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Vaqta

CLINICAL PHARMACOLOGY

Hepatitis A Disease

Hepatitis A virus is one of several hepatitis viruses that cause a systemic infection with pathology in the liver. The incubation period ranges from approximately 20 to 50 days. The course of the disease following infection ranges from asymptomatic infection to fulminant hepatitis and death.1

Protection from hepatitis A disease has been shown to be related to the presence of antibody. Protection after vaccination with VAQTA (hepatitis a vaccine, inactivated) has been associated with the onset of seroconversion ( ≥ 10 mIU/mL of hepatitis A antibody, measured by a modification of the HAVAB**radioimmunoassay [RIA]2) and with an anamnestic antibody response following booster vaccination with VAQTA (hepatitis a vaccine, inactivated) .

Efficacy of VAQTA (hepatitis a vaccine, inactivated)

A very high degree of protection has been demonstrated after a single dose of VAQTA (hepatitis a vaccine, inactivated) in children and adolescents.3 The protective efficacy, immunogenicity and safety of VAQTA (hepatitis a vaccine, inactivated) were evaluated in a randomized, double-blind, placebo-controlled study involving 1037 susceptible healthy children and adolescents 2 through 16 years of age in a U.S. community with recurrent outbreaks of hepatitis A (the Monroe Efficacy Study). Each child received an intramuscular dose of VAQTA (hepatitis a vaccine, inactivated) (~25U) or placebo. Among those individuals who were initially seronegative (by modified HAVAB), seroconversion was achieved in > 99% of vaccine recipients within 4 weeks after vaccination. The onset of seroconversion following a single dose of VAQTA (hepatitis a vaccine, inactivated) was shown to parallel the onset of protection against clinical hepatitis A disease.

Because of the long incubation period of the disease (approximately 20 to 50 days, or longer in children4), the primary endpoint was based on clinically confirmed cases*** of hepatitis A occurring 50 days after vaccination in order to exclude any children incubating the infection before vaccination. In subjects who were initially seronegative, the protective efficacy of a single dose of VAQTA (hepatitis a vaccine, inactivated) was observed to be 100% with 21 cases of clinically confirmed hepatitis A occurring in the placebo group and none in the vaccine group (p < 0.001). A secondary endpoint was pre-defined as the number of clinically confirmed cases of hepatitis A ≥ 30 days after vaccination. With this secondary endpoint, 28 cases of clinically confirmed hepatitis A occurred in the placebo group while none occurred in the vaccine group ≥ 30 days after vaccination. In addition, it was observed in this trial that no cases of clinically confirmed hepatitis A occurred in the vaccine group after day 16.† Following demonstration of protection with a single dose and termination of the study, a booster dose was administered to a subset of vaccinees 6, 12, or 18 months after the primary dose. To date, no cases of clinically confirmed hepatitis A disease ≥ 50 days after vaccination have occurred in those vaccinees from The Monroe Efficacy Study monitored for up to 9 years.5

Although cases of imported infection have occurred, the study community has remained free of outbreaks, evidence for the effectiveness of VAQTA (hepatitis a vaccine, inactivated) for use in community outbreak control. In contrast, three nearby sister communities to Monroe have continued to experience outbreaks.3, 6

Other Clinical Studies

The efficacy of VAQTA (hepatitis a vaccine, inactivated) in other age groups was based upon immunogenicity measured 4 to 6 weeks following vaccination. VAQTA (hepatitis a vaccine, inactivated) was found to be highly immunogenic in all age groups.

In initially seronegative children 12 through 23 months of age, who received VAQTA (hepatitis a vaccine, inactivated) with or without other vaccines, 96% (n=471; 95% CI: 93.7%, 97.5%) seroconverted post dose 1 with a Geometric Mean Titer (GMT) of 48 mIU/mL (95% CI: 44.7, 51.6); and 100% (n=343; 95% CI: 99.3%, 100%) seroconverted post dose 2 with a GMT of 6920 mIU/mL (95% CI: 6136, 7801). Of children who received only VAQTA (hepatitis a vaccine, inactivated) at both visits, 100% (n=97) were seropositive after the second dose of VAQTA (hepatitis a vaccine, inactivated) . This rate was similar to the expected rate of 99% in 2 to 3 year old children.

