Haemophilus Influenza Type B (Hib)
- Haemophilus influenza type b (Hib) is a bacterial infection that can cause severe illnesses in children, including meningitis, epiglottitis, pneumonia, arthritis, and cellulitis.
- Meningitis caused by Hib is an infection of the membranes covering the brain.
- Hib is spread through person-to-person transmission, mostly through the air. It’s often found in the respiratory tracts of adults with no symptoms or adverse effects. Hib has to get into the bloodstream for it to cause meningitis or severe infections of the bones and joints.
- Hib is mostly a disease of young children under the age of 5 years old. Before the vaccine was introduced in the U.S., children who became sick from Hib were usually under 2 years old, and mostly between 6 and 7 months old.
- In general, Hib disease is not considered very contagious. Before the vaccine most children acquired natural immunity to Hib by the time they were 5 or 6 years old.
- There are six different Haemophilus influenzae type b (Hib) vaccines available in the U.S., including two for infants as young as 6 weeks old; one to be used only as the last dose for children ages 12 months and older. The five vaccines are: ActHIB; Hiberix; PedvaxHIB; Comvax, Pentacel and Menhibrix.
- While the CDC reports that the risk of Hib vaccine causing serious harm or death is extremely small, as of May 2012 there have been a total of 12,140 adverse events reported to the Vaccine Adverse Events Reporting System (VAERS). Most of these reports were in children under age 3 (11,252).
- Health officials admit that it’s difficult to know from clinical trial results exactly what kind adverse reactions to look for after your child gets a Hib vaccine because children in the clinical trials were given other vaccines at the same time they were given the experimental Hib vaccine. Administration of more than one vaccine at a time also makes it difficult to determine which vaccines might have been responsible for certain adverse reactions reported in the clinical studies and to VAERS.
NVIC “Quick Facts” is not a substitute for becoming fully informed about Haemophilus B and the Hib vaccine. NVIC recommends consumers read the more complete information following the "Quick Facts", as well as the vaccine manufacturer product information inserts, and speak with one or more trusted health care professionals before making a vaccination decision for yourself or your child.
Food & Drug Administration (FDA)
- ActHIB Product Insert – Hib, Tetanus Toxoid (Sanofi Pasteur) & Licensing Information
- Hiberix Product Insert – Hib, Tetanus Toxoid (GlaxoSmithKline) & Licensing Information
- PedvaxHIB Product Insert – Hib, Meninogococcal (Merck Sharp & Dohme Corp.) & Licensing Information
- Comvax Product Insert - Hib, Meningococcal, Hep B (Merck & Co, Inc.) & Licensing Information
- Pentacel Product Insert – Hib Diphtheria, Tetanus Toxoids, Pertussis, Polio (Sanofi Pasteur) & Licensing Information
- Menhibrix Product Insert – Hib, Meningococcal, Tetanus Toxoid (GlaxoSmithKline) & Licensing Information
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CDC on Hib Disease
CDC on Hib Vaccination
Hib Vaccine Information Statement
Table of Contents
What Is Haemophilus B (Hib)?
Haemophilus influenza (H. influenzae) is a bacterial infection that was erroneously first identified in 1892 as the cause of influenza. It was later determined to be an invasive bacterial infection that is exclusively a human pathogen spread by airborne droplets through sneezing or coughing, or by direct contact with secretions or fomites. Six major serotypes of H. influenzae have been identified and labeled with the letters a through f. Some strains, which don’t have a polysaccharide capsule, are still untyped.
Invasive H. influenza type b (Hib) can cause severe illness, including meningitis and systemic, invasive disease in the bones and joints. Invasive means that germs spread to other parts of the body. Hib is mostly found in infants and children under 5 to 6 years old. However, nontypable strains of H. influenzae can also be found in humans, particularly in the upper respiratory tracts of up to three-fourths of all healthy adults. The nontypable strains can cause otitis media in infants and children and lower respiratory tract infections in adults with chronic bronchitis. However, the incidence of invasive disease caused by nontypable strains is low.1,2
For infants and children under age 6, the most common types of invasive disease caused by Hib are meningitis, epiglottitis, pneumonia, arthritis, and cellulitis. Meningitis is an infection of the membranes covering the brain and spinal cord, and Hib was responsible for 50 to 65 percent of meningitis cases before the vaccine was introduced in the mid-1980s. Other causes of meningitis in infants and children are Neisseria meningitides and Streptococcus pneumoniae. Symptoms of Hib meningitis are fever, decreased mental status, and stiff neck.
Epiglottitis is an infection and swelling of the epiglottis, and can cause life-threatening airway obstructions. Septic arthritis (joint infection), cellulitis (rapidly progressing skin infection usually involving the face, head, or neck, and pneumonia, mild or severe, are also caused by Hib. Bone infections (osteomyelitis) and pericarditis are less common forms of the disease.3
The most common symptoms of severe Hib infection are fever and altered central nervous system function. Less common symptoms can be osteomyelitis, septic arthritis, pericarditis, orbital cellulitis, endophthalmitis, urinary tract infection, abscesses, and bacteremia.4 Back to Top
Is Hib Communicable?
Yes. H. Influenzae b is spread by airborne droplets or direct contact with secretions or fomites.5
In general, Hib disease is considered to be minimally contagious. It enters the body through the nasopharynx, and can remain there for several months with no symptoms. In some persons the organism causes an invasive infection and develops into meningitis. Although it’s not known how it gets into the bloodstream, it’s possible that a co-existing viral or mycoplasma infection of the upper respiratory tract may be a contributing factor.
Before vaccines were introduced in the U.S., health officials had identified a seasonal pattern to Hib, with a peak during September through December, and a second peak from March through May. For the most part, the contagious potential of Hib is considered to be limited, but close contact with persons who have the disease can lead to outbreaks of the disease. Before the vaccine approximately two-thirds of all cases of Hib affected infants and children under 15 months old.6,7 Hib is a largely age-dependent disease; it is not common beyond the age of 5 years old.8
Hib can spread rather quickly in populations in enclosed quarters, such as families and daycare centers.9
History of Hib in America
Before the Hib vaccine was introduced in the U.S., Hib-caused meningitis occurred in children ages 6 months to 2 years at the rate of 12,000 to 20,000 cases per year, and caused 500 deaths annually.10
From 1996 through 2000 after the introduction of the vaccine, an average of 1,247 invasive H. Influenzae infections per year were reported to the CDC. Of this number, about 272 were children under age 5. An average 68 cases per year were attributable to Hib.11 Back to Top
Can Hib Cause Injury and Death?
