Dosage Form: injection, suspension
COMVAX®
[HAEMOPHILUS b CONJUGATE (MENINGOCOCCAL PROTEIN CONJUGATE) and
HEPATITIS B (RECOMBINANT) VACCINE]
Comvax Vaccine Description
COMVAX® [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® [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] and RECOMBIVAX HB® [Hepatitis B Vaccine (Recombinant)]. These components are the Haemophilus influenzae type b capsular polysaccharide [polyribosylribitol phosphate (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 meningitidis serogroup B are grown in complex fermentation media. The primary ingredients of the phenol-inactivated fermentation medium for Haemophilus influenzae include an extract of yeast, nicotinamide adenine dinucleotide, hemin chloride, soy peptone, dextrose, and mineral salts and for Neisseria meningitidis include an extract of yeast, amino acids and mineral salts. 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 is necessary for enhanced immunogenicity of the PRP. This coupling is confirmed by analysis of the components of the conjugate following chemical treatment which yields a unique amino acid. After conjugation, the aqueous bulk is then adsorbed onto an amorphous aluminum hydroxyphosphate sulfate adjuvant (previously referred to as aluminum hydroxide).
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 fermentation process involves growth of Saccharomyces cerevisiae on a complex fermentation medium which consists of an extract of yeast, soy peptone, dextrose, amino acids and mineral salts.
The HBsAg protein is released from the yeast cells by mechanical cell disruption and detergent extraction, and purified by a series of physical and chemical methods, which includes ion and hydrophobic chromatography, and diafiltration. The purified protein is treated in phosphate buffer with formaldehyde and then coprecipitated with alum (potassium aluminum sulfate) to form bulk vaccine adjuvanted with amorphous aluminum hydroxyphosphate sulfate. The vaccine contains no detectable yeast DNA, and 1% or less of the protein is of yeast origin.
The individual PRP-OMPC and HBsAg adjuvanted bulks are combined to produce COMVAX. Each 0.5 mL dose of COMVAX is formulated to contain 7.5 mcg PRP conjugated to approximately 125 mcg OMPC, 5 mcg HBsAg, approximately 225 mcg aluminum as amorphous aluminum hydroxyphosphate sulfate, and 35 mcg sodium borate (decahydrate) as a pH stabilizer, in 0.9% sodium chloride. The vaccine contains not more than 0.0004% (w/v) residual formaldehyde.
The potency of the PRP-OMPC component is measured by quantitating the polysaccharide concentration by an HPLC method. The potency of the HBsAg component is measured relative to a standard by an in vitro immunoassay.
The product contains no preservative.
COMVAX is a sterile suspension for intramuscular injection.
Comvax Vaccine - 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}
- Blacks{11} (especially those who lack the Km(1) immunoglobulin allotype){12}
- Caucasians who lack the G2m(23) immunoglobulin allotype{13}
- Native Americans{14-16}
- Household contacts of cases{17}
- Individuals with asplenia, sickle cell disease, or antibody deficiency syndromes.{18,19}
Prevention of Hib Disease with Vaccine
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 Trials with PedvaxHIB
The protective efficacy of the PRP-OMPC component of COMVAX was demonstrated in a randomized, double-blind, placebo-controlled study involving 3486 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 (Diphtheria and Tetanus Toxoids and whole cell Pertussis Vaccine, Adsorbed) and OPV (Poliovirus Vaccine Live Oral Trivalent) 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 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 (C.I.) 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). 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 7 of the original placebo recipients prior to receiving vaccine and in 1 of the original vaccine recipients (who had received only 1 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.{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.
Hepatitis B Disease
Hepatitis B virus is an important cause of viral hepatitis. According to the Centers for Disease Control (CDC), there are an estimated 200,000-300,000 new cases of Hepatitis B infection annually in the United States.{32} 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.{34}
Hepatitis B infection fails to resolve and progresses to a chronic carrier state in 5 to 10% of older children and adults and in up to 90% of infants; chronic infection also occurs more frequently after initial anicteric hepatitis B than after initial icteric disease.{34} Consequently, carriers of HBsAg frequently give no history of having had recognized acute hepatitis. It has been estimated that more than 285 million people in the world today are persistently infected with hepatitis B virus.{35} The CDC estimates that there are approximately 1 million-1.25 million chronic carriers of hepatitis B virus in the USA.{32} Chronic carriers represent the largest human reservoir of hepatitis B virus.
