Pediarix (Diphtheria Toxoid / Tetanus Toxoid / Acellular Pertussis / Hepatitis B Recombinant Vaccine / Inactivated Poliovirus Vaccine) - Description and Clinical Pharmacology

DESCRIPTION

PEDIARIX™ [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant) and Inactivated Poliovirus Vaccine Combined] is a noninfectious, sterile, multivalent vaccine for intramuscular administration manufactured by GlaxoSmithKline Biologicals. It contains diphtheria and tetanus toxoids, 3 pertussis antigens (inactivated pertussis toxin [PT], filamentous hemagglutinin [FHA], and pertactin [69 kiloDalton outer membrane protein]), hepatitis B surface antigen, plus poliovirus Type 1 (Mahoney), Type 2 (MEF-1), and Type 3 (Saukett). The diphtheria toxoid, tetanus toxoid, and pertussis antigens are the same as those in INFANRIX® (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed). The hepatitis B surface antigen is the same as that in ENGERIX-B® [Hepatitis B Vaccine (Recombinant)].

The diphtheria toxin is produced by growing Corynebacterium diphtheriae in Fenton medium containing a bovine extract. Tetanus toxin is produced by growing Clostridium tetani in a modified Latham medium derived from bovine casein. The bovine materials used in these extracts are sourced from countries which the United States Department of Agriculture (USDA) has determined neither have nor are at risk of bovine spongiform encephalopathy (BSE). Both toxins are detoxified with formaldehyde, concentrated by ultrafiltration, and purified by precipitation, dialysis, and sterile filtration.

The 3 acellular pertussis antigens (PT, FHA, and pertactin) are isolated from Bordetella pertussis culture grown in modified Stainer-Scholte liquid medium. PT and FHA are isolated from the fermentation broth; pertactin is extracted from the cells by heat treatment and flocculation. The antigens are purified in successive chromatographic and precipitation steps. PT is detoxified using glutaraldehyde and formaldehyde. FHA and pertactin are treated with formaldehyde.

The 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 medium. The surface antigen expressed in the S. cerevisiae cells is purified by several physiochemical steps, which include precipitation, ion exchange chromatography, and ultrafiltration. The purified HBsAg undergoes dialysis with cysteine to remove residual thimerosal.

The inactivated poliovirus component of PEDIARIX is an enhanced potency component. Each of the 3 strains of poliovirus is individually grown in VERO cells, a continuous line of monkey kidney cells, cultivated on microcarriers. Calf serum and lactalbumin hydrolysate are used during VERO cell culture and/or virus culture. Calf serum is sourced from countries the USDA has determined neither have nor are at risk of BSE. After clarification, each viral suspension is purified by ultrafiltration, diafiltration, and successive chromatographic steps, and inactivated with formaldehyde. The 3 purified viral strains are then pooled to form a trivalent concentrate.

The diphtheria, tetanus, and pertussis antigens are individually adsorbed onto aluminum hydroxide; hepatitis B component is adsorbed onto aluminum phosphate. All antigens are then diluted and combined to produce the final formulated vaccine. Each 0.5-mL dose is formulated to contain 25 Lf of diphtheria toxoid, 10 Lf of tetanus toxoid, 25 mcg of inactivated PT, 25 mcg of FHA, 8 mcg of pertactin, 10 mcg of HBsAg, 40 D-antigen Units (DU) of Type 1 poliovirus, 8 DU of Type 2 poliovirus, and 32 DU of Type 3 poliovirus.

Diphtheria and tetanus toxoid potency is determined by measuring the amount of neutralizing antitoxin in previously immunized guinea pigs. The potency of the acellular pertussis components (PT, FHA, and pertactin) is determined by enzyme-linked immunosorbent assay (ELISA) on sera from previously immunized mice. Potency of the hepatitis B component is established by HBsAg ELISA. The potency of the inactivated poliovirus component is determined by using the D-antigen ELISA and by a poliovirus neutralizing cell culture assay on sera from previously immunized rats.

