Vaccine Information: PedvaxHIB

PEDVAXHIB- haemophilus influenzae type b capsular polysaccharide meningococcal outer membrane protein conjugate antigen injection, suspension
Merck Sharp & Dohme Corp.

DESCRIPTION

PedvaxHIB® [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] is a highly purified capsular polysaccharide (polyribosylribitol phosphate or PRP) of Haemophilus influenzae type b (Haemophilus b, Ross strain) that is covalently bound to an outer membrane protein complex (OMPC) of the B11 strain of Neisseria meningitidis serogroup B. The covalent bonding of the PRP to the OMPC which is necessary for enhanced immunogenicity of the PRP is confirmed by quantitative analysis of the conjugate’s components following chemical treatment which yields a unique amino acid. The potency of PedvaxHIB is determined by assay of PRP.

Haemophilus influenzae type b and Neisseria meningitidis 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.

Liquid PedvaxHIB is ready to use and does not require a diluent. Each 0.5 mL dose of Liquid PedvaxHIB is a sterile product formulated to contain: 7.5 mcg of Haemophilus b PRP, 125 mcg of Neisseria meningitidis OMPC and 225 mcg of aluminum as amorphous aluminum hydroxyphosphate sulfate (previously referred to as aluminum hydroxide), in 0.9% sodium chloride, but does not contain lactose or thimerosal. Liquid PedvaxHIB is a slightly opaque white suspension.

This vaccine is for intramuscular administration and not for intravenous injection. (See DOSAGE AND ADMINISTRATION.)

CLINICAL PHARMACOLOGY

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.{1,2,3,4}

Hib disease occurred primarily in children under 5 years of age in the United States prior to the initiation of a vaccine program and 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.{7} The peak incidence of Hib meningitis occurs between 6 to 11 months of age. Forty-seven percent of all cases occur 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{8,9}
  • Lower socio-economic groups{10}
  • Blacks{11} (especially those who lack the Km(1) immunoglobulin allotype){12}
  • Caucasians who lack the G2m(n or 23) immunoglobulin allotype{13}
  • Native Americans{14,15,16}
  • Household contacts of cases{17}
  • 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 >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.

Clinical Evaluation of PedvaxHIB

PedvaxHIB, in a lyophilized formulation (lyophilized PedvaxHIB), was initially evaluated in 3,486 Native American (Navajo) infants, who completed the primary two-dose regimen in a randomized, double-blind, placebo-controlled study (The Protective Efficacy Study). At the time of the study, this population had a much higher incidence of Hib disease than the United States population as a whole and also had a lower antibody response to Haemophilus b Conjugate Vaccines, including PedvaxHIB.{14,15,16,30,33}

Each infant in this study received two doses of either placebo or lyophilized PedvaxHIB 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. Antibody levels were measured in a subset of each group (TABLE 1).

TABLE 1: Antibody Responses in Navajo Infants
Vaccine No. ofSubjects Time % Subjects with Anti-PRP GMT(mcg/mL)
>0.15 mcg/mL >1.0 mcg/mL
*
Post-Vaccination values obtained approximately 1–3 months after each dose.
The Protective Efficacy Study
Immunogenicity Trial{34}
§
Booster given at 12 months of age; Post-Vaccination values obtained 1 month after administration of booster dose.
LyophilizedPedvaxHIB * 416 Pre-Vaccination 44 10 0.16
416 Post-Dose 1 88 52 0.95
416 Post-Dose 2 91 60 1.43
Placebo * 461 Pre-Vaccination 44 9 0.16
461 Post-Dose 1 21 2 0.09
461 Post-Dose 2 14 1 0.08
LyophilizedPedvaxHIB 27 Prebooster 70 33 0.51
27 Postbooster § 100 89 8.39

Most subjects were initially followed until 15 to 18 months of age. During this time, 22 cases of invasive Hib 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% (p=0.001, two-tailed). 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, two-tailed); however, a primary two-dose regimen is required for infants 2-14 months of age.

At termination of the study, placebo recipients were offered vaccine. All original participants were then followed two years and nine months from termination of the study. During this extended follow-up, invasive Hib disease occurred in an additional seven of the original placebo recipients prior to receiving vaccine and in one of the original vaccine recipients (who had received only one dose of vaccine). No cases of invasive Hib disease were observed in placebo recipients after they received at least one dose of vaccine. Efficacy for this follow-up period, estimated from person-days at risk, was 96.6% (95 C.I., 72.2-99.9%) in children under 18 months of age and 100% (95 C.I., 23.5-100%) in children over 18 months of age.{33}

Since protective efficacy with lyophilized PedvaxHIB was demonstrated in such a high risk population, it would be expected to be predictive of efficacy in other populations.

