PR Newswire, 810 Seventh Avenue, New York, NY 10019 - Friday, 4 October 1996

DESCRIPTION

COMVAX(TM)* (Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine) is a sterile bivalent vaccine made of the antigenic components used in producing PedvaxHIB(R) (Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)) and RECOMBIVAX HB(R) (Hepatitis B Vaccine (Recombinant)). These components are the Haemophilus influenzae type b capsular polysaccharide (PRP) that is covalently bound to an outer membrane protein complex (OMPC) of Neisseria meningitidis and hepatitis B surface antigen (HBsAg) from recombinant yeast cultures.

Haemophilus influenzae type b and Neisseria meningitides serogroup B are grown in complex fermentation media. The PRP is purified from the culture broth by purification procedures which include ethanol fractionation, enzyme digestion, phenol extraction and diafiltration. The OMPC from Neisseria meningitidis is purified by detergent extraction, ultracentrifugation, diafiltration and sterile filtration.

The PRP-OMPC conjugate is prepared by the chemical coupling of the highly purified PRP (polyribosylribitol phosphate) of Haemophilus influenzae type b (Haemophilus b, Ross strain) to an OMPC of the B11 strain of Neisseria meningitidis serogroup B. The coupling of the PRP to the OMPC, which is necessary for enhanced immunogenicity of the PRP, is confirmed by analysis of the conjugate's components following chemical treatment which yields a unique amino acid. After conjugation, the aqueous bulk is then adsorbed onto an aluminum hydroxide adjuvant.

HBsAg is produced in recombinant yeast cells. A portion of the hepatitis B virus gene, coding for HBsAg, is cloned into yeast, and the vaccine for hepatitis B is produced from cultures of this recombinant yeast strain according to methods developed in the Merck Research Laboratories. The antigen is harvested and purified from fermentation cultures of a recombinant strain of the yeast Saccharomyces cerevisiae containing the gene for the adw subtype of HBsAg.

The HBsAg protein is released from the yeast cells by cell disruption and purified by a series of physical and chemical methods. The vaccine contains no detectable yeast DNA but may contain not more than 1% yeast protein. The aqueous bulk is treated with formaldehyde and then adsorbed onto an aluminum hydroxide adjuvant.

After each PRP-OMPC and HBsAg aqueous bulk is adsorbed onto the aluminum hydroxide adjuvant, they are then combined to produce COMVAX. Each 0.5 mL dose of COMVAX is formulated to contain 7.5 mcg of Haemophilus b PRP, 125 mcg of Neisseria meningitidis OMPC, 5 mcg of HBsAg, approximately 225 mcg of aluminum as aluminum hydroxide, and 35 mcg sodium borate (decahydrate) as a pH stabilizer, in 0.9% sodium chloride.

The product contains no preservative.

COMVAX is a sterile suspension for intramuscular injection.

CLINICAL PHARMACOLOGY

Haemophilus influenzae type b Disease

Prior to the introduction of Haemophilus b conjugate vaccines, Haemophilus influenzae type b (Hib) was the most frequent cause of bacterial meningitis and a leading cause of serious systemic bacterial disease in young children worldwide. (1-4)

Hib disease occurred primarily in children under 5 years of age, and in the United States prior to the initiation of a vaccine program was estimated to account for nearly 20,000 cases of invasive infections annually, approximately 12,000 of which were meningitis. The mortality rate from Hib meningitis is about 5%. In addition, up to 35% of survivors develop neurologic sequelae including seizures, deafness, and mental retardation. (5,6) Other invasive diseases caused by this bacterium include cellulitis, epiglottitis, sepsis, pneumonia, septic arthritis, osteomyelitis, and pericarditis.

Prior to the introduction of the vaccine, it was estimated that 17% of all cases of Hib disease occurred in infants less than 6 months of age. The peak incidence of Hib meningitis occurred between 6 to 11 months of age. Forty- seven percent of all cases occurred by one year of age with the remaining 53% of cases occurring over the next four years. (2,20)

Among children under 5 years of age, the risk of invasive Hib disease is increased in certain populations including the following:

-- Daycare attendees (7,8,9)

-- Lower socio-economic groups (10)

-- B1acks (l1) (especially those who lack the Km(l) immunoglobulin allotype) (l2)

-- Caucasians who lack the G2m (23) immunoglobulin allotype (l3)

-- Native Americans (l4-16)

-- Household contacts of cases (l7)

