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What is Hib Vaccine?


History of Hib vaccine

Currently, there are four Haemophilus influenzae type b vaccines available for use by the United States Food and Drug Administration (FDA) and recommended by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control (CDC). These include: Sanofi Pasteur's ActHIB and GlaxoSmithKline Biological’s HIBERIX, both of which are tetanus toxoid and Haemophilus b conjugate vaccines; Merck, Sharp & Dohme’s PedvaxHIB, which is a meningococcal protein and Haemophilus b conjugate; and Sanofi Pasteur’s Pentacel, which consists of diphtheria and tetanus toxoids, acellular pertussis adsorbed, inactivated poliovirus, and Haemophilus b conjugate (tetanus toxoid conjugate); On December 21, 2018, the FDA approved VAXELIS, a 6 in 1 (hexavalent) combination vaccine containing Haemophilus influenzae type b conjugate vaccine in combination with diphtheria and tetanus toxoid and acellular pertussis (DTaP), inactivated poliomyelis (IPV), and recombinant hepatitis B vaccine.1 VAXELIS combines diphtheria and tetanus toxoids, acellular pertussis and inactivated poliomyelis antigens manufactured by Sanofi Pasteur with Haemophilus influenzae type b conjugate and hepatitis B recombinant vaccines, manufactured by Merck. VAXELIS is expected to be available for use in the United States in 2020,2 however, at this time, the CDC’s Advisory Committee on Immunization Practices (ACIP) has not made any recommendations regarding the use of VAXELIS.

Haemophilus influenzae type b (HIB) vaccines do not provide any protection against invasive disease resulting from non-b type and nontypeable H. influenzae.3

ActHIB: is a conjugate vaccine made by Sanofi Pasteur that is indicated for use in infants and children ages 2 months through 5 years of age for the prevention of H. influenzae type b. ActHIB vaccine is a sterile powder that requires reconstitution with 0.4% Sodium Chloride solution. The vaccine is comprised of the Haemophilus influenzae type b capsular polysaccharide (polyribosyl-ribitol-phosphate, or PRP). PRP is formed from H. influenzae type b strain 1482 that has been cultivated in a semi-synthetic growth medium and bound to tetanus toxoid. The tetanus toxin has been taken from the Harvard strain of Clostridium tetani, purified with ammonium sulfate, rendered inactive by formalin, and grown in a modified Mueller and Miller medium, a culture medium containing raw materials made from milk. During the manufacturing process, formaldehyde levels are reduced below 0.5mcg per dose and the toxoid is sterilized prior to being conjugated. The ActHIB vaccine powder and Sodium Chloride diluent do not contain any preservatives. This vaccine is administered intramuscularly.

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.4

HIBERIX: is a conjugate vaccine made by GlaxoSmithKline that is approved for use in infants and children ages 6 weeks through 4 years of age, prior to the fifth birthday, for the prevention of Haemophilus influenzae type b. HIBERIX 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, or PRP), 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.

When 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. HIBERIX does not contain preservatives and the vial stoppers of both the lyophilized powder and saline diluent do not contain latex.5

PedvaxHIB is a conjugate vaccine manufactured by Merck, Sharp & Dohme Co. that is indicated for vaccination against Haemophilus influenzae type b in infants and children ages 2 to 71 months of age. 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. PedvaxHIB does not contain lactose or thimerosal. 6

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(prior to the fifth birthday). It is injected into the muscle in a 4-dose schedule, recommended to be administered at 2, 4, 6, and between 12 and 15 months. 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.7 Specifically, according to the manufacturer’s product insert,8 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. 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.9 10

Additional ingredients in each 0.5ml 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, 3.3 mg of 2-phenoxyethanol, less than 50 ng residual bovine serum albumin, less than 4 pg of both polymyxin B sulfate and neomycin.