A serious complication of acute hepatitis B virus infection is massive hepatic necrosis while sequelae of chronic hepatitis B include cirrhosis of the liver, chronic active hepatitis, and hepatocellular carcinoma. Chronic carriers of HBsAg appear to be at increased risk of developing hepatocellular carcinoma. Although a number of etiologic factors are associated with development of hepatocellular carcinoma, the single most important etiologic factor appears to be chronic infection with hepatitis B virus.{36} According to the CDC, hepatitis B vaccine is recognized as the first anti-cancer vaccine because it can prevent primary liver cancer.{67}
The vehicles for transmission of the virus are most often blood and blood products but the viral antigen has also been found in tears, saliva, breast milk, urine, semen, and vaginal secretions. Hepatitis B virus is capable of surviving for days on environmental surfaces exposed to body fluids containing hepatitis B virus. Infection may occur when hepatitis B virus, transmitted by infected body fluids, is implanted via mucous surfaces or percutaneously introduced through accidental or deliberate breaks in the skin. Transmission of hepatitis B virus infection is often associated with close interpersonal contact with an infected individual and with crowded living conditions.{37}
Prevention of Hepatitis B Disease with Vaccine
Hepatitis B infection and disease can be prevented through immunization with vaccines that contain viral surface antigen (HBsAg) and induce formation of protective antibody (anti-HBs).{38-39}
Multiple clinical studies have defined a protective level of anti-HBs as 1) 10 or more sample ratio units (SRU or S/N) as determined by radioimmunoassay or 2) a positive result as determined by enzyme immunoassay.{40-46} Note: 10 SRU is comparable to 10 mIU/mL of antibody.{36} The ACIP and an international group of hepatitis B experts consider an anti-HBs titer ≥10 mIU/mL an adequate response to a complete course of hepatitis B vaccine and protective against clinically significant infection (antigenemia with or without clinical disease).{36,46}
Clinical Trials with RECOMBIVAX HB
In clinical studies, 100% of 92 infants under 1 year of age born of non-carrier mothers developed a protective level of antibody (anti-HBs ≥10 mIU/mL) after receiving three 5-mcg doses of RECOMBIVAX HB at intervals of 0, 1, and 6 months.{31}
In one clinical study of RECOMBIVAX HB (2.5 mcg), which examined a different regimen of RECOMBIVAX HB, protective levels of antibody were achieved in 98% of 52 healthy infants vaccinated at 2, 4, and 12 months of age. Protective anti-HBs levels were achieved in 100% of 50 infants vaccinated at 2, 4, and 15 months of age.{47}
The protective efficacy of three 5-mcg doses of RECOMBIVAX HB, given at birth (with Hepatitis B Immune Globulin), 1, and 6 months of age, has been demonstrated in neonates born of mothers positive for both HBsAg and HBeAg (a core-associated antigenic complex which correlates with high infectivity). In this trial, after nine months of follow-up, chronic infection had not occurred in 96% of 130 infants.{48} The estimated efficacy in prevention of chronic hepatitis B infection was 95% as compared to the infection rate in untreated historical controls.{49}
Immunogenicity of COMVAX
The immunogenicity of COMVAX (7.5 mcg Haemophilus b PRP, 5 mcg HBsAg) was assessed in 1602 infants and children 6 weeks to 15 months of age in 5 clinical studies. In 2 controlled clinical trials (n=684), the immune response of COMVAX was compared with that obtained using the monovalent vaccines, PedvaxHIB (7.5 mcg Haemophilus b PRP) and RECOMBIVAX HB (5 mcg HBsAg) given at separate sites, either concurrently or one month apart. The immunogenicity of COMVAX was further assessed in 2 uncontrolled studies (n=852). In the first, a complete three-dose series of COMVAX was administered concurrently with other routine pediatric vaccines. In the second, COMVAX was administered as the third dose of Haemophilus b PRP and HBsAg concurrently with routine pediatric vaccines. COMVAX was also administered as the control arm in the evaluation of an investigational vaccine (n=66).
