Havrix (Hepatitis A Vaccine (Inactivated)) - Description and Clinical Pharmacology

DESCRIPTION

HAVRIX (Hepatitis A Vaccine, Inactivated) is a noninfectious hepatitis A vaccine developed and manufactured by GlaxoSmithKline Biologicals. The virus (strain HM175) is propagated in MRC₅ human diploid cells. After removal of the cell culture medium, the cells are lysed to form a suspension. This suspension is purified through ultrafiltration and gel permeation chromatography procedures. Treatment of this lysate with formalin ensures viral inactivation. HAVRIX contains a sterile suspension of inactivated virus; viral antigen activity is referenced to a standard using an enzyme linked immunosorbent assay (ELISA), and is therefore expressed in terms of ELISA Units (EL.U.).

HAVRIX is supplied as a sterile suspension for intramuscular administration. The vaccine is ready for use without reconstitution; it must be shaken before administration since a fine white deposit with a clear colorless supernatant may form on storage. After shaking, the vaccine is a slightly turbid white suspension.

Each 1-mL adult dose of vaccine consists of not less than 1440 EL.U. of viral antigen, adsorbed on 0.5 mg of aluminum as aluminum hydroxide.

There are 2 pediatric dose formulations, each with its own dosing schedule (see DOSAGE AND ADMINISTRATION). The formulations are: Not less than 360 EL.U. of viral antigen/0.5 mL; not less than 720 EL.U. of viral antigen/0.5 mL. Each dose is adsorbed onto 0.25 mg of aluminum as aluminum hydroxide.

The vaccine preparations also contain 0.5% (w/v) of 2-phenoxyethanol as a preservative. Other excipients are: Amino acid supplement (0.3% w/v) in a phosphate-buffered saline solution and polysorbate 20 (0.05 mg/mL). Residual MRC₅ cellular proteins (not more than 5 mcg/mL) and traces of formalin (not more than 0.1 mg/mL) are present. Neomycin sulfate, an aminoglycoside antibiotic, is included in the cell growth media; only trace amounts (not more than 40 ng/mL) remain following purification.

CLINICAL PHARMACOLOGY

The hepatitis A virus (HAV) belongs to the picornavirus family. Only one serotype of HAV has been described. ¹

Hepatitis A is highly contagious with the predominant mode of transmission being person-to-person via the fecal-oral route. Infection has been shown to be spread (1) by contaminated water or food; (2) by infected food handlers²; (3) after breakdown in usual sanitary conditions or after floods or natural disasters; (4) by ingestion of raw or undercooked shellfish (oysters, clams, mussels) from contaminated waters³; (5) during travel to areas of the world with poor hygienic conditions^4,5; (6) among institutionalized children and adults⁶; (7) in day-care centers where children have not been toilet trained⁷; (8) by parenteral transmission, either blood transfusions or sharing needles with infected people. ¹

The level of economic development influences the prevalence of hepatitis A and the age at which it is most likely to occur. In developing countries with poor hygiene and sanitation, about 90% of children are infected by age 5 years. ¹ As conditions improve, the prevalence decreases and the age at which infection occurs increases. Hence it is more likely to occur in adulthood, when disease is generally more severe and more likely to be fatal.¹ In the United States, attack rates for hepatitis A infection are cyclical and vary by population. The rates have increased gradually from 9.2 per 100,000 in 1983 to 14.6 per 100,000 in 1989. ⁸

The incubation period for hepatitis A averages 28 days (range: 15 to 50 days). ⁹ The course of hepatitis A infection is extremely variable, ranging from asymptomatic infection to icteric hepatitis. However, most adults (76% to 97%) become symptomatic.¹⁰ Symptoms range from mild and transient to severe and prolonged and may include fever, nausea, vomiting, and diarrhea in the prodromal phase, followed by jaundice in up to 88% of adults, as well as hepatomegaly and biochemical evidence of hepatocellular damage.¹⁰ Recovery is generally complete and followed by protection against HAV infection. However, illness may be prolonged, and relapse of clinical illness and viral shedding have been described. ¹¹