Each 0.5-mL dose also contains 2.5 mg of 2-phenoxyethanol as a preservative, 4.5 mg of NaCl, and aluminum adjuvant (not more than 0.85 mg aluminum by assay). Each dose also contains </=100 mcg of residual formaldehyde and </=100 mcg of polysorbate 80 (Tween 80). Thimerosal is used at the early stages of manufacture and is removed by subsequent purification steps to below the analytical limit of detection (<25 ng of mercury/20 mcg HBsAg) which upon calculation is <12.5 ng mercury per dose. Neomycin sulfate and polymyxin B are used in the polio vaccine manufacturing process and may be present in the final vaccine at </=0.05 ng neomycin and </=0.01 ng polymyxin B per dose. The procedures used to manufacture the HBsAg antigen result in a product that contains </=5% yeast protein.

The vaccine must be well shaken before administration and is a turbid white suspension after shaking.

Diphtheria and Tetanus Toxoids Adsorbed Bulk Concentrate (For Further Manufacturing) is manufactured by Chiron Behring GmbH & Co, Marburg, Germany. The acellular pertussis antigens, the hepatitis B surface antigen, and the inactivated poliovirus antigens are manufactured by GlaxoSmithKline Biologicals, Rixensart, Belgium. Formulation, filling, testing, packaging, and release of the vaccine are performed by GlaxoSmithKline Biologicals Manufacturing (wholly-owned subsidiary of GlaxoSmithKline Biologicals).

CLINICAL PHARMACOLOGY

The efficacy of PEDIARIX is based on the immunogenicity of the individual antigens compared to licensed vaccines. The efficacy of the pertussis component, which does not have a well established correlate of protection, was determined in clinical trials of INFANRIX. The efficacy of the HBsAg was determined in clinical studies of ENGERIX-B. Serological correlates of protection exist for the diphtheria, tetanus, hepatitis B, and poliovirus components.

Diphtheria:    Diphtheria is an acute toxin-mediated infectious disease caused by toxigenic strains of C. diphtheriae. Although the incidence of diphtheria in the United States has decreased from more than 200,000 cases reported in 1921, ¹ before the general use of diphtheria toxoid, to only 51 cases of respiratory diphtheria reported from 1980 through 2000, ² the case-fatality rate has remained constant at about 10%. Of 41 cases reported between 1980 and 1994, 15 (37%) patients had never been immunized, 21 (51%) had been inadequately immunized, and immunization history was unknown for 5 (12%). All 4 (10%) fatalities in this time period occurred in unvaccinated children 9 years and younger. ³ Although diphtheria is rare in the United States, toxigenic C. diphtheriae strains continue to circulate in previously endemic areas. ⁴ Protection against disease is due to the development of neutralizing antibodies to the diphtheria toxin. Following adequate immunization with diphtheria toxoid, it is thought that protection persists for at least 10 years. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection.⁵ Antitoxin levels of at least 0.1 IU/mL are generally regarded as protective. ⁵ Immunization with diphtheria toxoid does not, however, eliminate carriage of C. diphtheriae in the pharynx or nares or on the skin.¹

Efficacy of diphtheria toxoid used in INFANRIX was determined on the basis of immunogenicity studies. A VERO cell toxin neutralizing test confirmed the ability of infant sera (N = 45), obtained 1 month after a 3-dose primary series, to neutralize diphtheria toxin. Levels of diphtheria antitoxin >/=0.01 IU/mL were achieved in 100% of the sera tested.

Tetanus:    Tetanus is a condition manifested primarily by neuromuscular dysfunction caused by a potent exotoxin released by C. tetani. Following the introduction of vaccination with tetanus toxoid in the 1940s, the overall incidence of tetanus declined from 0.4 per 100,000 population in 1947 to 0.02 during the latter half of the 1990s. ⁶ Adults 60 years of age and older are at greatest risk for tetanus and tetanus-related mortality.⁶ Of 124 cases of tetanus reported from 1995 through 1997, 12 (9.7%) occurred among persons younger than 25 years, one of which was a case of neonatal tetanus.⁷ Overall, the case-fatality rate was 11%. The disease continues to occur almost exclusively among persons who are unvaccinated, inadequately vaccinated, or whose vaccination histories are unknown or uncertain. ⁷