These studies demonstrate COMVAX to be highly immunogenic. The antibody responses are summarized below.
Antibody Responses to COMVAX in Infants Not Previously Vaccinated with Hib or Hepatitis B Vaccine
In the pivotal, controlled, multicenter, randomized, open-label study, 882 infants approximately 2 months of age, who had not previously received any Hib or hepatitis B vaccine, were assigned to receive a three-dose regimen of either COMVAX or PedvaxHIB plus RECOMBIVAX HB at approximately 2, 4, and 12-15 months of age. The proportions of evaluable vaccinees developing clinically important levels of anti-PRP (percent with >1.0 mcg/mL after the second dose, n=762) and anti-HBs (percent with ≥10 mIU/mL after the third dose, n=750) were similar in children given COMVAX or concurrent PedvaxHIB and RECOMBIVAX HB (Table 1).
The anti-PRP response after the second dose among infants given COMVAX in this study was 72.4% (C.I. 68.7, 76.0) >1.0 mcg/mL with a GMT=2.5 mcg/mL (C.I. 2.2, 2.8) and was comparable to that of infants given the PedvaxHIB and RECOMBIVAX HB controls which was 76.3% (C.I. 70.2, 82.5) with a GMT=2.8 mcg/mL (C.I. 2.2, 3.5). These responses exceed the response of Native American (Navajo) infants in a previous study of lyophilized PedvaxHIB (60% >1.0 mcg/mL; GMT=1.43 mcg/mL) that was associated with a 93% reduction in the incidence of invasive Hib disease. The efficacy of COMVAX in the prevention of invasive Hib disease is expected to be similar to that obtained with monovalent lyophilized PedvaxHIB in the Protective Efficacy Trial (see CLINICAL PHARMACOLOGY, Clinical Trials with PedvaxHIB).
The anti-HBs response after the third dose among infants given COMVAX in this study was 98.4% ≥10 mIU/mL (C.I. 97.0, 99.3) with a GMT of 4467.5 (C.I. 3786.3, 5271.3) compared to 100.0% (C.I. 97.9, 100.0) with a GMT of 6943.9 (C.I. 5555.9, 8678.7) among infants given COMVAX or concurrent PedvaxHIB and RECOMBIVAX HB.
Although the difference in anti-HBs GMT is statistically significant (p=0.011), both values are much greater than the level of 10 mIU/mL previously established as marking a protective response to hepatitis B.{42,44-46,51,52} These GMTs are higher than those observed in young infants who received the currently licensed regimen of RECOMBIVAX HB consisting of 5-mcg doses administered on the standard 0, 1, and 6-month schedule (GMT ~ 1359.9 mIU/mL).{53-55} In addition, two studies have shown that infants given 2.5-mcg doses of RECOMBIVAX HB according to the schedule used for COMVAX (2, 4, and 12-15 months of age) developed GMTs of 1245-3424 mIU/mL.{47,64} While a difference in GMT may result in differential retention of ≥10 mIU/mL of anti-HBs after a number of years, this is of no apparent clinical significance because of immunologic memory.{56,57}
Because the HBsAg component of COMVAX induces a comparable anti-HBs response to that obtained with RECOMBIVAX HB, the efficacy of COMVAX is expected to be similar (Table 1).
Vaccine | Age | Time | n | Anti-PRP | Anti-PRP GMT | n | Anti-HBs % Subjects | Anti-HBs (mIU/mL) | |
| |||||||||
COMVAX | Prevaccination | 633 | 34.4 | 4.7 | 0.1 | 603 | 10.6 | 0.6 | |
(7.5 mcg PRP, | 2 | Dose 1* | 620 | 88.9 | 51.5 | 1.0 | 595 | 34.3 | 4.2 |
5 mcg HBsAg) | 4 | Dose 2* | 576 | 94.8 | 72.4† | 2.5† | 571 | 92.1 | 113.9 |
[N=661] | 12/15 | Dose 3‡ | 570 | 99.3 | 92.6 | 9.5 | 571 | 98.4 | 4467.5† |
PedvaxHIB | Prevaccination | 208 | 33.7 | 5.8 | 0.1 | 196 | 7.1 | 0.5 | |
(7.5 mcg PRP) | 2 | Dose 1* | 202 | 90.1 | 53.5 | 1.1 | 198 | 41.9 | 5.3 |
+ | 4 | Dose 2* | 186 | 95.2 | 76.3† | 2.8† | 185 | 98.4† | 255.7 |
RECOMBIVAX HB (5 mcg HBsAg) [N=221] | 12/15 | Dose 3‡ | 181 | 98.9 | 92.3 | 10.2 | 179 | 100.0† | 6943.9† |
Antibody Responses to COMVAX in Infants Previously Vaccinated with Hepatitis B Vaccine at Birth
Two clinical studies assessed antibody responses to a three-dose series of COMVAX in 128 evaluable infants who were previously given a birth dose of hepatitis B vaccine. Table 2 summarizes the anti-PRP and anti-HBs responses of these infants. The antibody responses were clinically comparable to those observed in the pivotal trial of COMVAX (Table 1).