Yes, Hib can cause injury, but rarely causes death. According to Harrison’s Principles of Internal Medicine, the mortality rate for meningitis caused by Hib is around 5 percent. Of survivors, 6 percent of the 5 percent will have permanent sensorineural hearing loss, and about one-fourth will have a significant handicap of some sort. Up to half may have some neurologic problems such as partial hearing loss and delay in language development.12 Acute (life-threatening) complications of Hib can include cerebral edema, increased cranial pressure, ventriculitis (usually in association with obstruction to cerebrospinal fluid flow), cerebritis, hydrocephalus, brain abscess, cerebral infraction, and subdural effusion or empyema.13 Back to Top
Who Is at Highest Risk for Getting Hib?
According to the CDC, the most striking feature of Hib is that it is age-dependent and uncommon after the age of 5 years old. Before the vaccine was introduced in the U.S., the age at which most children were stricken with invasive Hib was between 6 and 7 months old, and usually under the age of 2 years.14,15
Risk factors for Hib disease include household crowding, large household size, child care attendance, low socioeconomic status, low parental education levels, and school-aged siblings. Gender is also a factor―males are at a higher risk of getting the disease than females. Also, chances of household contacts of a child who has invasive Hib are about 600 times higher than the risk for the general population.16
Certain population groups have a higher incidence of Hib than others, for example, the incidence of meningitis due to Hib is three to four times higher among black children than among whites. Also, according to Harrison’s Principles of Internal Medicine, the incidence of meningitis caused by invasive Hib is 10 times higher in certain Native American groups than in the general population. Researchers speculate that age of exposure, socioeconomic conditions, and genetic differences may account for the inability to mount an immune response to the bacterium. Epiglottis caused by Hib is different in that it usually occurs in occurs in children ages 2 years through 7 years old. Interestingly, Navajo Indians and Alaskan Eskimos don’t usually get epiglottis.
Cellulitis caused by Hib usually occurs in young children on the head or neck, and sometimes appears bluish-red in color. Most patients with Hib-caused cellulitis also have bacteremia, and 10 percent have an additional infection. Hib can also cause pneumonia in infants that is clinically indistinguishable from other types of bacterial pneumonia.
Household members of a family where a child has Hib should be treated with a prophylaxis dose of oral rifampin if they are under age 4 and not vaccinated for Hib. Children over age 4 and under 12 also should receive a dose.17 Back to Top
Who Is at Highest Risk for Suffering Complications of Hib?
Asplenic patients (people without a spleen or with dysfunctional spleens such as those with sickle cell anemia are predisposed to getting severe bacteremic infections from S. pneumoniae, N. meningitides, and Hib.18 Hib infections also occur more frequently in patients who have cancer, who are undergoing chemotherapy, and who have congenital or acquired immunodeficienies.19 The risk of dying or developing complications from Hib is related to age and underlying condition of the patient, severity of the disease, and when antibiotic therapy is begun.20 Back to Top
Hib Prevention and Treatment Options
Before the vaccine, most children acquired natural immunity to Hib by the time they were 5 or 6 years old through asymptomatic infection. Passive protection is also provided to infants by antibodies acquired from the mother through the placenta and by breastfeeding during the first 6 months of life. If a child is diagnosed with severe symptoms of Hib, hospitalization is usually required, and tests are administered to identify the bacteria and to determine what type it is, if it is indeed Haemophilus influenzae. The child is then treated with an antimicrobial therapy for 10 days.21
Additionally, glucocorticoids may be given to reduce the incidence of neurologic problems by reducing inflammation that occurs when the antibiotic begins working. An intravenous drug called Dexamethasone may also be used on children over 2 months old. While fluoroquinolones can also treat H. influenzae, it isn’t recommended for children or pregnant women. Back to Top
What Is Hib Vaccine?
The Haemophilus influenzae type b (Hib) polysaccharide-protein conjugate vaccine has been available in the U.S. since December 1987. Conjugation is the process of chemically bonding a polysaccharide to a protein “carrier” to increase the effectiveness of the polysaccharide antigen.22 Two conjugate Hib vaccines are licensed for use in the U.S. for infants as young as 6 weeks old. A third is approved only for the last dose of Hib among children ages 12 months and older.
Three combination vaccines that contain Hib conjugate vaccine are also available, for a total of six vaccines containing Haemophilis B that are licensed for vaccination and distribution in the U.S. One of the three combination vaccines was only approved by the FDA on June 14, 2012, a Meningococcal Groups C and Y and Haemophilus b tetanus toxoid conjugate vaccine for infants and children ages 6 weeks through 18 months.23,24
The six vaccines are: Sanofi Pasteur’s ActHIB, which is a conjugate vaccine containing Haemophilus b and meningococcal protein conjugate; GlaxoSmithKline Biologicals’ Hiberix, which is a tetanus toxoid and Haemophilus b conjugate vaccine; Merck, Sharpe & Dohm’s PedvaxHIB, which is a meningococcal protein and Haemophilus b conjugate; Merck & Co.’s Comvax, which contains Haemophilus b conjugate, meningococcal protein conjugate and hepatitis B vaccine (recombinant); Sanofi Pasteur’s Pentacel, which consists of diphtheria and tetanus toxoids, acellular pertussis adsorbed, inactivated poliovirus, and Haemophilus b conjugate (tetanus toxoid conjugate); and GlaxoSmithKline’s MenHibrix, which consists of meningococcal groups C and Y and Haemophilus b tetanus toxoid conjugate.
None of the Hib vaccines protect against any other types of Haemophilus infection than type b. It also does not protect against meningitis caused by any other bacteria. It is not known whether Hib vaccine protects against ear infections.25
The Advisory Committee on Immunization Practices (ACIP) has approved the Hib vaccine for use with children at 2, 4, 6 and 12-15 months of age. The new vaccine, MenHibrix, has been approved for children ages 6 weeks through 18 months. Depending on which brand of Hib is used, some children may not need the dose at 6 months. Although generally speaking children over age 5 years old do not need the Hib vaccine, sometimes it is given those children and even adults with special health conditions such as those with sickle cell disease, or HIV/AIDS, or those who have had their spleens removed, had a bone marrow transplant or have cancer treatments with drugs.26,27
- ActHIB is a conjugate vaccine made by Sanofi Pasteur that is indicated for vaccinated infants and children ages 2 months through 18 months for the prevention of H. influenzae type b and/or diphtheria, tetanus and pertussis.28 The protein carrier is tetanus toxoid.29 It is a lyophilized powder that is reconstituted at the time of use with either saline (0.4% sodium chloride) or with Sanofi’s Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed (whole-cell pertussis vaccine DTP) or with Tripedia, Sanofi Pasteur’s Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed (DTap) (when reconstituted known as TriHIBit).
ActHIB is injected into the muscle. According to the manufacturer’s product insert, the vaccine consists of Haemophilus b capsular polysaccharide (polyribosyl-ribitol-phosphate, PRP), a high molecular weight polymer prepared from the Haemophilus influenzae type b strain 1482 grown in a semi-synthetic medium covalently bound to tetanus toxoid. The tetanus toxoid is prepared by extraction, ammonium sulfate purification, and formalin inactivation of the toxin from cultures of Clostridium tetani (Harvard strain) grown in a modified Mueller and Miller medium. Further manufacturing steps reduce residual formaldehyde levels.