Hepatitis A infection is often asymptomatic in children under 2 years of age, who nonetheless excrete the virus in their stool and thereby serve as a source of infection.¹⁰ In older patients and persons with underlying liver disease, it is generally much more severe. ¹ This is reflected in mortality rates. While an overall case fatality rate of 0.6% has been reported, a case fatality rate of 2.7% has been reported in patients >/=49 years of age. ¹ Indeed, while 67% of cases occur in children, over 70% of deaths occur in those over the age of 49 years. ¹

There is no chronic carrier state. The virus replicates in the liver and is excreted in bile. The highest concentrations of HAV are found in stools of infected persons during the 2-week period immediately before the onset of jaundice and decline after jaundice appears. ¹² Children and infants may shed HAV for longer periods than adults, possibly lasting as long as several weeks after the onset of clinical illness.¹³ Chronic shedding of HAV in feces has not been demonstrated, but relapses of hepatitis A can occur in as many as 20% of patients, ^1,14 and fecal shedding of HAV may recur at this time.¹¹

The presence of antibodies to HAV (anti-HAV) confers protection against hepatitis A infection. However, the lowest titer needed to confer protection has not been determined.

In a chimpanzee challenge study, the quality of protection afforded by immune globulin (IG) prepared from initially seronegative human volunteers vaccinated with HAVRIX was comparable to that afforded by commercial IG. In this experiment, chimpanzees immunized with either preparation developed passive-active immunity when challenged with wild-type HAV. No animal in either group developed clinical illness.

In vitro studies in a randomly selected subset of human subjects (n = 80) showed anti-HAV induced by HAVRIX to have functional activity. This was demonstrated by a neutralization assay and a competitive inhibition assay using a panel of monoclonal antibodies known to have neutralizing activity.

Immunogenicity in Adults: In 3 clinical studies involving over 400 healthy adult volunteers given a single 1440 EL.U. dose of HAVRIX, specific humoral antibodies against HAV were elicited in more than 96% of subjects when measured 1 month after vaccination. By day 15, 80% to 98% of vaccinees had already seroconverted (anti-HAV >/=20 mIU/mL [the lower limit of antibody measurement by current assay]). Geometric mean titers (GMTs) of seroconverters ranged from 264 to 339 mIU/mL at day 15 and increased to a range of 335 to 637 mIU/mL by 1 month following vaccination.¹⁵

The GMTs obtained following a single dose of HAVRIX are at least several times higher than that expected following receipt of IG.

In a clinical study using 2.5 to 5 times the standard dose of IG (standard dose = 0.02 to 0.06 mL/kg), the GMT in recipients was 146 mIU/mL at 5 days post-administration, 77 mIU/mL at month 1, and 63 mIU/mL at month 2.¹⁵

In 2 clinical trials in which a booster dose of 1440 EL.U. was given 6 months following the initial dose, 100% of vaccinees (n = 269) were seropositive 1 month after the booster dose, with GMTs ranging from 3,318 mIU/mL to 5,925 mIU/mL. The titers obtained from this additional dose approximate those observed several years after natural infection.

In a subset of vaccinees (n = 89), a single dose of HAVRIX 1440 EL.U. elicited specific anti-HAV neutralizing antibodies in more than 94% of vaccinees when measured 1 month after vaccination. These neutralizing antibodies persisted until month 6. One hundred percent of vaccinees had neutralizing antibodies when measured 1 month after a booster dose given at month 6.

Immunogenicity of HAVRIX was studied in subjects with chronic liver disease of various etiologies. 189 healthy adults and 220 adults with either chronic hepatitis B (n = 46), chronic hepatitis C (n = 104), or moderate chronic liver disease of other etiology (n = 70) were vaccinated with HAVRIX 1440 EL.U. on a 0- and 6-month schedule. The last group consisted of alcoholic cirrhosis (n = 17), autoimmune hepatitis (n = 10), chronic hepatitis/cryptogenic cirrhosis (n = 9), hemochromatosis (n = 2), primary biliary cirrhosis (n = 15), primary sclerosing cholangitis (n = 4), and unspecified (n = 13). At each time point, GMTs were lower for subjects with chronic liver disease than for healthy subjects. At month 7, the GMTs ranged from 478 mIU/mL (chronic hepatitis C) to 1,245 mIU/mL (healthy), as determined by a commercial ELISA. The relevance of these data to the duration of protection afforded by HAVRIX is unknown. One month after the first dose, seroconversion rates in adults with chronic liver disease were lower than in healthy adults. However, 1 month after the booster dose at month 6, seroconversion rates were similiar in all groups; rates ranged from 94.7% to 98.1%.