Study | Age | Time | n | Anti-PRP | Anti-PRP GMT | n | Anti-HBs % Subjects | Anti-HBs (mIU/mL) | |
| |||||||||
Prevaccination | 119 | 24.4 | 5.9 | 0.1 | 71 | 25.4 | 2.9 | ||
| Study 1 | 2 | Dose 1 | ---------------------------------------Not Measured------------------------------------------------ | ||||||
| [N=126] | 4 | Dose 2* | 111 | 94.6 | 81.1 | 3.3 | 111 | 98.2 | 417.2 |
| 14/15 | Dose 3* | 88 | 100 | 93.2 | 11.0 | 87 | 98.9 | 3500.7 | |
Prevaccination | 17 | 58.8 | 0 | 0.2 | 15 | 6.7 | 0.7 | ||
| Study 2 | 2 | Dose 1† | 17 | 88.2 | 47.1 | 0.9 | 16 | 81.3 | 35.2 |
| [N=19] | 4 | Dose 2† | 17 | 100 | 76.5 | 2.8 | 16 | 100 | 281.8 |
| 15 | Dose 3† | 15 | 100 | 100 | 8.5 | 16 | 100 | 3913.4 | |
Interchangeability of COMVAX and Licensed Haemophilus b Conjugate Vaccines or Recombinant Hepatitis B Vaccines
Among 58 children previously given a primary course of PedvaxHIB, 90% (95% C.I. 78.8%, 96.1%) developed an anti-PRP response >1 mcg/mL with a GMT of 9.6 mcg/mL (95% C.I. 6.6, 14.1) in response to a dose of COMVAX at 12-15 months of age. Among 683 children previously given a primary course of another HIB or HIB-containing vaccine, 99% (95% C.I. 97.9%, 99.6%) developed an anti-PRP response >1 mcg/mL with a GMT of 14.9 mcg/mL (95% C.I. 13.7, 16.3) in response to a dose of COMVAX at 12-15 months of age.
In another study, COMVAX was administered either concomitantly or six weeks after vaccination with M-M-R® II and VARIVAX® (Varicella Virus Vaccine Live, Oka/Merck). Among 149 children who previously received 2 doses of monovalent Hepatitis B vaccine, 100% (95% C.I. 97.6%, 100.0%) developed an anti-HBs response ≥10 mIU/mL with a GMT of 2194.6 mIU/mL (95% C.I. 1667.8, 2887.8) in response to a dose of COMVAX at 12-15 months of age.
Antibody Responses to COMVAX and Concurrently Administered Vaccines
Immunogenicity results from open-labeled studies indicate that COMVAX can be administered concomitantly with DTP, DTaP, OPV, IPV (inactivated poliomyelitis vaccine), M-M-R II, and VARIVAX using separate sites and syringes for injectable vaccines.
DTP and DTaP
After a primary series of DTP (2, 4, 6 months of age) given concomitantly with COMVAX (2 and 4 months of age), 98.2% of 57 infants developed a 4-fold rise in antibody to diphtheria, 100% of 57 infants developed a 4-fold rise in antibody to tetanus, and 89.5% to 96.5% of 57 infants developed a 4-fold rise in antibody to pertussis antigens, depending on the assay used and adjusted for maternal antibody. In this trial, after 2 doses of COMVAX, 79.0% of 62 infants developed anti-PRP >1.0 mcg/mL and after 3 doses (2, 4, and 15 months of age), 100% of 59 infants developed ≥10 mIU/mL of anti-HBs.