Spores of C. tetani are ubiquitous. Naturally acquired immunity to tetanus toxin does not occur. Thus, universal primary immunization and timed booster doses to maintain adequate tetanus antitoxin levels are necessary to protect all age groups. ¹ Protection against disease is due to the development of neutralizing antibodies to the tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assays, is considered the minimum protective level.^8,9 More recently a level >/=0.1 to 0.2 IU/mL has been considered as protective. ¹⁰ It is thought that protection persists for at least 10 years. ¹

Efficacy of tetanus toxoid used in INFANRIX was determined on the basis of immunogenicity studies. An in vivo mouse neutralization assay confirmed the ability of infant sera (N = 45), obtained 1 month after a 3-dose primary series, to neutralize tetanus toxin. Levels of tetanus antitoxin >/=0.01 IU/mL were achieved in 100% of the sera tested.

Pertussis:    Pertussis (whooping cough) is a disease of the respiratory tract caused by B. pertussis. Pertussis is highly communicable (attack rates in unimmunized household contacts of up to 100% have been reported^1,11) and can cause severe disease, particularly in young infants. ¹ Since immunization against pertussis became widespread, the number of reported cases and associated mortality in the United States has declined from an average annual incidence and mortality of 150 cases and 6 deaths per 100,000 population, respectively, in the early 1940s to an annual reported incidence of 2.7 cases per 100,000 population in 2000. ¹² Of 28,187 cases of pertussis reported among all ages from 1997 to 2000, 62 (0.2%) resulted in death.¹² The highest number of pertussis cases (7,867) since 1967 was reported in 2000. From 1997 to 2000, infants younger than 1 year had the highest average annual incidence rate (55.5 cases per 100,000 population). During this period, of the 8,276 pertussis cases reported nationally in infants younger than 1 year, 59% were hospitalized, 11% had pneumonia, 1.3% had seizures, 0.2% had encephalopathy, and 0.7% died. Older children, adolescents, and adults, in whom classic signs are often absent, may go undiagnosed and may serve as reservoirs of disease.^1,13 The incidence of reported pertussis among adolescents and adults increased during the 1980s and 1990s. ^12,14

The role of the different components produced by B. pertussis in either the pathogenesis of, or the immunity to, pertussis is not well understood.

Efficacy of a 3-dose primary series of INFANRIX has been assessed in 2 clinical studies. ^15,16

A double-blind, randomized, active Diphtheria and Tetanus Toxoids (DT)-controlled trial conducted in Italy, sponsored by the National Institutes of Health (NIH), assessed the absolute protective efficacy of INFANRIX when administered at 2, 4, and 6 months of age. ¹⁵ A total of 15,601 infants were immunized with 1 of 2 acellular DTP (DTaP) vaccines, a US-licensed whole-cell DTP vaccine, or with DT vaccine alone. The mean length of follow-up was 17 months (mean age 24 months), beginning 30 days after the third dose of vaccine. The population used in the primary analysis of the efficacy of INFANRIX included 4,481 infants vaccinated with INFANRIX and 1,470 DT vaccinees. After 3 doses, the absolute protective efficacy of INFANRIX against WHO-defined typical pertussis (21 days or more of paroxysmal cough with infection confirmed by culture and/or serologic testing) was 84% (95% CI: 76% to 89%). When the definition of pertussis was expanded to include clinically milder disease with respect to type and duration of cough, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX was calculated to be 71% (95% CI: 60% to 78%) against >7 days of any cough and 73% (95% CI: 63% to 80%) against >/=14 days of any cough. A second follow-up period to a mean age of 33 months was conducted in a partially unblinded cohort (children who received DT were offered pertussis vaccine and those who declined were retained in the study cohort). A longer unblinded follow-up period showed that after 3 doses and with no booster dose in the second year of life, the efficacy of INFANRIX against WHO-defined pertussis was 86% (95% CI: 79% to 91%) among children followed to 6 years of age. ¹⁷