-- Individuals with asplenia, sickle cell disease, or antibody deficiency syndromes. (18,19)

An important virulence factor of the Hib bacterium is its polysaccharide capsule (PRP). Antibody to PRP (anti-PRP) has been shown to correlate with protection against Hib disease. (3,21) While the anti-PRP level associated with protection using conjugated vaccines has not yet been determined, the level of anti-PRP associated with protection in studies using bacterial polysaccharide immune globulin or nonconjugated PRP vaccines ranged from greater >0.15 to >1.0 mcg/mL. (22-28)

Nonconjugated PRP vaccines are capable of stimulating B-lymphocytes to produce antibody without the help of T-lymphocytes (T-independent). The responses to many other antigens are augmented by helper T-lymphocytes (T- dependent). PedvaxHIB is a PRP-conjugate vaccine in which the PRP is covalently bound to the OMPC carrier (29) producing an antigen which is postulated to convert the T-independent antigen (PRP alone) into a T-dependent antigen resulting in both an enhanced antibody response and immunologic memory.

The protective efficacy of the PRP-OMPC component of COMVAX was demonstrated in a randomized, double-blind, placebo-controlled study involving 3,486 Native American (Navajo) infants (The Protective Efficacy Study) who completed the primary two-dose regimen for lyophilized PedvaxHIB. This population has a much higher incidence of Hib disease than the United States population as a whole and also has a lower antibody response to Haemophilus b conjugate vaccines, including PedvaxHIB. (14-16,30,31)

Each infant in this study received two doses of either placebo or lyophilized PedvaxHIB (15 mcg Haemophilus b PRP) with the first dose administered at a mean of 8 weeks of age and the second administered approximately two months later; DTP and OPV were administered concomitantly. In a subset of 416 subjects, lyophilized PedvaxHIB (15 mcg Haemophilus b PRP) induced anti-PRP levels >0.15 mcg/mL in 88% and >1.0 mcg/mL in 52% with a geometric mean titer (GMT) of 0.95 mcg/mL one to three months after the first dose; the corresponding anti-PRP levels one to three months following the second dose were 91% and 60%, respectively, with a GMT of 1.43 mcg/mL. These antibody responses were associated with a high level of protection.

Most subjects were initially followed until 15 to l8 months of age. During this time, 22 cases of invasive Haemophilus b disease occurred in the placebo group (8 cases after the first dose and 14 cases after the second dose) and only 1 case in the vaccine group (none after the first dose and 1 after the second dose). Following the primary two-dose regimen, the protective efficacy of lyophilized PedvaxHIB was calculated to be 93% with a 95% confidence interval of 57-98%. In the two months between the first and second doses, the difference in number of cases of disease between placebo and vaccine recipients (8 vs. 0 cases, respectively) was statistically significant (p=0.008). (31)

Thus, in this study, a protective efficacy of 93% was achieved with an anti-PRP level of >1.0 mcg/mL in 60% of vaccinees and a GMT of 1.43 mcg/mL one to three months after the second dose. In a randomized, multicenter study comparing COMVAX (7.5 mcg Haemophilus b PRP; 5 mcg HBsAg) to concurrent administration of monovalent Liquid PedvaxHIB and monovalent RECOMBIVAX HB, anti-PRP levels were measured in 576 of 645 infants who received two doses of COMVAX. In these infants, COMVAX induced anti-PIRP levels >0.15 mcg/mL in 95% and >1.0 mcg/mL in 72% with a GMT of 2.5 mcg/mL, approximately two months after the second dose (see Table 1). Because the PRP-OMPC component of COMVAX induces a comparable anti-PRP response (see Table 1), the efficacy of COMVAX is expected to be similar to that obtained with monovalent Lyophilized PedvaxHIB in the Protective Efficacy Trial in the prevention of invasive Hib disease.

Hepatitis B Disease

Hepatitis B virus is an important cause of viral hepatitis. There is no specific treatment for this disease. The incubation period for hepatitis B is relatively long; six weeks to six months may elapse between exposure and the onset of clinical symptoms. The prognosis following infection with hepatitis B virus is variable and dependent on at least three factors: (1) Age -- Infants and younger children usually experience milder initial disease than older persons but are much more likely to remain persistently infected and become at risk of developing serious chronic liver disease; (2) Dose of virus -- The higher the dose, the more likely acute icteric hepatitis B will result; and, (3) Severity of associated underlying disease -- underlying malignancy or pre-existing hepatic disease predisposes to increased mortality and morbidity. (32)

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