According to the manufacturer, when ActHIB is reconstituted with saline, each dose is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to 24 mcg of inactivated tetanus toxoid and 8.5% of sucrose. When it is combined with Sanofi’s DTP vaccine, each dose is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to 24 mcg of inactivated tetanus toxoid, 8.5% of sucrose, 6.7 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid, and an estimate of 4 protective units of pertussis vaccine. Thimerosal is added as a preservative to the DTP vaccine.
When Act HIB is combined with Tripedia (TrHIBit) by reconstitution for booster dose, each dose is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to 24 mcg of inactivated tetanus toxoid, 8.5% of sucrose, 6.7 Lf of diphtheria toxoid, 5 Lf of tetanus toxoid and 46.8 mcg of pertussis antigens. Tripedia is formulated without preservatives, but contains a trace amount of thimerosal from the manufacturing process.
- Hiberix is a conjugate vaccine made by GlaxoSmithKline that is indicated for vaccination as a booster dose for use in children ages 15 months through 4 years of age, prior to the fifth birthday, for the prevention of Haemophilus type b.30 The protein carrier is tetanus toxoid. It is a lyophilized vaccine that is reconstituted with saline and then injected into the muscle. According to the manufacturer’s product insert, Hiberix contains Haemophilus b capsular polysaccharide (polyribosyl-ribitol-phosphate), a high molecular weight polymer prepared from the Haemophilus influenzae type b strain 20,752 grown in a synthetic medium. The tetanus toxin in the vaccine is prepared from Clostridium tetani grown in a semi-synthetic medium, and detoxified with formaldehyde. The polysaccharide is covalently bound to the tetanus toxoid.
Once it’s reconstituted, each dose of Hiberix is formulated to contain 10 mcg of purified capsular polysaccharide conjugated to approximately 25 mcg of tetanus toxoid, 12.6 mg of lactose, and less than or equal to 0.5 mcg of residual formaldehyde. It does not contain preservatives or latex.
- PedvaxHIB, is a conjugate vaccine manufactured by Merck & Co. that is indicated for vaccination against Haemophilus influennzae type b in infants and children ages 2 to 71 months of age.31 It is a liquid conjugate vaccine with meningococcal group B outer membrane as the protein carrier. It does not need to be reconstituted, and is injected into the muscle. It is a purified polysaccharide (polyribosylribitol phosphate or PRP) of Haemophilus influenzae type b (Haemophilus b, Ross strain) covalently bound to an outer membrane protein complex of the B11 strain of Neisseria meningitides serogroup B. The covalent bonding is necessary for enhanced immunogenicity.
Each dose of Liquid PedvaxHIB is formulated to contain 7.5 mcg of Haemophilus b PRP, 125 mcg of Neisseria meningitides OMPC and 225 mcg of aluminum as amorphous aluminum hydroxyphosphate sulfate (previously referred to as aluminum hydroxide), in 0.9 percent sodium chloride. It does not contain lactose or thimerosal.
- Comvax is manufactured by Merck & co., and is indicated for vaccination against Haemophilus influenzae type b and against infection caused by all known subtypes of hepatitis B in infants 6 weeks to 15 months of age born to HBsAg-negative mothers.32 According to the manufacturer’s product insert vaccination with Comvax should begin at approximately 2 months of age or as soon thereafter as possible, and no later than 10 months of age. It is administered on a 3-dose schedule; however, infants who do not receive a PRP-OMPC-containing product (PedvaxHIB, Comvax) until 11 months of age do not require three doses, even though three doses of an HBsAg-containing product are required for complete vaccination against hepatitis B regardless of age.
- Pentacel is manufactured by Sanofi Pasteur and is indicated for vaccination against diphtheria, tetanus, pertussis, poliomyelitis and Haemophilus influenzae type b in children ages 6 weeks through 4 years of age and prior to the fifth birthday.33 It is injected into the muscle in a 4-dose schedule. The antigenic forms in the vaccine include a mixture of two toxoids with five acellular pertussis antigens, three types of poliovirus, and Hib conjugated to tetanus toxoid.34 Specifically, according to the manufacturer’s product insert35, each dose of Pentacel contains 15 Lf diphtheria toxoid, 5 Lf tetanus toxoid, acellular pertussis antigens, 20 mcg detoxified pertussis toxin (PT), 20 mcg filamentous hemagglutinin (FHA), 3 mcg pertactin (PRN), 5 mcg fimbriae types 2 and 3 (FIM) inactivated polioviruses (40 D-angigen units DU Type 1 Mahoney, 8 DU Type 2 MEF-1, 32 DU Type 3 Saukett) and 10 mcg PRP of Haemophilus influenzae type b.
Other ingredients in each dose of Pentacel include 1.5 mg aluminum phosphate (0.33 mg aluminum) as the adjuvant, polysorbate 80 (approximately 10 ppm), less than or equal to 5 mcg residual formaldehyde, less than 50 ng residual glutaraldehyde, less than 50 ng residual bovine serum albumin, 3.3 mg (0.6% v/v) 2-phenoxyethanol (not as preservative), less than 4 pg of neomycin and less than 4 pg polymyxin B sulfate.
The Cornyebacterium diphtheria is grown in modified Mueller’s growth medium and purified by ammonium sulfate fractionation. The diphtheria toxin is detoxified with formaldehyde and diafiltered. Clostridium tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion. The tetanus toxin is detoxified with formaldehyde and purified by ammonium sulfate fractionation and diafiltration. The diphtheria and tetanus toxoids are individually adsorbed onto aluminum phosphate. The acellular pertussis antigens are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium and modified by the addition of casamino acids and dimethyl-beta-cyclodextrin. PT, FHA, and PRN are isolated separately from the supernatant culture medium. FIM are extracted and copurified from the bacterial cells. The pertussis antigens are purified by sequential filtration, salt precipitation ultrafiltration and chromoatography. PT is detoxified with glutaraldehyde. FHA is treated with formaldhyde and the residual aldehydes are removed by ultrafiltration. The individual antigens are adsorbed separately onto aluminum phosphate.
According to the manufacturer’s product insert, poliovirus Types 1, 2, and 3 are each grown in separate cultures of MRC-5 cells (a line of human diploid cells obtained from the normal lung tissue of a 14-week-old male fetus36). The cells are grown in CMRL 1969 medium supplemented with calf serum. After clarification and filtration, the viral suspensions are concentrated by ultrafiltration and purified by liquid chromatography. The viral suspensions are inactivated with formaldehyde. The monovalents are then combined to produce the trivalent poliovirus concentrate.
