Twinrix (Hepatitis A Inactivated and Hepatitis B (Recombinant) Vaccine) - Description and Clinical Pharmacology

DESCRIPTION

TWINRIX® [Hepatitis A Inactivated & Hepatitis B (Recombinant) Vaccine] is a sterile bivalent vaccine containing the antigenic components used in producing HAVRIX® (Hepatitis A Vaccine, Inactivated) and ENGERIX-B® [Hepatitis B Vaccine (Recombinant)]. TWINRIX is a sterile suspension of inactivated hepatitis A virus (strain HM175) propagated in MRC₅ cells, and combined with purified surface antigen of the hepatitis B virus. The purified hepatitis B surface antigen (HBsAg) is obtained by culturing genetically engineered Saccharomyces cerevisiae cells, which carry the surface antigen gene of the hepatitis B virus, in synthetic media containing inorganic salts, amino acids, dextrose, and vitamins. Bulk preparations of each antigen are adsorbed separately onto aluminum salts and then pooled during formulation.

A 1.0-mL dose of vaccine contains not less than 720 ELISA Units of inactivated hepatitis A virus and 20 mcg of recombinant HBsAg protein. One dose of vaccine also contains 0.45 mg of aluminum in the form of aluminum phosphate and aluminum hydroxide as adjuvants, amino acids, 5.0 mg 2-phenoxyethanol as a preservative, sodium chloride, phosphate buffer, polysorbate 20, Water for Injection, traces of formalin (not more than 0.1 mg), a trace amount of thimerosal (<1 mcg mercury) from the manufacturing process, and residual MRC₅ cellular proteins (not more than 2.5 mcg). Neomycin sulfate, an aminoglycoside antibiotic, is included in the cell growth media; only trace amounts (not more than 20 ng) remain following purification. The manufacturing procedures used to manufacture TWINRIX result in a product that contains no more than 5% yeast protein.

TWINRIX 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.

CLINICAL PHARMACOLOGY

Several hepatitis viruses (A, B, C, D, and E) are known to cause a systemic infection resulting in major pathologic changes in the liver. Features of hepatitis A and hepatitis B are described below.

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

Hepatitis A is a highly contagious disease 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 conditions⁴; (6) among institutionalized children and adults⁵; (7) in day-care centers⁶; and (8) by parenteral transmission, either blood transfusions or sharing needles with infected people. ⁷

In the United States, attack rates for hepatitis A disease are cyclical and vary by population. The rates have increased gradually from 10.4 per 100,000 in 1987 to 11.7 per 100,000 in 1996. 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 Up to 22% of adults who contract hepatitis A are hospitalized and approximately 100 patients die annually in the United States from complications of hepatitis A.¹²

Chronic shedding of HAV in feces has not been demonstrated, but relapses of hepatitis A can occur in as many as 20% of patients^11,13 and fecal shedding of HAV may recur at this time.¹¹ Approximately 70% of pediatric patients less than 6 years of age infected with hepatitis A are asymptomatic, and serve as a reservoir for infection among adults. ¹²

The presence of antibodies to HAV, as detected in a standardized assay (HAVAB), is an indication of the presence of protective antibodies against hepatitis A disease. Natural infection provides lifelong immunity even when antibodies to hepatitis A are undetectable. At present, studies show the duration of protection afforded by TWINRIX against hepatitis A lasts at least 4 years. ¹⁴

Hepatitis B: The hepatitis B virus (HBV) belongs to a family of genetically related DNA-containing animal viruses, which are hepatotropic. The incubation period of hepatitis B ranges between 30 and 180 days. The mode of transmission of hepatitis B may be: By contact (contaminated body secretions including semen, vaginal secretions, blood, saliva); percutaneously (usually through accidental needlesticks or by sharing needles with infected people); or by maternal-neonatal transmission.¹⁵

HBV infection occurs throughout the world with highly variable prevalences. A human reservoir of persistently infected persons is present in nearly all communities of the world. In the United States, parenteral drug abuse, unprotected sexual activity, occupationally acquired infection, or travelers returning from high prevalence countries may be the principal mechanisms of HBV transmission.

Clinical infection with hepatitis B may occur in 2 major forms: Asymptomatic or symptomatic hepatitis. Asymptomatic HBV infection can be subclinical or inapparent. In subclinical infection, patients have abnormal liver enzymes without jaundice, while inapparent asymptomatic infection is identified only by serological testing. One in 4 adults who has symptomatic disease has jaundice (anicteric/icteric hepatitis).