After a primary series of DTaP and COMVAX given concomitantly at 2, 4, and 6 months of age, 100% of 18 infants had ≥0.01 antitoxin units/mL to diphtheria and tetanus and 94.4% to 100% of 18 infants developed a ≥4-fold rise in antibody to pertussis antigens, depending on the assay used and adjusted for maternal antibody. In this trial, after 2 doses of COMVAX, 85.7% of 63 infants developed anti-PRP >1.0 mcg/mL and after 3 doses administered on the compressed schedule of 2, 4, and 6 months of age, 92.9% of 56 infants developed ≥10 mIU/mL of anti-HBs.
OPV and IPV
After a primary series of OPV (2, 4, 6 months of age) given concomitantly with COMVAX (2 and 4 months of age), 98.3% of 60 infants had neutralizing antibody ≥1:4 to poliovirus type 1, 100% of 57 infants had neutralizing antibody ≥1:4 to poliovirus type 2 and 98.1% of 53 infants had neutralizing antibody ≥1:4 to poliovirus type 3. In this trial, after 2 doses of COMVAX, 79.0% of 62 infants developed anti-PRP >1.0 mcg/mL and after 3 doses, 100% of 59 infants developed ≥10 mIU/mL of anti-HBs.
After a primary series of IPV and COMVAX given concomitantly at 2, 4, and 6 months of age, 100% of 38 infants had neutralizing antibody ≥1:4 to poliovirus types 1, 2, and 3. In this trial, after 2 doses of COMVAX, 85.7% of 63 infants developed anti-PRP >1.0 mcg/mL and after 3 doses administered on the compressed schedule of 2, 4, and 6 months of age, 92.9% of 56 infants developed ≥10 mIU/mL of anti-HBs.
M-M-R II and VARIVAX
After concomitant vaccination of M-M-R II and VARIVAX with COMVAX (12 to 15 months of age), 99.4% of 313 children developed antibody to measles, 99.2% of 354 children developed antibody to mumps, 100% of 358 children developed antibody to rubella and 100% of 276 children developed antibody to varicella. In this trial, infants received the primary series of Hib vaccine and the first two doses of Hepatitis B vaccine in the first year of life. After the dose of COMVAX, 97.8% of 368 infants developed >1.0 mcg/mL of anti-PRP and 99.2% developed ≥10 mIU/mL of anti-HBs.
Indications and Usage for Comvax Vaccine
COMVAX is indicated for vaccination against invasive disease caused by Haemophilus influenzae type b and against infection caused by all known subtypes of hepatitis B virus in infants 6 weeks to 15 months of age born of HBsAg negative mothers.
Infants born to HBsAg positive mothers should receive Hepatitis B Immune Globulin and Hepatitis B Vaccine (Recombinant) at birth and should complete the hepatitis B vaccination series given according to a particular schedule (see manufacturer's circular for Hepatitis B Vaccine [Recombinant]).
Infants born to mothers of unknown HBsAg status should receive Hepatitis B Vaccine (Recombinant) at birth and should complete the hepatitis B vaccination series given according to a particular schedule (see manufacturer's circular for Hepatitis B Vaccine [Recombinant]).
Vaccination with COMVAX should ideally begin at approximately 2 months of age or as soon thereafter as possible. In order to complete the three-dose regimen of COMVAX, vaccination should be initiated no later than 10 months of age. Infants in whom vaccination with a PRP-OMPC-containing product (i.e., PedvaxHIB, COMVAX) is not initiated until 11 months of age do not require three doses of PRP-OMPC; however, three doses of an HBsAg-containing product are required for complete vaccination against hepatitis B, regardless of age. For infants and children not vaccinated according to the recommended schedule see DOSAGE AND ADMINISTRATION.
COMVAX will not protect against invasive disease caused by Haemophilus influenzae other than type b or against invasive disease (such as meningitis or sepsis) caused by other microorganisms. COMVAX will not prevent hepatitis caused by other viruses known to infect the liver. Because of the long incubation period for hepatitis B, it is possible for unrecognized infection to be present at the time the vaccine is given. The vaccine may not prevent hepatitis B in such patients.