A prospective efficacy trial was also conducted in Germany employing a household contact study design. ¹⁶ In preparation for this study, 3 doses of INFANRIX were administered at 3, 4, and 5 months of age to more than 22,000 children living in 6 areas of Germany in a safety and immunogenicity study. Infants who did not participate in the safety and immunogenicity study could have received a whole-cell DTP vaccine or DT vaccine. Index cases were identified by spontaneous presentation to a physician. Households with at least one other member (i.e., besides index case) aged 6 through 47 months were enrolled. Household contacts of index cases were monitored for incidence of pertussis by a physician who was blinded to the vaccination status of the household. Calculation of vaccine efficacy was based on attack rates of pertussis in household contacts classified by vaccination status. Of the 173 household contacts who had not received a pertussis vaccine, 96 developed WHO-defined pertussis, as compared to 7 of 112 contacts vaccinated with INFANRIX. The protective efficacy of INFANRIX was calculated to be 89% (95% CI: 77% to 95%), with no indication of waning of protection up until the time of the booster vaccination. The average age of infants vaccinated with INFANRIX at the end of follow-up in this trial was 13 months (range 6 to 25 months). When the definition of pertussis was expanded to include clinically milder disease, with infection confirmed by culture and/or serologic testing, the efficacy of INFANRIX against >/=7 days of any cough was 67% (95% CI: 52% to 78%) and against >/=7 days of paroxysmal cough was 81% (95% CI: 68% to 89%). The corresponding efficacy rates of INFANRIX against >/=14 days of any cough or paroxysmal cough were 73% (95% CI: 59% to 82%) and 84% (95% CI: 71% to 91%), respectively.

Hepatitis B:    Several hepatitis viruses are known to cause a systemic infection resulting in major pathologic changes in the liver (e.g., A, B, C, D, and E). The estimated lifetime risk of hepatitis B infection in the United States varies from almost 100% for the highest-risk groups to approximately 5% for the population as a whole. ¹⁸ The modes of transmission of hepatitis B include sexual contact (contaminated body secretions including semen, vaginal secretions, blood, and saliva); parenteral exposure (e.g., blood transfusions, accidental needlesticks or sharing needles from infected individuals); or maternal-neonatal transmission.¹⁹ Hepatitis B infection can have serious consequences including acute massive hepatic necrosis, chronic active hepatitis, and cirrhosis of the liver. Up to 90% of neonates, 30% to 50% of children aged 1 to 5 years, and 6% to 10% of older children and adults who are infected in the United States will become hepatitis B virus carriers. ¹⁹ It has been estimated that 200 to 300 million people in the world are chronically infected with hepatitis B virus,¹⁹ and that there are approximately 1.25 million chronic carriers of hepatitis B virus in the United States. ²⁰ Those patients who become chronic carriers can infect others and are at increased risk of developing primary hepatocellular carcinoma. Among other factors, infection with hepatitis B may be the single most important factor for development of this carcinoma.^20,21

Mothers infected with hepatitis B virus can infect their infants at, or shortly after, birth if they are carriers of the HBsAg or develop an active infection during the third trimester of pregnancy. Infected infants usually become chronic carriers. Therefore, screening of pregnant women for hepatitis B is recommended. ¹⁰ There is no specific treatment for acute hepatitis B infection. Persons who develop anti-HBs antibodies after active infection are usually protected against subsequent infection. Antibody concentrations >/=10 mIU/mL against HBsAg are recognized as conferring protection against hepatitis B.²²

Protective efficacy with ENGERIX-B has been demonstrated in a clinical trial in neonates at high risk of hepatitis B infection.^23,24 Fifty-eight neonates born of mothers who were both HBsAg- and HBeAg-positive were given ENGERIX-B (10 mcg at 0, 1, and 2 months) without concomitant hepatitis B immune globulin. Two infants became chronic carriers in the 12-month follow-up period after initial inoculation. Assuming an expected carrier rate of 70%, the protective efficacy rate against the chronic carrier state during the first 12 months of life was 95%.