The adsorbed diphtheria, tetanus and acellular pertussis antigens are combined with aluminum phosphate as an adjuvant, 2-phenoxyethanol (not preservative) and water for injection. The trivalent poliovirus concentrate is then added and the DTaP-IPV component is diluted to its final concentration. The DTaP-IPV component does not contain preservative.
Also according to the manufacturer, Pentacel contains the same pertussis antigens as another vaccine, Daptacel, and is manufactured by the same process as Daptacel; however, Pentacel vaccine contains twice as much detoxified PT and four times as much FHA as Daptacel.
- MenHibrix is manufactured by GlaxoSmithKline and was approved by the FDA on June 14, 2012 for vaccination against Neisseria meningitides serogroups C and Y and Haemophilus influenzae be for children ages 6 weeks through 18 months old. It is injected into the muscle in a 4-dose schedule.37 MenHibrix is reconstituted with a saline dilutent. According to the manufacturer’s product insert, MenHibrix contains Neisseria meningitides serogroup C and Y capsular polysaccharide antigens and Haemophilus b capsular polysaccharide (polyribosyl-ribitol-phosphate — PRP). The Neisseria meningitides C strain and Y strain are grown in a synthetic medium.
The tetanus toxin is prepared from Clostridium tetani grown in a semi-synthetic medium and detoxified with formaldehyde. Each capsular polysaccharide is individually covalently bound to the inactivated tetanus toxoid. After purification the conjugate is lyophilized in the presence of sucrose as a stabilizer. When reconstituted each dose of MenHibrix is formulated to contain 5 mcg of purified Neisseria meningitidis C capsular polysaccharide conjugated to approximately 5 mcg of tetanus toxoid, and 2.5 mcg of purified Haemophilus b capsular polysaccharide conjugated to approximately 6.25 mcg of tetanus toxoid. Each dose also conatins 96.8 mcg of trometamol-HCI, 12.6 mg of sucrose, and about 0.72 mcg of residual formaldehyde. This vaccine does not contain preservatives. Back to Top
History of Hib Vaccine Use in America
Scientists began experimenting with a vaccine to prevent Haemophilus influenzae type b more than 30 years ago. One of the first ones was a polysaccharide vaccine that only induced protective levels in children older than 18 to 24 months old. When reinjection did not induce a booster effect at any age, researchers reported that, if they were going to achieve immunoprophylactic control of meningitis caused by Hib, they were going to have to come up with a more effective vaccine.38
After researchers discovered that a conjugation process offered better effects, the first conjugated Hib vaccine, ProHIBIT, was introduced in the U.S. in December 1987. ProHIBIT and other early conjugated vaccines (Hib TITER, PRP-D) are no longer available in the U.S. Today the only conjugated vaccines available in the U.S. are ActHIB, Hiberix, and PedvaxHIB.
The first combination vaccine―hepatitis B and Hib―was licensed in the U.S. in October 1996. Today there are two combination vaccines available in the U.S.: Pentacel, which contains H. influenzae b, diphtheria, tetanus, pertussis, and polio; and Comvax, which contains H. influenzae b and hepatitis B. Back to Top
How Effective Is Hib Vaccine?
The Hib vaccine in general provides titer (antibody) levels indicating protection against invasive Hib in about 90 to 95 percent of infants who have received two to three doses of the vaccine. There is some evidence that suggests that giving Hib conjugate vaccines to infants before the age of 6 weeks old may reduce the vaccine’s effectiveness overall when the second and third doses are given. Efficacy studies have not been done in populations with increased risk of invasive disease (for example, immunocompromised invidivudals). Even so, according to the CDC, Hib vaccine offers protection to patients with increased risk of getting this disease, including those with sickle-cell disease, leukemia, and those who have had a splenectomy. For those who have human immunodeficiency virus (HIV), the vaccine’s effectiveness varies with the stage of infection and degree of immunocompromise.39,40
- ActHIB — According to the manufacturer’s product insert, ActHIB induces antibodies in 90 percent of infants after the primary series and 98 percent of infants after a booster dose. However, Native Americans, who have been noted to have high rates of Hib, also have low immune responses to the Hib conjugate vaccines. The manufacturer reports that following a full three doses of the vaccine between 6 weeks and 6 months of age, only 75 percent of Native American infants had acceptable antibody levels. In children with sickle cell anemia, two doses of ActHIB produced acceptable antibodies in 89 percent of children.
Also, if ActHIB or ActHIB reconstituted with DTP or Tripedia is administered to immunosuppressed person receiving immunosuppressive therapy, expected antibody responses may not be obtained. This includes patients with asymptomatic or symptomatic HIV-infection, severe combined immunodeficiency, hypogammaglobulinemia or agammaglobulinemia; altered immune status due to diseases such as leukemia, lymphoma, or generalized malignancy, or an immune system compromised by treatment with corticosteroids, alkylating drugs, antimetabolites or radiation.
ActHIB has been found to be effective in children with sickle cell anemia. Antibody levels associated with protection against Hib with this vaccine may not be achieved until two weeks following the last recommended dose; ActHIB may not protect 100 percent of individuals. Additionally, persons who have been vaccinated with polysaccharide vaccines like ActHIB may still get HIB after vaccination and before the protective effects of the vaccine begin.41
- Hiberix — According to the manufacturer’s product insert, neither safety nor effectiveness of Hiberix in immunosuppressed children has been evaluated. If Hiberix is administered to immunosuppressed children, including those receiving immunosuppressive therapy, the expected immune response may not be obtained. Immunosuppressive therapies that may reduce immune response to Hiberix include irradiation, antimetabolites, alkylating agents, cytotoxic drugs and corticosteroids used in greater than physiologic doses. Vaccination with Hiberix does not substitute for a routine tetanus vaccine. Also, there is not enough data available to confirm whether administering Hiberix at the same time as other vaccines could interfere with immune responses to those vaccines. In clinical trials effectiveness of Hiberix was measured by antibody titers produced after administration of the vaccine.42
- PedvaxHIB — According to the manufacturer’s product insert, the protective efficacy of PedvaxHIB measured during clinical trials of high-risk populations was estimated to be 93 to 100 percent, depending on the age of the child. A booster shot of PedvaxHIB is required in infants who complete the primary two-dose regimen before 12 months of age to maintain antibody levels.43
- Comvax — According to the manufacturer’s product insert, the protective efficacy of Comvax for Hib following the primary two-dose regimen in clinical trials was 93 percent. In the follow-up period post-clinical trials, the efficacy was 96.6 to 100 percent depending on the age of the child. Comvax’s total efficacy for HIB and hepatitis B was compared with the protective antibodies obtained from monovalent vaccines that showed adequate antibody responses of 72.4 to 100 percent depending on the population of children being studied and whether they had received prior doses of monovalent vaccines.44
- Pentacel — According to the manufacturer’s product insert, the protective efficacy of the pentavalent vaccine Pentacel may not extend to all individuals. If Pentacel is administered to immunocompromised persons, including those receiving immunosuppressive therapy, the expected immune response may not be obtained. Immunosuppressive therapies, including irradiation, antimetabolities, alkylating agents, cytotoxic drugs and corticosteroids used in greater than physiologic doses may also reduce the immune response to Pentacel. Neither the safety nor the effectiveness of Pentacel in infants less than 6 weeks old or in children ages 5 to 16 years old have been established.