The Cornyebacterium diphtheria is grown in modified Mueller’s growth medium, purified by ammonium sulfate fractionation and the diphtheria toxin is detoxified with formaldehyde and diafiltered. Clostridium tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion and the tetanus toxin is detoxified with formaldehyde then purified by ammonium sulfate fractionation and diafiltration. The tetanus and diphtheria toxoids are each adsorbed onto aluminum phosphate. The acellular pertussis antigens are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium, modified by the addition of casamino acids and dimethyl-beta-cyclodextrin. PT, FHA, and PRN are isolated individually from the culture medium. FIM are removed and copurified from the bacterial cells. The pertussis antigens are purified by sequential filtration, ultrafiltration, salt precipitation and chromoatography. PT is detoxified with glutaraldehyde, FHA is treated with formaldhyde and the residual aldehydes are removed by ultrafiltration. The antigens are adsorbed individually 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 fetus.11 The cells are grown in CMRL 1969 medium with supplemented calf serum. After filtration and clarification, the viral suspensions are concentrated by ultrafiltration then purified by liquid chromatography and inactivated with formaldehyde. The monovalents concentrates are then combined to produce the trivalent poliovirus concentrate.

The adsorbed diphtheria, tetanus and acellular pertussis antigens are mixed with the aluminum phosphate adjuvant, 2-phenoxyethanol and water for injection. The trivalent poliovirus concentrate is then added and the DTaP-polio component is diluted to its final concentration. There is no preservative in the DTaP-polio component.

Polyribosyl-ribitol-phosphate (PRP) is made from the Haemophilus influenzae type b strain 1482 grown in a semi-synthetic medium.  The tetanus toxin has been taken from the Harvard strain of Clostridium tetani, purified with ammonium sulfate, rendered inactive by formalin, and grown in a modified Mueller and Miller medium, a culture medium containing raw materials made from milk. The toxoid is sterilized prior to being conjugated. ActHIB does not contain a preservative. 12

VAXELIS is manufactured in partnership by Sanofi Pasteur and Merck and is indicated for vaccination against diphtheria, tetanus, pertussis, poliomyelitis, Haemophilus influenzae type b, and Hepatitis B in children ages 6 weeks through 4 years of age (prior to the fifth birthday). It is injected into the muscle in a 3-dose schedule and recommended to be administered at 2, 4, and 6 months. Specifically, according to the manufacturer’s product insert, each 0.5 mL dose of VAXELIS is formulated to contain 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 (29 D-antigen units (DU) Type 1 Mahoney, 7 DU Type 2 MEF-1, 26 DU Type 3 Saukett, 3 mcg polyribosylribitol phosphate (PRP) of H. influenzae type b bound to 50 mcg of the outer membrane protein complex (OMPC) of Neisseria meningitidis serogroup B, and 10 mcg hepatitis B surface antigen (HBsAg). Each 0.5 mL dose of VAXLEIS contains 319 mcg of aluminum salts as an adjuvant.

Additional ingredients in each 0.5ml dose of VAXELIS includes 319 mcg of aluminum salts as the adjuvant, <0.0056 percent polysorbate 80, less than or equal to 14 mcg residual formaldehyde, less than or equal to 50 ng residual glutaraldehyde, less than or equal to 50 ng residual residual bovine serum albumin, less than 25 ng of polymyxin B sulfate, less than 5ng of neomycin, less than 200ng of streptomycin sulfate, less than or equal to 0.1ng yeast protein, and less than or equal to 0.125 ng ammonium thiocyanate.

The Cornyebacterium diphtheria is grown in modified Mueller’s growth medium, purified by ammonium sulfate fractionation and the diphtheria toxin is detoxified with formaldehyde and diafiltered. Clostridium tetani is grown in modified Mueller-Miller casamino acid medium without beef heart infusion and the tetanus toxin is detoxified with formaldehyde then purified by ammonium sulfate fractionation and diafiltration. The tetanus and diphtheria toxoids are each adsorbed onto aluminum phosphate. The acellular pertussis antigens are produced from Bordetella pertussis cultures grown in Stainer-Scholte medium, modified by the addition of casamino acids and dimethyl-beta-cyclodextrin. PT, FHA, and PRN and are isolated individually from the culture medium. FIM are removed and copurified from the bacterial cells. The pertussis antigens are purified by sequential filtration, ultrafiltration, salt precipitation and chromoatography. PT is detoxified with glutaraldehyde, FHA is treated with formaldhyde and the residual aldehydes are removed by ultrafiltration. The antigens are adsorbed individually onto aluminum phosphate.