HBV infection can have serious consequences including acute massive hepatic necrosis, chronic active hepatitis, and cirrhosis of the liver. As many as 90% of infants and 6% to 10% of adults who are infected in the United States will become HBV carriers. ¹² An estimated 200 to 300 million people are chronic carriers of HBV worldwide. ¹² The Centers for Disease Control and Prevention (CDC) estimates that there are approximately 1 million to 1.25 million chronic carriers of HBV in the United States. ¹² About 50,000 cases of hepatitis are reported per year, about half of which are hepatitis B. Unreported cases may be 10 times greater. Close contact (sexual contact or household contact) or exposure to blood from infected individuals is associated with increased risk of infection. Those patients who become chronic carriers can infect others and are at increased risk of developing primary hepatocellular carcinoma. Among other factors, infection with HBV may be the single most important factor for development of this carcinoma.^12,16

Reduced Risk of Hepatocellular Carcinoma: A clear link has been demonstrated between chronic HBV infection and the occurrence of hepatocellular carcinoma. In a Taiwanese study, the institution of universal childhood immunization against HBV has been shown to decrease the incidence of hepatocellular carcinoma among children. ¹⁷ In a Korean study in adult males, vaccination against HBV has been shown to decrease the incidence of, and risk of, developing hepatocellular carcinoma in adults. ¹⁸

There is no definitive treatment for acute HBV infection. However, those who develop antibodies to HBsAg after active infection are protected against subsequent infection. Antibody titers >/=10 mIU/mL against HBsAg are recognized as conferring protection against HBV. ¹⁹ Seroconversion is defined as an antibody titer >/=1 mIU/mL.

Clinical Trials: Immunogenicity in Adults: Sera from 1,551 healthy adult volunteers ages 17 to 70, including 555 male subjects and 996 female subjects, in 11 clinical trials were analyzed following administration of 3 doses of TWINRIX on a 0-, 1-, and 6-month schedule. Seroconversion for antibodies against HAV was elicited in 99.9% of vaccinees, and protective antibodies against HBV were detected in 98.5%, 1 month after completion of the 3-dose series.

One of the 11 trials was a comparative trial conducted in a US population given either TWINRIX (on a 0-, 1-, and 6-month schedule) or HAVRIX (0- and 6-month schedule) and ENGERIX-B (0-, 1-, and 6-month schedule). The monovalent vaccines were given concurrently in opposite arms. Of a total of 773 adults (ages 18 to 70 years) enrolled in this trial, an immunogenicity analysis was performed in 533 subjects who completed the study according to protocol. Of these, 264 subjects received TWINRIX and 269 subjects received HAVRIX and ENGERIX-B. Seroconversion against HAV and seroprotection against HBV are shown in Table 2.

Since the immune responses to hepatitis A and hepatitis B induced by TWINRIX were non-inferior to the monovalent vaccines, efficacy is expected to be similar to the efficacy for each of the monovalent vaccines (Table 3).

It was noted that the antibody titers achieved 1 month after the final dose of TWINRIX were higher than titers achieved 1 month after the final dose of HAVRIX in these clinical trials. This may have been due to a difference in the recommended dosage regimens for these 2 vaccines, whereby TWINRIX vaccinees received 3 doses of 720 EL.U. of hepatitis A antigen at 0, 1, and 6 months, whereas HAVRIX vaccinees received 2 doses of 1440 EL.U. of the same antigen (at 0 and 6 months). However, these differences in peak titer have not been shown to be clinically significant.

Two clinical trials involving a total of 129 subjects demonstrated that antibodies to both HAV and HBV persisted for at least 4 years after the first vaccine dose in a 3-dose series of TWINRIX, given on a 0-, 1-, and 6-month schedule. For comparison, after the recommended immunization regimens for HAVRIX and ENGERIX-B, respectively, similar studies involving a total of 114 subjects have shown that seropositivity to HAV and HBV also persists for at least 4 years.

The effect of age on immune response to TWINRIX was studied in 2 trials comparing subjects over 40 years of age (n = 183, mean age = 48 in one trial and n = 72, mean age = 50 in the other) with those 99% of subjects achieved protective antibody levels in both age groups, and antibody titers were comparable to 2 doses of hepatitis A vaccine alone in age matched controls.

The response to hepatitis B immunization is known to decline in vaccinees over 40 years of age. TWINRIX elicited a seroprotective response to hepatitis B in 97% of younger subjects and 93% to 94% of the older subjects, as compared to 92% of older subjects given hepatitis B vaccine alone. Geometric mean titers elicited by TWINRIX were 2,285 in the younger subjects and 1,890 or 1,038 for the older subjects in the 2 trials. Hepatitis B vaccine alone gave titers of 2,896 in younger subjects and 1,157 in those over 40 years of age.

It has been shown in open randomized clinical trials that combining the hepatitis A antigen with the hepatitis B surface antigen in TWINRIX resulted in comparable anti-HAV or anti-HBsAg titers, relative to vaccination with the individual monovalent vaccines or the concomitant administration of each vaccine in opposite arms.

Immune Response to Simultaneously Administered Vaccines: There have been no studies of concomitant administration of TWINRIX with other vaccines.