In clinical studies with Pentacel, efficacy was measured by antibody responses to the individual five disease components contained in the vaccine. The efficacy against pertussis, which has no well-established serological correlate of protection, is based in part on a comparison of pertussis immune responses following Pentacel vaccine in U.S. children to responses following Daptacel vaccine (Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine Adsorbed―DTAP. Immune responses to Pentacel were evaluated in four U.S. studies.
The efficacy for diphtheria one month following three and four doses of Pentacel was 98 to 100 percent. Tetanus antibodies were reported at 99.7 to 100 percent. Pertussis efficacy was reported at 68.8 to 95.8 percent, depending on which study was being looked at. Protective antibodies against poliomyelitis with Pentacel in clinical trials were reported at 99.4 percent. Protection against invasive disease due to Hib was 90 to 98.2 percent depending on the study.45
- MenHibrix efficacy for Hib is evaluated by antibody levels of PRP measured in the blood and compared to similar vaccines containing H. influenza type b and then compared to other Hib-containing vaccines. According to the manufacturer, antibody levels for Hib efficacy were equal to other Hib vaccines. Antibodies to N. Meningitidis were reported at 95 percent and 98 percent during a clinical study. Immunosuppressive therapies, including irradiation, antimetabolites, alkylating agents, cytotoxic drugs, and corticosteroids may reduce the efficacy of this vaccine.46 Back to Top
Can Hib Vaccine Cause Injury & Death?
Mild side effects such as redness, warmth, or swelling where the shot was given have been reported in connection with administration of Hib vaccines. Fever over 101 degrees F may occur, and can last two to three days. Sysemic reactions include irritability and lethargy. However, more severe reactions have also been reported in both clinical trials with all of the vaccines as well as to the Vaccine Adverse Events Reporting System (VAERS). According to MedAlerts.org (a searchable VAERS database) as of June 2012, there have been 12,140 serious adverse events reported to VAERS in connection with all Hib vaccines combined. Most of this number were children under age 3 (11,278). Serious reactions included deaths (471) and such things as anaphylactic reaction, asthma, pneumonia, convulsions, noninfectious encephalitis, acute pancreatitis, peripheral neuropathy, Guillain-Barre syndrome, sepsis, seizures, cerebral edema.
In clinical trials the severity of adverse reactions varied depending on which vaccine was given, and which other vaccines were given with them at the same time. Some of the events reported by the manufacturers included:
- ActHIB — tenderness, erythema, induration, fever, irritability, drowsiness, anorexia, diarrhea, vomiting; when combined with DTP vaccine by reconstitution, adverse reactions included: tenderness, erythema, induration, fever, irritability, drowsiness, anorexia, diarrhea, persistent crying, and one hypotonic/hypresponsive episode (which is consistent with the HHE rate observed with DTP vaccination alone)
- Hiberix — when co-administered with DTaP-HBV-IPV: redness, pain and swelling at injection site, fever, fussiness, loss of appetite, restlessness, sleepiness, diarrhea, vomiting; post-marketing reported adverse events included extensive swelling of the vaccinated limb, anaphylactic reactions, angioedema, convulsions, hypotonic-hyporesponsive episode, syncope, apnea, rash, urticarial, somnolence.
- PedvaxHIB — adverse events during clinical trials included irritability, sleepiness, injection siter pain/soreness, erythema, swelling induration, unusual high-pitched crying, prolonged crying (more than 4 hours), diarrhea, vomiting, crying, pain, otitis media, rash, and upper respiratory infection; potential adverse events may include early onset of Hib disease and Guillain-Barre syndrome; in post-marketing, reported adverse events included lymphadenopathy, angioedema, febrile seizures and injection site abscess.
- Comvax — (children in clinical trials were monitored five days) with the most frequently cited events being mild, transient signs and symptoms of inflammation at the injection site, pain/soreness, erythema, swelling, induration, somnolence, irritability, anorexia, vomiting, otitis media, fever, diarrhea, upper respiratory infection, rash, rhinorrhea, respiratory congestion, cough, candidiasis; in post-marketing: anaplylaxis, angioedema, urticarial, erythema multiforme, thrombocytopenia, seizure, febrile seizures, lymphadenopathy, pruritus, arthralgia, dyspnea, tachycardia, syncope, elevation of liver enzymes, increased erythrocyte sedimentation rate, arthritis, Bell’s Palsy, Guillain-Barre syndrome, agitation, Stevens-Johnson syndrome, alopecia, conjunctivitis, visual disturbances.
- Pentacel — redness, swelling, tenderness at injection site, increase in arm circumference (dose 4), fever, lethargy, inconsolable crying, fussiness, irritability, hypotonic hyporesponsive episodes, seizures, febrile seizures, bronchiolitis, dehydration, pneumonia, gastroenteritis, asthma, pneumonia, encephalopathy, and four deaths attributed to asphyxia due to suffocation, head trauma, Sudden Infant Death syndrome (SIDS), and neuroblastoma; in post-marketing, reported adverse events included cyanosis, vomiting, diarrhea, extensive swelling of injected limb including swelling that involved adjacent joints, invasive Hib disease (classified as vaccine failure), rash, urticarial, meningitis, rhinitis, viral infection, decreased appetitie, somnolence, HHE, depressed level of consciousness, screaming, apnea, cough, erythema, skin discoloroation, and pallor.
- MenHibrix — redness, swelling and pain at injection site, irritability, drowsiness, loss of appetitie, fever, and syncope. For more severe reactions such as nervous system disorders and other serious events, the manufacturer referred to reactions reported by the use of Hiberix rather than its own vaccine. It is not known whether MenHibrix can cause fetal harm when administered to a pregnant woman or whether it can affect reproduction capacity. 47
Besides the deaths reported in the clinical trials, deaths have been recorded in post-marketing reports as well. In fact, an open letter to Dr. Margaret Chan, director general of the World Health Organization, in March 2012 calls attention to the deaths the author says are connected with the pentavalent (DPT + Hib + Hepatitis B vaccine in India, Sri Lanka, Bhutan, and Pakistan.48 The authors add that the cause of the problem is unrelated to the brand or manufacturer or lot of the vaccine:
“It appears to be a form of ‘hypersensitivity reaction’ as described in the post mortem report on one of the children in Kerala. The vaccine can be administered to many patients without problems and there is no available method at present to predict which infant will react adversely.”