Immunogenicity in Children and Adolescents: In 6 clinical studies involving pediatric vaccinees (n = 762) ranging from 1 to 18 years of age, the GMT following 2 doses of HAVRIX 360 EL.U. given 1 month apart ranged from 197 to 660 mIU/mL. Ninety-nine percent of subjects seroconverted following 2 doses. When a booster (third) dose of HAVRIX 360 EL.U. was administered 6 months following the initial dose, all subjects were seropositive 1 month following the booster dose, with GMTs rising to a range of 3,388 to 4,643 mIU/mL. In 1 study in which children were followed for an additional 6 months, all subjects remained seropositive. Solicited adverse effects were similar in frequency and nature to those seen following administration of ENGERIX-B^® [Hepatitis B Vaccine (Recombinant)].

In 4 clinical studies, children and adolescents (n = 314), ranging from 2 to 19 years of age, were immunized with 2 doses of HAVRIX 720 EL.U./0.5 mL given 6 months apart. One month after the first dose, seroconversion ranged from 96.8% to 100%, with GMTs of 194 mIU/mL to 305 mIU/mL. In studies in which sera were obtained 2 weeks following the initial dose, seroconversion ranged from 91.6% to 96.1%. One month following a booster dose at month 6, all subjects were seropositive, with GMTs ranging from 2,495 mIU/mL to 3,644 mIU/mL. ¹⁵

In 1 additional study in which the booster dose was delayed until 1 year following the initial dose, 95.2% of the subjects were seropositive just prior to administration of the booster dose. One month later, all subjects were seropositive, with a GMT of 2,657 mIU/mL. ¹⁵

Also, HAVRIX has been found to be highly efficacious in a clinical study of children at high risk of HAV infection (see below).

At present, the duration of protection afforded by HAVRIX has not been established. Therefore it is unknown if the protection provided to immunized children will last until adulthood.

Protective Efficacy: Protective efficacy with HAVRIX has been demonstrated in a double-blind, randomized controlled study in school children (age 1 to 16 years) in Thailand who were at high risk of HAV infection. A total of 40,119 children were randomized to be vaccinated with either HAVRIX 360 EL.U. or ENGERIX-B at 0, 1, and 12 months. 19,037 children received a primary course (0 and 1 months) of HAVRIX and 19,120 children received a primary course (0 and 1 months) of ENGERIX-B. 38,157 children entered surveillance at day 138 and were observed for an additional 8 months. Using the protocol-defined endpoint (>/=2 days absence from school, ALT level >45 U/mL, and a positive result in the HAVAB-M test), 32 cases of clinical hepatitis A occurred in the control group; in the HAVRIX group, 2 cases were identified. These 2 cases were mild both in terms of biochemical and clinical indices of hepatitis A disease. Thus the calculated efficacy rate for prevention of clinical hepatitis A was 94% (95% confidence intervals 74% to 98%). ¹⁶

In outbreak investigations occurring in the trial, 26 clinical cases of hepatitis A (of a total of 34 occurring in the trial) occurred. No cases occurred in HAVRIX vaccinees.

Using additional virological and serological analyses post hoc, the efficacy of HAVRIX was confirmed. Up to 3 additional cases of very mild clinical illness may have occurred in vaccinees. Using available testing, these illnesses could neither be proven nor disproven to have been caused by HAV. By including these as cases, the calculated efficacy rate for prevention of clinical hepatitis A would be 84% (95% confidence intervals 60% to 94%).

In a study designed to interrupt an epidemic of hepatitis A among Native Americans in Alaska, vaccination with a single dose of HAVRIX (1440 EL.U./mL in adults, 720 EL.U./0.5 mL in children and adolescents) appeared to be efficacious. ¹⁷