The safety and immunogenicity of lyophilized PedvaxHIB were evaluated in infants and children in other clinical studies that were conducted in various locations throughout the United States. PedvaxHIB was highly immunogenic in all age groups studied.{31,32}

Lyophilized PedvaxHIB induced antibody levels greater than 1.0 mcg/mL in children who were poor responders to nonconjugated PRP vaccines. In a study involving such a subpopulation,{33,34} 34 children ranging in age from 27 to 61 months who developed invasive Hib disease despite previous vaccination with nonconjugated PRP vaccines were randomly assigned to 2 groups. One group (n=14) was vaccinated with lyophilized PedvaxHIB and the other group (n=20) with a nonconjugated PRP vaccine at a mean interval of approximately 12 months after recovery from disease. All 14 children vaccinated with lyophilized PedvaxHIB but only 6 of 20 children re-vaccinated with a nonconjugated PRP vaccine achieved an antibody level of >1.0 mcg/mL. The 14 children who had not responded to revaccination with the nonconjugated PRP vaccine were then vaccinated with a single dose of lyophilized PedvaxHIB; following this vaccination, all achieved antibody levels of >1.0 mcg/mL.

In addition, lyophilized PedvaxHIB has been studied in children at high risk of Hib disease because of genetically-related deficiencies [Blacks who were Km(1) allotype negative and Caucasians who were G2m(23) allotype negative] and are considered hyporesponsive to nonconjugated PRP vaccines on this basis.{35} The hyporesponsive children had anti-PRP responses comparable to those of allotype positive children of similar age range when vaccinated with lyophilized PedvaxHIB. All children achieved anti-PRP levels of >1.0 mcg/mL.

The safety and immunogenicity of Liquid PedvaxHIB were compared with those of lyophilized PedvaxHIB in a randomized clinical study involving 903 infants 2 to 6 months of age from the general U.S. population. DTP and OPV were administered concomitantly to most subjects. The antibody responses induced by each formulation of PedvaxHIB were similar. TABLE 2 shows antibody responses from this clinical study in subjects who received their first dose at 2 to 3 months of age.

TABLE 2: Antibody Responses to Liquid and Lyophilized PedvaxHIB in Infants From the General U.S. Population
Formulation Age(Months) Time No. ofSubjects % Subjects with anti-PRP Anti-PRP GMT(mcg/mL)
>0.15 mcg/mL >1.0 mcg/mL
*
Approximately two months Post-Vaccination
Approximately one month Post-Vaccination
Approximately
Liquid PedvaxHIB(7.5 mcg PRP) Pre-Vaccination 487 32 7 0.12
2-3 Post-Dose 1* 480 94 64 1.55
Post-Dose 2 393 97 80 3.22
12-15 Prebooster 284 80 30 0.49
Postbooster 284 99 95 10.23
24 Persistence 94 97 55 1.29
LyophilizedPedvaxHIB(15 mcg PRP) Pre-Vaccination 171 37 6 0.13
2-3 Post-Dose 1* 169 97 72 1.88
Post-Dose 2 133 99 81 2.69
12-15 Prebooster 87 71 28 0.39
Postbooster 87 99 91 7.64
24 Persistence 37 97 54 1.10

A booster dose of PedvaxHIB is required in infants who complete the primary two-dose regimen before 12 months of age. This booster dose will help maintain antibody levels during the first two years of life when children are at highest risk for invasive Hib disease. (See TABLE 2 and DOSAGE AND ADMINISTRATION.)

In four United States studies, antibody responses to lyophilized PedvaxHIB were evaluated in several subpopulations of infants initially vaccinated between 2 to 3 months of age. (See TABLE 3.)

TABLE 3: Antibody Responses * After Two Doses of Lyophilized PedvaxHIB Among Infants Initially Vaccinated at 2–3 Months of Age By Racial/Ethnic Group
LYOPHILIZED
Racial/EthnicGroups No. ofSubjects % Subjects With Anti-PRP Anti-PRP GMT(mcg/mL)
>0.15 mcg/mL >1.0 mcg/mL
*
One month after the second dose
Apache and Navajo
Native American 54 96 70 2.47
Caucasian 201 99 82 3.52
Hispanic 76 99 88 3.54
Black 23 100 96 5.40

In two United States studies, antibody responses to Liquid PedvaxHIB were evaluated in several subpopulations of infants initially vaccinated between 2 to 3 months of age. (See TABLE 4.)

TABLE 4: Antibody Responses * After Two Doses of Liquid PedvaxHIB Among Infants Initially Vaccinated at 2–3 Months of Age By Racial/Ethnic Group
LIQUID
Racial/EthnicGroups No. ofSubjects % Subjects With Anti-PRP Anti-PRP GMT(mcg/mL)
>0.15 mcg/mL >1.0 mcg/mL
*
One month after the second dose
Apache and Navajo
Native American 90 97 78 2.76
Caucasian 143 94 72 2.16
Hispanic 184 98 85 4.34
Black 18 100 94 7.58

Antibodies to the OMPC of N. meningitidis have been demonstrated in vaccinee sera, but the clinical relevance of these antibodies has not been established.{33}

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