In a pediatric safety and use review of Pentacel in February 2010 the U.S. FDA discussed reported adverse reactions attributed to the vaccine in post-marketing, noting that Pentacel is now marketed in 11 countries, and there have been no safety-related labeling revisions. At the meeting, the FDA reported that 775 adverse reactions, 177 of which were considered serious including 26 deaths, had been reported to VAERS in connection with Pentacel between June 20, 2008 (when Pentacel was licensed) and October 31, 2009. The deaths were attributed to SIDS (12 cases), congenital/genetic conditions, respiratory infections, positional asphyxia, anoxic encephalopathy, cardiac arrest of undetermined etiology, dilated and hypertrophic cardiomyopathy, two deaths of undetermined cause, one death with no records obtainable, and two deaths with information pending.
The FDA said the SIDS reports “do not raise any concerns about a causal relationship with Pentacel.” The FDA also quoted the Institue of Medicine, which reviewed the data, and the IOM said: “The evidence favors rejection of a causal relationship between exposure to multiple vaccines and SIDS.” The FDA noted that “the sponsor is voluntarily conducting a descriptive, epidemiological safety surveillance study that will include at least 10,000 Pentacel recipients” with comparison groups of infants who receive other DTaP-containing products.49
Antigenuria has been reported after receipt of purified capsular polysaccharide H. influenza b vaccine. In one reported case, a 27-month-old child developed asceptic meningitis two days after getting the vaccine. Tests revealed that antigenuria was secondary to the vaccination.50,51,52 None of the vaccines have been evaluated for carcinogenic or mutagenic potential, or potential to impair fertility. Back to Top
Who Is at Highest Risk for Complications from Hib Vaccine?
Persons at highest risk for complications from Hib vaccine are those listed below who are advised not to get Hib vaccine. Back to Top
Who Should Not Get Hib Vaccine?
According to the CDC anyone who has ever had a life-threatening allergic reaction to a previous dose of Hib vaccine should not get another dose. Children under 6 weeks old should not get this vaccine either. Also, people who are moderately or severely ill at the time the shot is scheduled should wait until they recover before getting this vaccine.53
In general, vaccination of children older than 59 months is not recommended, mainly because by that age the majority of children have acquired natural immunity to it. However, the CDC says that some older children and adults who are at increased risk of getting the disease may be vaccinated. Those persons include those with functional or anatomic asplenia such as sickle cell disease, immunodeficiency, immunosuppression from cancer chemotherapy, infection with HIV, and those who have received a hematopoietic stem cell transplant.54
Also, according to the manufacturer’s product inserts:
- ActHIB should not be given to children with a history or hypersensitivity to any component of the vaccine and to any component of DTP or Tripedia vaccine when combined by reconstitution with these vaccines. Any contraindication to DTP and/or Tripedia is a contraindication for receiving ActHib reconstituted with Tripedia. Also, ActHIB should not be given to infants younger than 15 months old.55
- Hiberix should not be used as a primary vaccination. Anyone who has suffered severe allergic reactions or anaphylaxis after a previous dose of any Hib vaccine or tetanus-toxoid-containing vaccine or any component of Hiberix should not get this vaccine. If Guillain-Barre syndrome has occurred within six weeks of receipt of a prior vaccine containing tetanus toxoid, the decision to give Hiberix should be based on careful consideration of the potential benefits vs. possible risks.56
- PedvaxHib should not be given to anyone with a hypersensitivity to any component of the vaccine or the diluent. Persons who develop symptoms suggestive of hypersensitivity after an injection should not receive further injections of the vaccine. Use caution with children allergic to latex as the vial stopper contains dry natural latex rubber. The decision to administer or delay vaccination because of current or recent febrile illness depends on the severity of symptoms and etiology of the disease. Persons with moderate or severe febrile illness should be vaccinated after they have recovered. Persons over age 6 years or infants under 6 weeks of age should not get PedvaxHib. This vaccine is NOT recommended for use in adult populations.57
- Comvax should not be given to any infant before the age of 6 weeks. Comvax is not recommended for use in women of childbearing age because it is not known whether Comvax can cause fetal harm when administered to pregnant women. This vaccine is NOT recommended for use in adult populations. Deferral of vaccination with Comvax may be considered in individuals receiving immunosuppressive therapy. 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.58
- Pentacel should not be given to anyone who has suffered severe allergic reactions (anaphylaxis) after a previous dose of this vaccine, any ingredient of Pentacel vaccine, or any other diphtheria toxoid, tetanus toxoid, pertussis-containing vaccine, inactivated poliovirus vaccine or Hib vaccine. Pentacel should not be given to anyone who has suffered encephalopathy within seven days of a previous pertussis-containing vaccine with no other identifiable cause. Persons with a progressive neurologic disorder should not receive Pentacel until a treatment regimen has been established and the condition has stabilized. Careful consideration should be given to the benefits vs. risks before administering Pentacel to someone with a history of fever at or above 105 degrees F, a hypotonic-hyporesponsive episode, or persistent, inconsolable crying lasting more than three hours within 48 hours after a pertussis-containing vaccine, or who has suffered seizures within three days after a previous pertiussis-containing vaccine. If Guillain-Barre syndrome occurred within six weeks of receipt of a prior vaccine containing tetanus toxoid, the risk for Guillain-Barre syndrome may be increased following Pentacel.59
- MenHibrix should not be given to any child that has suffered Guillain-Barre syndrome within 6 weeks of receipt of a prior vaccine containing tetanus toxoid. The decision to administer it should be based on careful consideration of the possible benefits and risks of the vaccine. Careful consideration should also be given as to whether to give this vaccine to premature infants, since apnea following the injection in premature infants has occurred. Any child that has had a severe allergic reaction (anaphylaxis) to a previous dose of any meningococcal, Hib or tetanus-toxoid-containing vaccine or any component of MenHibrix should not receive this vaccine. It is not known whether MenHibrix can cause fetal harm when administered to a pregnant woman, or if it can affect reproduction capacity. Safety and effectiveness of MenHibrix in children younger than 6 weeks of age and children 19 months to 16 years old have not been established.60 Back to Top
Questions to Ask Doctors about Hib Vaccine
NVIC’s If You Vaccinate, Ask 8! Webpage
downloadable brochure suggests asking eight questions before you make a vaccination decision for yourself, or for your child. If you review these questions before
your appointment, you will be better prepared to ask your doctor questions. Also make sure that the nurse or doctor gives you the relevant Vaccine Information Statement (VIS) for the vaccine or vaccines you are considering well ahead of time to allow you to review it before
you or your child gets vaccinated. Copies of VIS for each vaccine are also available on the CDC's website and there is a link to the VIS for Hib vaccine on NVIC's “Quick Facts” at the top of this page.