In combined clinical studies in children and adolescents 2 through 18 years of age, 97% (n=1230; 95% CI: 96%, 98%) and 100% (n=1057; 95% CI: 99.5%, 100%) of subjects seroconverted after the first and second doses with a GMT of 43 mIU/mL (95% CI: 40, 45) and 10,077 mIU/mL (95% CI: 9394, 10,810), respectively. In combined clinical studies in adults 19 years of age and older who received VAQTA (hepatitis a vaccine, inactivated) (50 U/1.0 mL) 95% (n=1411; 95% CI: 94%, 96%) and 99.9% (n=1244; 95% CI: 99.4%, 100%) of subjects seroconverted with a GMT of 37 mIU/mL (95% CI: 35, 38) and 6013 mIU/mL (95% CI: 5592, 6467), respectively, after the first and second doses. Furthermore, at 2 weeks post-vaccination, 69.2% (n=744; 95% CI: 65.7%, 72.5%) of adults seroconverted with a GMT of 16 mIU/mL after a single dose of VAQTA (hepatitis a vaccine, inactivated) .

Persistence

In follow-up of subjects in The Monroe Efficacy Study, in children ( ≥ 2 years of age) and adolescents who received two doses (~25U) of VAQTA, detectable levels of anti-HAV antibodies ( ≥ 10 mIU/mL) were present in 100% of subjects for up to 6 years postvaccination. In subjects who received VAQTA (hepatitis a vaccine, inactivated) at 0 and 6 months, the GMT was 819 mIU/mL (n=175) at 2.5 to 3.5 years and 505 mIU/mL (n=174) at 5 to 6 years postvaccination. In subjects who received VAQTA (hepatitis a vaccine, inactivated) at 0 and 12 months, the GMT was 2224 mIU/mL (n=49) at 2.5 to 3.5 years and 1191 mIU/mL (n=47) at 5 to 6 years postvaccination. In subjects who received VAQTA (hepatitis a vaccine, inactivated) at 0 and 18 months, the GMT was 2501 mIU/mL (n=53) at 2.5 to 3.5 years and 1500 mIU/mL (n=53) at 5 to 6 years postvaccination.

In adults that were administered VAQTA (hepatitis a vaccine, inactivated) at 0 and 6 months, the hepatitis A antibody response to date has been shown to persist up to 6 years in adults. Detectable levels of anti-HAV antibodies ( ≥ 10 mIU/mL) were present in 100% (378/378) of subjects with a GMT of 1734 mIU/mL at 1 year, 99.2% (252/254) of subjects with a GMT of 687 mIU/mL at 2 to 3 years, 99.1% (219/221) of subjects with a GMT of 605 mIU/mL at 4 years, and 99.4% (170/171) of subjects with a GMT of 684 mIU/mL at 6 years postvaccination.

The total duration of the protective effect of VAQTA (hepatitis a vaccine, inactivated) in healthy vaccinees is unknown at present.

Immune memory was demonstrated by an anamnestic response in individuals who received either a ~25U/0.5 mL (Table 1—Monroe Efficacy Study) or a ~50U/1.0 mL (adult clinical study) booster dose 6 to 18 months after the primary dose.

Table 1 : Children/Adolescents from the Monroe Efficacy Study Seroconversion Rates (%) and Geometric Mean Titers (GMT) for Cohorts of Initially Seronegative Vaccinees at the Time of the Booster (~25U) and 4 Weeks Later

Months Following Initial ~25U Dose Cohort* (n=960)
0 and 6 Months
Cohort* (n=35)
0 and 12 Months
Cohort* (n=39)
0 and 18 Months
  Seroconversion Rate GMT (mIU/mL) (95% CI)
6 97% __ __
107 (98, 117)    
7 100% __ __
10433 (9681, 11243)    
12 __ 91% __
  48 (33, 71)  
13 __ 100% __
  12308 (9337, 16226)  
18 __ __ 90%
    50 (28, 89)
19 __ __ 100%
    9591 (7613, 12082)
 * Blood samples were taken at prebooster and postbooster time points.

