17.3 years). Immunization with Epaxal Junior administered with RCVs at 12 months elicited protective response beyond 7.5 years in almost all children. Assessing the kinetic of anti-HAV antibody titers decline over time, the moment to reach antibody concentrations below the accepted protective level may occur earlier than previously estimated.

Long-term immunogenicity of inactivated hepatitis A vaccine: Follow-up at 15 years

We conducted a 10-15 years follow-up to a long-term prospective cohort study on the immunogenicity of inactivated hepatitis A vaccine in Alaska Native children, who were initially vaccinated between 3-6 years of age. Children received three vaccine doses (320 E.U.) and were randomized into the following vaccination schedules: A (0, 1, 2 months); B (0, 1, 6 months); and C (0, 1, 12 months). Sera were collected every 2 years and tested for hepatitis A virus (anti-HAV). Levels 20 mIU/mL were considered protective. Anti-HAV geometric mean concentrations were compared by vaccination schedule at 10, 12 and 14 years of follow-up, using ANOVA. Antibody decline over the entire 15-year follow-up period was also analyzed. While none of the inter-schedule comparisons differed significantly from each other at the 10, 12 and 14-year periods, schedules B and C had significantly higher anti-HAV levels than schedule A over the entire 15 years of the study ( P< 0.01). All schedule B and C children maintained seroprotective levels in all follow-up periods. Fourteen percent of schedule A children fell below seroprotective levels at 14 years. Our model estimated that anti-HAV geometric mean concentrations would fall below seroprotective levels at 26, 30 and 32 years for schedules A, B and C, respectively. The data indicate that hepatitis A immunity lasts at least 15 years after vaccination in children and that a booster dose is not needed during that time. However, continued monitoring is necessary to assess the need for a booster dose later in the second and third decade after receipt of the primary series.

Five-year follow-up of immune response after one or two doses of inactivated hepatitis A vaccine given at 1 year of age in the Mendoza Province of Argentina.

Our study was conducted to further investigate the single-dose approach of hepatitis A vaccination, while providing supportive data on the flexibility of booster administration. Participants received at least one dose of Avaxim 80U Pediatric at 11-23 months of age, and they will be followed for 10 years. We report here the fourth and fifth years after the first vaccination. Group assignment was based on whether the children received 1 dose and no booster during the study (Group 1) or 2 doses and no further booster (Group 2). Anti-HAV antibody concentrations were assessed at each annual visit. Of the 546 initial participants, 441 (80.8%) and 412 (75.5%) were followed up 4 and 5 years after vaccination, respectively. Of the 411 subjects evaluable at Year 5, 318 had received one vaccine dose and 85 had received two. Seroprotection rates were still high in Group 1 (99.7%) and in Group 2 (100%) 5 years after one or two doses of Avaxim 80U Pediatric, correspondingly. Anti-HAV geometric mean concentrations decreased in both groups compared to what they were 3 years after vaccination, while remaining well above the 10 mIU/mL threshold 5 years after vaccination. The highest concentrations were found in the children who received 2 vaccine doses. Hepatitis A humoral immunity induced by a single dose of inactivated hepatitis A vaccine can persist for at least 5 years in a paediatric population. The study results also support recommendations in favour of a flexible time window for booster vaccination.

Immunogenicity, safety, and interchangeability of two inactivated hepatitis A vaccines in Chilean children

To compare the immunogenicity, safety, and interchangeability of two pediatric hepatitis A vaccines, Avaxim 80U-Pediatric and Havrix 720, in Chilean children. In this randomized trial, 332 hepatitis A virus (HAV) seronegative children from 1 to 15 years of age received two doses of Avaxim, two doses of Havrix, or Havrix followed by Avaxim, 6 months apart. Anti-HAV antibody titers were measured before and 14 days after the first dose of vaccine, and before and 28 days after the second dose of vaccine. Immediate reactions were monitored; reactogenicity was evaluated from parental reports. Seroconversion rates after the first vaccination were 99.4% and 100% for Avaxim and Havrix, respectively. Anti-HAV geometric mean concentrations (GMCs) were 138 mIU/ml for Havrix (95% confidence interval (CI): 120; 159) and 311 mIU/ml for Avaxim (95% CI: 274; 353). GMCs increased to 4008 mIU/ml after two doses of Havrix, 8537 mIU/ml following two doses of Avaxim, and 7144 mIU/ml in children who received Havrix with Avaxim as the second dose. Following the first injection, 36% of subjects given Avaxim and 44% given Havrix reported local reactions; 38% of subjects in the Avaxim group and 40% in the Havrix group reported systemic reactions related to vaccination. Solicited reactions were less frequent after the second dose of Avaxim or Havrix, occurring in 27% to 37% of subjects. No significant difference in seroconversion rates was seen 14 days after a single dose of vaccine. A two-dose schedule with either vaccine or with Havrix/Avaxim provided a strong booster response. Both vaccines were well tolerated and can be recommended for routine vaccination of Chilean children. Avaxim 80 may be used to complete a vaccine schedule begun with Havrix 720.

Interchangeability of a hepatitis A vaccine second dose: Avaxim 80 following a first dose of Vaqta 25 or Havrix 720 in children in Turkey

This randomised, observer-blind clinical trial conducted in Turkey evaluated the immunogenicity, safety and interchangeability of three paediatric inactivated hepatitis A vaccines in 424 seronegative children between 1 and 15 years of age. Potential subjects were screened for anti-hepatitis A virus (HAV) antibodies prior to receiving a first dose of Avaxim 80, Havrix 720 or Vaqta 25, followed by a second dose of either the same vaccine or Avaxim 6 months later. Anti-HAV antibody concentrations were measured 2 weeks after the first injection, at 24 weeks (before the second dose) and at 28 weeks for the evaluation of the immune response. Nearly 80% of the children between 1 and 5 years of age and half of those between the ages of 6 and 10 in the population from which the subjects were recruited were seronegative for HAV antibodies. Two weeks after the first dose, 98.2% of all subjects had anti-HAV antibody concentrations equal to or higher than 20 mIU/mL, believed to be seroprotective, and all subjects were seroprotected before and after the second dose. Anti-HAV geometric mean concentrations (GMCs) 2 weeks after the first dose and before the second were similar in children who received Avaxim and Vaqta (P = 0.2), but both were higher than Havrix (P < 0.01). There were no significant differences in the anti-HAV GMCs between the study groups that received two doses of the same vaccine compared with two doses of different vaccines. There were no significant differences in the frequency of any local or systemic adverse events among the study groups following either of the two doses. All three vaccines are safe and highly immunogenic in healthy children aged 1 to 15 years. Avaxim 80 may also be given as the second dose when Havrix 720 or Vaqta 25 are given as the first dose. The pattern of seroprevalence seen here is similar to that reported in a number of recent evaluations in Turkey, and are supportive of the routine hepatitis A vaccination of young children.