It is also a good idea to read the vaccine manufacturer product insert (in this case, Hib vaccine manufacturer product inserts) that can be obtained from your doctor or public health clinic. Federal law requires drug companies marketing vaccines to include certain kinds of vaccine benefit, risk and use information in product information inserts that may not be available in other published information. Links to Hib vaccine manufacturer product inserts produced by different vaccine manufacturers are listed under “Food and Drug Administration” above.
Other questions that may be useful to discuss with your doctor before getting a Hib containing vaccine are:
- If other vaccines in addition to a Hib containing vaccines are scheduled for my child at this office visit, am I allowed to modify the schedule so fewer vaccines are given at once?
- What should I do if my child has a high fever or appears very ill after vaccination?
- What other kinds of reaction symptoms should I call to report after vaccination with a Hib containing vaccine?
- If the Hib vaccine doesn’t protect my child, do I have any other options for preventing Hib infection?
Under the National Childhood Vaccine Injury Act of 1986, doctors and all vaccine providers are legally required to give you vaccine benefit and risk information before vaccination; record serious health problems following vaccination in the permanent medical record; keep a permanent record of all vaccines given, including the manufacturer’s name and lot number; and report serious health problems, injuries and deaths that follow vaccination to VAERS.
Remember, if you choose to vaccinate, always keep a written record of exactly which shots/vaccines you or your child have received, including the manufacturer’s name and vaccine lot number. Write down and describe in detail any serious health problems that develop after vaccination, and keep vaccination records in a file you can access easily.
It also is important to be able to recognize a vaccine reaction and seek immediate medical attention if the reaction appears serious, as well as know how to make a vaccine reaction report to federal health officials at the Vaccine Adverse Reporting System (VAERS). NVIC’s Report Vaccine Reactions—It’s the Law webpage can help you file a vaccine reaction report yourself to VAERS if your doctor fails or refuses to make a report. Back to Top
NVIC Press Releases/Statements/Commentaries
Additional Bibliography of References
Salimnia H, Lephart PR, Asmar BI, et al. Aerosolized Vaccine as an Unexpected Source of False-Positive Bordetella Pertussis PCR Results. J Clin Microbiol. February 2012. (Epub Dec 2011). Vol 50 No 2. pp 472-474. Online. (Accessed June 2012)
National Institute of Allergy and Infectious Diseases. Sinusitis: Are Researchers Studying Sinusitis? March 9, 2011. Online. (Accessed June 2012)
Karnoven M, Cepaitis Z, Tuomilehto J. Association Between Type 1 Diabetes and haemophilus Influenzae Type b Vaccination: Birth Cohort Study. BMJ. May 1, 1999. 318(7192), 1169-1172. Online. (Accessed June 2012)
Adams WG, Deaver KA, Cochi SL, et al. Decline of Childhood Haemophilus Influenzae Type b (Hib) Disease in the Hib Vaccine Era. JAMA. Jan. 13, 1993, Vol 269, No 2. Online. (Accessed June 2012)
Chappelle R. FDA Approves New Combination Vaccine that Protects Children Against Two Bacterial Diseases. FDA Press Release. June 14, 2012. Online. (Accessed June 2012)
Fox News. FDA Approves GlaxoSmithKline's Menhibrix. Dow Jones Newswires. June 14, 2012. Online. (Accessed June 2012)
Varshney V. Vaccine Woes Continue. Down to Earth. March 12, 2012. Online. (Accessed June 2012)
Kaur R. Officials Push Five-in-One Vaccine. Down to Earth. July 31, 2010. Online. (Accessed June 2012)
Rothman J. Meningitis Caused by Haemophilus Influenzae Type b (Hib). Everyday Health. Nov. 4, 2009. Online. (Accessed June 2012)
Lavenda L. U.S. FDA Licenses Sanofi Pasteur's New Pediatric Combination Vaccine, Pentacel. Eurekalert. June 23, 2008. Online. (Accessed June 2012)
Pichichero ME. Are Combo Vaccines Really Simpler? Pediatric News. April 1, 2007. Onlinel. (Accessed June 2012)
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1 Kasper DL, Fauci AS, Braunwald E, et al. Harrison’s Principles of Internal Medicine 16th Edition. 2005. pp 864-866.
2 WebMD. Hib (H. Influenzae Type b) Vaccine. Children’s Vaccines Health Center. Aug. 31, 2009. Online. (Accessed June 2012)
3 CDC.gov. Haemophilus Influenzae Type B. The Pink Book. No Date. Online. (Accessed June 2012)
4 Kasper DL, Fauci AS, Braunwald E, et al. Harrison’s Principles of Internal Medicine 16th Edition. 2005. pp 864-866.
5 Kasper DL, Fauci AS, Braunwald E, et al. Harrison’s Principles of Internal Medicine 16th Edition. 2005. pp 864-866.
6 Broome CV. Epidemiology of Haemophilus Influenzae Type b Infections in the United States. Pediatr Infect Dis J. Aug 1987. Vol 6 Issue 8 pp 779-782. Online. (Accessed June 2012)
7 FDA.gov. Haemophilus b Conjugate Vaccine Manufacturer’s Product Insert. Sanofi Pasteur. May 6, 2009. Online. (Accessed June 2012)
8 CDC.gov. Haemophilus Influenzae Type B. The Pink Book. No Date. Online. (Accessed June 2012)
9 Devarajan VR, Cunha BA. Haemophilus Influenzae Infections. Medscape. Jan. 10, 2012. Online. (Accessed June 2012)
10 Todar K. Todar’s Online Textbook of Bacteriology. Haemophilus influenzae and Hib meningitis. 2008-2012. Online. (Accessed June 2012)