In a clinical study involving healthy adults who received two doses (~50U) of VAQTA (hepatitis a vaccine, inactivated) , 4 weeks after the booster dose was administered at 6, 12, and 18 months after the first dose, 100% of 1201 subjects, 98% of 91 subjects, and 100% of 84 subjects were seropositive, respectively. GMTs in mIU/mL one month after the subjects received the booster dose at 6, 12, or 18 months after the primary dose were 5987 mIU/mL (95% CI: 5561, 6445), 4896 (95% CI: 3589, 6679), and 6043 (95% CI: 4687, 7793), respectively.

Post Exposure Prophylaxis

While a study evaluating VAQTA (hepatitis a vaccine, inactivated) alone in a post-exposure setting has not been conducted, the concurrent use of VAQTA (hepatitis a vaccine, inactivated) (~50U) and immune globulin (IG, 0.06 mL/kg) was evaluated in a clinical study involving healthy adults 18 to 39 years of age. Table 2 provides seroconversion rates and GMT at 4 and 24 weeks after the first dose in each treatment group and at one month after a booster dose of VAQTA (hepatitis a vaccine, inactivated) (administered at 24 weeks).

Table 2 : Seroconversion Rates (%) and Geometric Mean Titers (GMT) After Vaccination With VAQTA (hepatitis a vaccine, inactivated) Plus IG, VAQTA (hepatitis a vaccine, inactivated) Alone, and IG Alone

Weeks VAQTA plus IG VAQTA IG
Seroconversion Rate GMT (mIU/mL) (95% CI)
4 100% 96% 87%
42 (39, 45) 38 (33, 42) 19 ( 15, 23)
(n=129) (n=135) (n=30)
24 92% 97%* 0%
83 (65, 105) 137* (112, 169) Undetectable†
(n=125) (n=132) (n=28)
28 100% 100% N/A
4872 (3716, 6388) 6498 (5111, 8261)  
(n=114) (n=128)  
 Undetectable is defined as < 10mIU/mL.
*The seroconversion rate and the GMT in the group receiving VAQTA (hepatitis a vaccine, inactivated) alone were significantly higher than in the group receiving VAQTA (hepatitis a vaccine, inactivated) plus IG (p=0.05, p < 0.001, respectively). N/A = Not Applicable

Interchangeability of the Booster Dose

A clinical study in 537 healthy adults, 18 to 83 years of age, evaluated the immune response to a booster dose of VAQTA and HAVRIX†† (hepatitis A vaccine, inactivated) given at 6 or 12 months following an initial dose of HAVRIX. When VAQTA was given as a booster dose following HAVRIX, the vaccine produced an adequate immune response (see Table 3). (See DOSAGE AND ADMINISTRATION, Interchangeability of the Booster Dose.)

Table 3 : VAQTA Versus HAVRIX Seropositivity Rate, Booster Response Rate and Geometric Mean Titer at 4 Weeks Postbooster

First Dose Booster Dose Seropositivity Rate Booster Response Rate† Geometric Mean Titer
HAVRIX
1440 EL.U.
VAQTA
50 U
99.7% (n=313) 86.1% (n=310) 3272 (n=313)
HAVRIX
1440 EL.U.
HAVRIX
1440 EL.U.
99.3% (n=151) 80.1% (n=151) 2423 (n=151)
  Booster Response Rate is defined as greater than or equal to a tenfold rise from prebooster to postbooster titer and postbooster titer 100 mIU/mL.