As with other vaccines, COMVAX may not induce protective antibody levels immediately following vaccination and may not result in a protective antibody response in all individuals given the vaccine.
Use With Other Vaccines
Immunogenicity results from open-labeled studies indicate that COMVAX can be administered concomitantly with DTP, DTaP, OPV, IPV, M-M-R II, and VARIVAX using separate sites and syringes for injectable vaccines (see CLINICAL PHARMACOLOGY).
Contraindications
Hypersensitivity to yeast or any component of the vaccine.
The decision to administer or delay vaccination because of current or recent febrile illness depends on the severity of symptoms and on the etiology of the disease. The ACIP has recommended that immunization should be delayed during the course of an acute febrile illness.{63} All vaccines can be administered to persons with minor illnesses such as diarrhea, mild upper-respiratory infection with or without low-grade fever, or other low-grade febrile illness. Persons with moderate or severe febrile illness should be vaccinated as soon as they have recovered from the acute phase of the illness.
Warnings
Patients who develop symptoms suggestive of hypersensitivity after an injection should not receive further injections of the vaccine (see CONTRAINDICATIONS).
Precautions
General
General care is to be taken by the health-care provider for the safe and effective use of this product.
As for any vaccine, adequate treatment provisions, including epinephrine, should be available for immediate use should an anaphylactic or anaphylactoid reaction occur.
Use caution when vaccinating latex-sensitive individuals since the vial stopper contains dry natural latex rubber that may cause allergic reactions.
As reported with Haemophilus b Polysaccharide Vaccine and another Haemophilus b Conjugate Vaccine, cases of Haemophilus b disease may occur in the week after vaccination, prior to the onset of the protective effects of the vaccines.
The packaging stopper of this product contains natural rubber latex which may cause allergic reactions.
Instructions to Health-care Provider
The health-care provider should determine the current health status and previous vaccination history of the vaccinee.
The health-care provider should question the patient, parent or guardian about reactions to a previous dose of COMVAX, PedvaxHIB or other Haemophilus b conjugate vaccines or RECOMBIVAX HB or other hepatitis B vaccines.
Injection of a blood vessel should be avoided.
COMVAX should be given with caution in infants with bleeding disorders such as hemophilia or thrombocytopenia, with steps taken to avoid the risk of hematoma following the injection.
If COMVAX is used in persons with malignancies or those receiving immunosuppressive therapy or who are otherwise immunocompromised, the expected immune response may not be obtained.
COMVAX is not contraindicated in the presence of HIV infection.{68}
Information for Vaccine Recipients and Parents/Guardians
The health-care provider should provide the vaccine information required to be given with each vaccination to the patient, parent or guardian.
The health-care provider should inform the patient, parent or guardian of the benefits and risks associated with vaccination. For risks associated with vaccination, see WARNINGS, PRECAUTIONS, and ADVERSE REACTIONS.
Laboratory Test Interactions
Sensitive tests (e.g., Latex Agglutination Kits) may detect PRP derived from the vaccine in the urine of some vaccinees for at least 30 days following vaccination with lyophilized PedvaxHIB{58}; in clinical studies with lyophilized PedvaxHIB, such children demonstrated a normal immune response to the vaccine. It is not known whether antigenuria will occur after vaccination with COMVAX.
Drug Interaction
Deferral of immunization may be considered in individuals receiving immunosuppressive therapy.
Carcinogenesis, Mutagenesis, Impairment of Fertility
COMVAX has not been evaluated for its carcinogenic or mutagenic potential, or its potential to impair fertility.
Pregnancy
Pregnancy Category C:
Animal reproduction studies have not been conducted with COMVAX. It is also not known whether COMVAX can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. COMVAX is not recommended for use in women of childbearing age.
Pediatric Use
Safety and effectiveness of COMVAX in infants below the age of 6 weeks and above the age of 15 months have not been established. However, studies have demonstrated that PedvaxHIB is safe and immunogenic when administered to infants and children up to the age of 71 months and RECOMBIVAX HB is safe and immunogenic in persons of all ages.
COMVAX should not be used in infants younger than 6 weeks of age because this will lead to a reduced anti-PRP response and may lead to immune tolerance (impaired ability to respond to su
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