Reduced Risk of Hepatocellular Carcinoma:    According to the Centers for Disease Control and Prevention (CDC), hepatitis B vaccine is recognized as the first anti-cancer vaccine because it can prevent primary liver cancer.²⁵ A clear link has been demonstrated between chronic hepatitis B infection and the occurrence of hepatocellular carcinoma. In a Taiwanese study, the institution of universal childhood immunization against hepatitis B virus has been shown to decrease the incidence of hepatocellular carcinoma among children. ²⁶ In a Korean study in adult males, vaccination against the hepatitis B virus has been shown to decrease the incidence and risk of developing hepatocellular carcinoma in adults. ²⁷

Poliomyelitis:    Poliovirus is an enterovirus that belongs to the picornavirus family.²⁸ Three serotypes of poliovirus have been identified (Types 1, 2, and 3). Poliovirus is highly contagious with the predominant mode of transmission being person-to-person via the fecal-oral route. The virus may also be spread indirectly through contact with infectious saliva or feces or by contaminated water or sewage. ²⁹

Replication of poliovirus in the pharynx and intestine is followed by a viremic phase in which involvement of the central nervous system (CNS) can occur. Whereas poliovirus infections are asymptomatic or cause nonspecific symptoms (low-grade fever, malaise, anorexia, and sore throat) in 90% to 95% of individuals, up to 2% of infected persons develop paralytic disease.²⁸

As a result of the introduction of poliovirus vaccines in the 1950s and 1960s, and their subsequent widespread use, poliomyelitis control has been achieved in the United States. ^30,31 After introduction of conventional (non-enhanced) inactivated poliovirus vaccine (IPV) in 1955, the annual incidence of paralytic disease of 11.4 cases per 100,000 population declined to 0.5 cases per 100,000 population in 1961, when oral poliovirus vaccine (OPV) was introduced. Incidence continued to decline thereafter, with rates of 0.00-0.01 cases per 100,000 population during the years 1990-2000. ³² Evidence suggests that endemic circulation of wild polioviruses ceased in the United States in the 1960s. The last indigenously acquired cases of poliomyelitis caused by wild poliovirus were detected in 1979 and were due to imported viruses. Since then, vaccine-associated paralytic poliomyelitis (VAPP) attributable to live OPV has been the only indigenous form of the disease in the United States. ³³ To eliminate the risk for VAPP, since 2000, an all IPV schedule has been recommended for routine childhood polio vaccination in the United States. Although the likelihood of poliovirus importation has decreased substantially since 1997 as a result of decreases in the number of polio cases worldwide, the potential for importation will remain until global eradication is achieved.

IPV induces the production of neutralizing antibodies against each poliovirus serotype; these neutralizing antibodies are recognized as conferring protection against poliomyelitis disease.³⁴

Immune Response to PEDIARIX Administered as a 3-Dose Primary Series:    In a study conducted in the United States, the immune responses to each of the antigens contained in PEDIARIX were evaluated in sera obtained 1 month after the third dose of vaccine and were compared to those following administration of US-licensed vaccines (INFANRIX and ENGERIX-B concomitantly at separate sites, and OPV [Poliovirus Vaccine Live Oral Trivalent, Lederle Laboratories]). ³⁵ Both groups received a US-licensed Haemophilus influenzae type b (Hib) vaccine (Aventis Pasteur) concomitantly at separate sites. The schedule of administration was 2, 4, and 6 months of age. One month after the third dose of PEDIARIX, vaccine response rates for each of the pertussis antigens (with the exception of FHA), geometric mean antibody concentrations for each of the pertussis antigens, and seroprotection rates for diphtheria, tetanus, hepatitis B, and the polioviruses, were shown to be non-inferior to those achieved following separately administered vaccines (see Table 1). The vaccine response to FHA marginally exceeded the 10% limit for non-inferiority. ³⁵

Immune Response to Concomitantly Administered Vaccines:    In a clinical trial in the United States, PEDIARIX was given concomitantly, at separate sites, with Hib vaccine (Aventis Pasteur) to infants at 2, 4, and 6 months of age. ³⁵ Immunogenicity data are available in 90 infants one month after the third dose of the vaccines; 98.9% (95% CI: 94% to 100%) of infants demonstrated anti-PRP antibodies >/=0.15 mcg/mL and 94.4% (95% CI: 87.5% to 98.2%) demonstrated anti-PRP antibodies >/=1.0 mcg/mL.

Immunogenicity data are not available on the concurrent administration of PEDIARIX with pneumococcal conjugate vaccine.