Immune Response to Concomitantly Administered Vaccines

Concomitant administration of routinely administered recommended childhood vaccines with VAQTA (hepatitis a vaccine, inactivated) was assessed in a study of 617 children. In this study, the immune response to VAQTA (hepatitis a vaccine, inactivated) (~25U) was assessed in 471 children randomized to receive VAQTA (hepatitis a vaccine, inactivated) with or without M-M-R* II (Measles, Mumps, and Rubella Vaccine, Live) and VARIVAX* (Varicella Virus Vaccine Live [Oka/Merck]) at 12 months of age. Rates of seroprotection to hepatitis A were similar among the two groups who received VAQTA (hepatitis a vaccine, inactivated) with or without M-M-R II and VARIVAX. Measles, mumps and rubella immune responses were 98.8% [95% CI: 96.4%, 99.7%], 99.6% [95% CI: 97.9%, 100%], and 100% [95% CI: 98.6%, 100%], respectively, which were similar to historical rates observed following vaccination with a first dose of M-M-R II in this age group. Data on the immune response to VARIVAX are insufficient to adequately assess the immunogenicity of VARIVAX when administered concomitantly with VAQTA (hepatitis a vaccine, inactivated) . In this same study, immune responses were evaluated in 183 subjects who were administered VAQTA (hepatitis a vaccine, inactivated) with and without DTaP (TRIPEDIA§) at 18 months of age. Rates of seroprotection to hepatitis A were similar among the two groups who received VAQTA (hepatitis a vaccine, inactivated) with or without DTaP. Data are insufficient to assess the immune response of DTaP when administered with VAQTA (hepatitis a vaccine, inactivated) . Data are insufficient to assess the immune response to VAQTA (hepatitis a vaccine, inactivated) and polio vaccine following concomitant administration of the vaccines. There are no data to assess the concomitant use of Haemophilus b conjugate vaccine and Prevnar§§ with VAQTA. (See DOSAGE AND ADMINISTRATION, Use With Other Vaccines.)

A controlled clinical study was conducted with 240 healthy adults, 18 to 54 years of age, who were randomized to receive either VAQTA (hepatitis a vaccine, inactivated) , typhoid and yellow fever vaccines concomitantly at separate injection sites, or VAQTA (hepatitis a vaccine, inactivated) alone. The seropositivity rate for hepatitis A when VAQTA (hepatitis a vaccine, inactivated) , typhoid and yellow fever vaccines were administered concomitantly was generally similar to when VAQTA (hepatitis a vaccine, inactivated) was given alone. The antibody response rates for typhoid and yellow fever were adequate when typhoid and yellow fever vaccines were administered concomitantly with and without VAQTA (hepatitis a vaccine, inactivated) . The GMTs for hepatitis A when VAQTA (hepatitis a vaccine, inactivated) , typhoid and yellow fever vaccines were administered concomitantly were reduced when compared to VAQTA (hepatitis a vaccine, inactivated) alone. Following receipt of the booster dose of VAQTA (hepatitis a vaccine, inactivated) , the GMTs for hepatitis A in these two groups were observed to be comparable. (See DOSAGE AND ADMINISTRATION, Use With Other Vaccines.)

REFERENCES

1. Lemon, S.M.: Type A viral hepatitis, new developments in an old disease, NEJM313(17): 1059-1067, 1985.

2. Miller, W.J., et al: Sensitive assays for hepatitis A antibodies, J Med Virol 41: 201-204, 1993.

3. Werzberger, A., et al: A Controlled trial of a formalin-inactivated hepatitis A vaccine in healthy children, NEJM 327(7): 453-457, 1992.

4. Ward, R., et al: Infectious Hepatitis, Studies of Its Natural History and Prevention, NEJM 258(9): 407-416, February 27, 1958.

5. Werzberger, A., et al: Effectiveness of hepatitis A vaccine in a former frequently affected community: 9 years' followup after the Monroe field trial of VAQTA® (hepatitis a vaccine, inactivated) , Vaccine 20: 1699-1701, 2002.

6. Werzberger, A., et al: Anatomy of a trial: a historical view of the Monroe inactivated hepatitis A protective efficacy trial, J Hepatol 18 (Suppl. 2): S46-S50, 1993.

** Trademark of Abbott Laboratories
*** The clinical case definition included all of the following occurring at the same time: 1) one or more typical clinical signs or symptoms of hepatitis A (e.g., jaundice, malaise, fever 38.3°C), 2) elevation of hepatitis A IgM antibody (HAVAB-M), 3) elevation of alanine transferase (ALT) 2 times the upper limit of normal.
† One vaccinee did not meet the pre-defined criteria for clinically confirmed hepatitis A but did have positive hepatitis A IgM and borderline liver enzyme (ALT) elevations on days 34, 50, and 58 after vaccination with mild clinical symptoms observed on days 49 and 50.
†† Registered trademark of GlaxoSmithKline
§ Registered trademark of Sanofi Pasteur, Inc.
§§ Registered trademark of Wyeth Pharmaceuticals, Inc.

Last reviewed on RxList: 3/5/2009
This monograph has been modified to include the generic and brand name in many instances.

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