11 CDC.gov. Haemophilus Influenzae Type B. The Pink Book. No Date. Online. (Accessed June 2012)
12 Kasper DL, Fauci AS, Braunwald E, et al. Harrison’s Principles of Internal Medicine 16th Edition. 2005. pp 864-866.
13 Kaplan SL. Neurologic Complications of Bacterial Meningitis in Children. Wolters Kluwer. Online. (Accessed June 2012)
14 CDC.gov. Haemophilus Influenzae Type B. The Pink Book. No Date. Online. (Accessed June 2012)
15 Kasper DL, Fauci AS, Braunwald E, et al. Harrison’s Principles of Internal Medicine 16th Edition. 2005. pp 864-866.
16 CDC.gov. Haemophilus Influenzae Type B. The Pink Book. No Date. Online. (Accessed June 2012)
17 Kasper DL, Fauci AS, Braunwald E, et al. Harrison’s Principles of Internal Medicine 16th Edition. 2005. pp 864-866.
18 The Merck Manual. Overview of Immunization. Online. July 2008. (Accessed June 2012)
19 Devarajan VR, Cunha BA. Haemophilus Influenzae Infections. Medscape. Jan. 10, 2012. Online. (Accessed June 2012)
20 Kaplan SL. Neurologic Complications of Bacterial Meningitis in Children. Wolters Kluwer. Online. (Accessed June 2012)
21 CDC.gov. Haemophilus Influenzae Type B. The Pink Book. No Date. Online. http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/hib.pdf. (Accessed June 2012)
22 CDC.gov. Haemophilus Influenzae Type B. The Pink Book. No Date. Online. http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/hib.pdf. (Accessed June 2012)
23 FDA.gov. Complete List of Vaccines Licensed for Immunization and Distribution in the U.S. Vaccines, Blood & Biologics. April 19, 2012. Online. (Accessed June 2012)
24 FDA.gov. FDA Approves New Combination Vaccine that Protects Children Against Two Bacterial Diseases. FDA News & Events. June 14, 2012. Online. (Accessed June 2012)
25 Todar K. Todar’s Online Textbook of Bacteriology. Haemophilus influenzae and Hib meningitis. 2008-2012. Online. (Accessed June 2012)
26 CDC.gov. Haemophilus Influenzae Type b (Hib) Vaccine. Vaccine Information Sheet. Dec. 16, 1998. Online. http://www.cdc.gov/vaccines/pubs/vis/downloads/vis-hib.pdf. (Accessed June 2012)
27 FDA.gov. FDA Approves New Combination Vaccine that Protects Children Against Two Bacterial Diseases. FDA News & Events. June 14, 2012. Online. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm308350.htm. (Accessed June 2012)
28 FDA.gov. ActHIB. Vaccines, Blood & Biologics. Aug. 18, 2011. Online. (Accessed June 2012)
29 FDA.gov. Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) ActHIB manufacturer’s product insert. May 6, 2009. Online. (Accessed June 20012)
30 FDA.gov. Hiberix Manufacturer’s Product Insert. No date. Online. (Accessed June 2012)
31 FDA.gov. PedvaxHIB Manufacturer’s Product Insert. 1998. Online. (Accessed June 2012)
32 FDA.gov. Comvax Manufacturer’s Product Insert. 2001. Online. (Accessed June 2012)
33 FDA.gov. Pentacel Manufacturer’s Product Insert. July 2011. Online. (Accessed June 2012)
34 Grabenstein JD. ImmunoFacts: Vaccines and Immunologic Drugs. Diphtheria & Tetanus Toxoids with Acellular Pertussis Adsorbed, Inactivated Poliovirus, and Haemophilus Influenzae Type b Conjugate Vaccine. 2011. pp 78-87.
35 FDA.gov. Pentacel Manufacturer’s Product Insert. July 2011. Online. (Accessed June 2012)
36 ViroMed.com. Selected Profiles of Cell Cultures―MRC-5. ViroMed Laboratories. No date. Online. (Accessed June 2012)
37 FDA.gov. Menhibrix Manufacturer’s Product Insert. June 2012. Online.. (Accessed June 2012)
38 Schneerson R, Barrera O, Sutton A, Robbins JB. Preparation, Characterization, and Immunogenicity of Haemophilus Influenzaee Type b Polysaccharide-Protein Conjugates. J Exp Med. Aug. 1, 1980. Online. (Accessed June 2012)
39 Todar K. Todar’s Online Textbook of Bacteriology. Haemophilus influenzae and Hib meningitis. 2008-2012. Online. (Accessed June 2012)
40 CDC.gov. Haemophilus Influenzae Type B. The Pink Book. No Date. Online. (Accessed June 2012)
41 FDA.gov. Haemophilus b Conjugate Vaccine ActHIB Manufacturer’s Product Insert. Sanofi Pasteur. May 6, 2009. Online. . (Accessed June 2012)
42 FDA.gov. Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) Hiberix Manufacturer’s Product Insert. GlaxoSmithKline. No Date. Online. (Accessed June 2012)
43 FDA.gov. Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) Liquid Pedvax HIB. Merck & Co. 1998. Online. (Accessed June 2012)
44 FDA.gov. Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine Comvax Product Insert. Merck & Co. 2001. Online. . (Accessed June 2012)
45 FDA.gov. Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Congugate (Tetanus Toxoid Conjugate Vaccine) Pentacel. Sanofi Pasteur. July 2011. Online. . (Accessed June 2012)
46 FDA.gov. Menhibrix Manufacturer’s Product Insert. June 2012. Online. (Accessed June 2012)
47 FDA.gov. Menhibrix Manufacturer’s Product Insert. June 2012. Online. (Accessed June 2012)
48 Puliyel J, Shiva M, Dabade G, et al. Open Letter to DG, WHO — Pentavalent Vaccine Related Deaths in India. All India Drug Action Network (AIDAN). March 12, 2012. Online. (Accessed June 2012)
49 FDA.gov. Pediatric Safety and Use Review for Pentacel. Advisory Committee. Feb 19, 2010. Online. (Accessed June 2012)
50 Scheifelie D, Bjornsen GL, Acand T, Jacobsen K. Antigenuria after Receipt of Haemophilus b Diphtheria Conjugate Vaccine. Pediatr Infect Dis J. Dec 1989. Vol 8 Issue 12 pp 887. Online. (Accessed June 2012)
51 Spinola SM, Sheaffer CI, Philbrick KB, Gilligan PH. Antigenuria after Haemophilus Influenzae Type b Polysaccharide Immunization: A Prospective Study. J Pediatr. 1986;109(5):835-838. Online. (Accessed June 2012)
52 FDA.gov. Haemophilus b Conjugate Vaccine Manufacturer’s Product Insert. Sanofi Pasteur. May 6, 2009. Online. (Accessed June 2012)
53 CDC.gov. Who Should NOT Get Vaccinated with These Vaccines? Hib Vaccine. Feb. 27, 2012. Online. (Accessed May 2012)
54 CDC.gov. Haemophilus Influenzae Type B. The Pink Book. No Date. Online.(Accessed June 2012)
55 FDA.gov. Haemophilus b Conjugate Vaccine ActHIB Manufacturer’s Product Insert. Sanofi Pasteur. May 6, 2009. Online. (Accessed June 2012)
56 FDA.gov. Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate) Hiberix Manufacturer’s Product Insert. GlaxoSmithKline. Dec 2010. Online.(Accessed June 2012)
57 FDA.gov. Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate) Liquid PedvaxHIB Manufacturer’s Product Insert. Merck & Co. 1998. Online. (Accessed June 2012)
58 FDA.gov. Haemophilus b Conjugate (Meningococcal Protein Conjugate) and Hepatitis B (Recombinant) Vaccine Comvax. Merck & Co. 2001. Online.(Accessed June 2012)
59 FDA.gov. Diphtheria and Tetanus Toxids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjuage (Tetanus Toxoid Conjugate) Pentacel Manufacturer’s Product Insert. Sanofi Pasteur. July 2011. Online. (Accessed June 2012)
60 FDA.gov. Menhibrix Manufacturer’s Product Insert. June 2012. Online. (Accessed June 2012)
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