Vaqta (Hepatitis A Vaccine Inactivated) - Clinical Pharmacology

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. While the course of the disease is generally benign and does not result in chronic hepatitis, infection with hepatitis A virus remains an important cause of morbidity and occasional fulminant hepatitis and death.

Hepatitis A is transmitted most often by the fecal-oral route, with infection occurring primarily within private households. Common-source outbreaks due to contaminated food and water supplies have occurred following consumption of certain foods such as raw shellfish, and uncooked foods prepared by an infected food-handler or otherwise contaminated prior to ingestion (salads, sandwiches, frozen raspberries, etc.). Bloodborne transmission, while uncommon, is possible via blood transfusion, contaminated blood products, or from needles shared with an infected viremic individual. Sexual transmission has also been reported.

The disease burden due to hepatitis A in the United States has been estimated to be approximately 143,000 infections per year, of which 75,800 result in clinical hepatitis A disease, 11,400 hospitalizations, and 80 deaths due to fulminant hepatitis. Worldwide, it has been estimated that 1.4 million cases are reported annually. The clinical manifestations of hepatitis A infection often pass unrecognized in children Clinical Trials

Clinical trials conducted worldwide with several formulations of the vaccine in 9421 healthy individuals ranging from 2 to 85 years of age have demonstrated that VAQTA is highly immunogenic and generally well tolerated.

Protection from hepatitis A disease has been shown to be related to the presence of antibody; an anamnestic antibody response occurs in healthy individuals with a history of infection who are subsequently re-exposed to hepatitis A virus. Similarly, protection after vaccination with VAQTA has been associated with the onset of serconversion (>/=10 mIU/mL of hepatitis A antibody, measured by a modification of the HAVAB ** radioimmunoassay [RIA]) and with an anamnestic antibody response following booster vaccination with VAQTA.

POST-MARKETING SAFETY STUDY

In a post-marketing short-term safety surveillance study, conducted at a large health maintenance organization in the United States, a total of 42,110 individuals >/=2 years of age received 1 or 2 doses of VAQTA (13,735 children/adolescent and 28,375 adult subjects). Safety was passively monitored by electronic search of the automated medical records database for emergency room and outpatient visits, hospitalizations, and deaths. Medical charts were reviewed when indicated. There was no serious, vaccine-related, adverse event identified among the 42,110 vaccine recipients in this study. Diarrhea/gastroenteritis, resulting in outpatient visits, was determined by the investigator to be the only vaccine-related nonserious adverse event in the study. There was no vaccine-related, adverse event identified that had not been reported in earlier clinical trials with VAQTA. (See ADVERSE REACTIONS, Post-marketing Safety Study.)

Immunology

In combined clinical studies, 97% of 1230 healthy children and adolescents 2 through 18 years of age seroconverted with a geometric mean titer (GMT) of 43 mIU/mL within 4 weeks after a single ~25U/0.5 mL intramuscular dose of VAQTA. Similarly, 95% of 1411 adults >/=19 years of age seroconverted with a GMT of 37 mIU/mL within 4 weeks after a single ~50U/1.0 mL intramuscular dose of VAQTA. Furthermore, at 2 weeks post-vaccination, 69% (n=744) of adults seroconverted with a GMT of 16 mIU/mL after a single dose of VAQTA. Immune memory was demonstrated by an anamnestic antibody response in individuals who received either a ~25U/0.5 mL or ~50U/1.0 mL booster dose (see Persistence).

A ~50U/1.0 mL intramuscular dose of VAQTA also was evaluated at four weeks post primary dose in healthy adolescents (18 years of age); 94% of 17 adolescents seroconverted with a GMT of 40 mIU/mL. In individuals 18 years of age, the GMT following a ~50 U/1.0 mL booster dose was greater than the GMT following a ~25U/0.5 mL booster dose. Both doses were immunogenic and were generally well tolerated. (See DOSAGE AND ADMINISTRATION.)

While a study evaluating VAQTA alone in a post-exposure setting has not been conducted, the concurrent use of VAQTA (~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 1 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 (administered at 24 weeks).

Efficacy

A very high degree of protection has been demonstrated after a single dose of VAQTA in children and adolescents. The protective efficacy, immunogenicity and safety of VAQTA 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 (~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 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 children), 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 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. With this secondary endpoint, 28 cases of clinically confirmed hepatitis A occurred in the placebo group while none occurrred 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.

Persistence

The total duration of the protective effect of VAQTA in healthy vaccinees is unknown at present. However, seropositivity was shown to persist up to 18 months after a single ~25U dose in a cohort of 35 out of 39 children and adolescents who participated in The Monroe Efficacy Study; 95% of this cohort responded anamnestically following a booster at 18 months. 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 6 years.

The effectiveness of VAQTA for use in community outbreak control has been demonstrated by the fact that, although cases of imported infection have occurred, the study community has remained free of outbreaks. In contrast, three nearby sister communities to Monroe have continued to experience outbreaks.

In adults, seropositivity has been shown to persist up to 18 months after a single ~50U dose. Persistence of immunologic memory was demonstrated with an anamnestic antibody response to a booster dose of ~25U given 6 to 18 months after the primary dose in children and adolescents (Table 2), and to a booster dose of ~50U given 6 to 18 months after the primary dose to adults (Table 3).

In a clinical study involving healthy children 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 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 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 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 studies of healthy adults who received two doses (~50U) of VAQTA at 0 and 6 months, the hepatitis A antibody response to date has been shown to persist up to 6 years. 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.

Studies in healthy children, adolescents and adults are ongoing to evaluate longer-term antibody persistence and the need, if any, for additional booster doses.

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 4) and was generally well tolerated. (See DOSAGE AND ADMINISTRATION, Interchangability of the Booster Dose.)

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, typhoid and yellow fever vaccines concomitantly at separate injection sites, typhoid and yellow fever vaccines concomitantly at separate injection sites, or VAQTA alone. The seropositivity rate for hepatitis A when VAQTA, typhoid and yellow fever vaccines were administered concomitantly was generally similar to when VAQTA 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. The GMTs for hepatitis A when VAQTA, typhoid and yellow fever vaccines were administered concomitantly were reduced when compared to VAQTA alone. Following receipt of the booster dose of VAQTA, the GMTs for hepatitis A in these two groups were observed to be comparable. The concomitant administration of these three vaccines at separate injection sites was generally well tolerated. (See INDICATIONS AND USAGE, Use With Other Vaccines and DOSAGE AND ADMINISTRATION, Use With Other Vaccines.)