Poliovirus Types 1, 2, and 3 are each grown separately in VERO cells and the viral products are then concentrated and purified before becoming inactivated by formaldehyde. Each poliovirus serotype is then mixed to form the trivalent poliovirus concentrate.

The hepatitis B virus surface antigen (HBsAg) is collected and purified from fermentation cultures of a recombinant strain of the yeast Saccharomyces cerevisiae containing the gene for the adw subtype of HBsAg. This 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 cell disruption and purified through several methods that include hydrophobic and ion chromatography, and diafiltration. This purified protein is treated in phosphate buffer with formaldehyde and then coprecipitated with potassium aluminum sulfate and amorphous aluminum hydroxyphosphate sulfate to form the vaccine adjuvant.

The purified polyribosylribitol phosphate (PRP) of H. influenzae type b (Haemophilus b, Ross strain) is covalently bound to an outer membrane protein complex (OMPC) of the B11 strain of Neisseria meningitides serogroup B. H. influenzae type b is grown in a fermentation medium which includes hemin chloride, soy peptone, an extract of yeast, nicotinamide adenine dinucleotide, dextrose, and mineral salts. The PRP is purified by procedures which include phenol extraction, ethanol fractionation, enzyme digestion, and diafiltration. N. meningitidis serogroup B is grown on a complex fermentation medium which consists an extract of yeast, amino acids and mineral salts. The OMPC is purified by, sterile filtration, ultracentrifugation, diafiltration, and detergent extraction. PRP is conjugated to OMPC by chemical coupling and then adsorbed onto an amorphous aluminum hydroxyphosphate sulfate adjuvant.

The adsorbed diphtheria, tetanus, and acellular pertussis antigens are mixed with aluminum phosphate, as an adjuvant, and water for injection into an intermediate concentrate. The individual hepatitis B virus surface antigen (HBsAg) and PRP-OMPC adjuvanted products are then added and followed by the trivalent poliovirus concentrate, to produce VAXELIS.

VAXELIS does not contain a preservative and the vaccine’s vial stopper does not contain natural rubber latex. 13

The CDC’s Advisory Committee on Immunization Practices (ACIP) has approved Hib vaccine for use in children at 2, 4, 6 and 12-15 months of age.14 The ACIP, however, has not made any recommendations regarding the use of the newly FDA approved 6 in 1 (hexavalent) vaccine, VAXELIS, at this time.  ACIP also recommends Hib vaccine for older children, adolescents, and adults over the age of 5 years who lack a functioning spleen, including persons with sickle cell anemia as well as to individuals who will be having their spleen removed as an elective surgery. Additionally, hematopoietic stem cell transplant recipients are also recommended to receive 3 doses of Hib vaccine 4 weeks apart beginning at least 6 months following transplant.15 It is important to note that while the ACIP has recommended the use of Hib vaccines persons over the age of 5 with the aforementioned medical conditions, no Hib vaccines are FDA approved for use in persons age 5 and older.

IMPORTANT NOTE: NVIC encourages you to become fully informed about Haemophilus Influenzae Type B (Hib) and the Hib vaccine by reading all sections in the Table of Contents, which contain many links and resources such as the manufacturer product information inserts, and to speak with one or more trusted health care professionals before making a vaccination decision for yourself or your child. This information is for educational purposes only and is not intended as medical advice.

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References

1 FDA VAXELIS Product Insert Dec. 21, 2018

2 Raines, K FDA Approves 6 in 1 Combo Vaccine for Babies The Vaccine Reaction Jan. 3, 2019

3 CDC Haemophilus influenzae Disease (including Hib) Prevention – Vaccine Feb 13, 2018

4 FDA ActHIB Product Insert Dec. 20, 2018

5 FDA Hiberix Product Insert Apr. 30, 2018

6 FDA Haemophilus B Conjugate Vaccine (Meningococcal Protein Conjugate) Apr. 27, 2011

7 CDC Licensure of a Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus, and Haemophilus b Conjugate Vaccine and Guidance for Use in Infants and Children MMWR Oct. 3, 2008; 57(39);1079-1080

9 FDA Daptacel – Product Insert Sep. 14, 2016

10 CDC Licensure of a Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus, and Haemophilus b Conjugate Vaccine and Guidance for Use in Infants and Children MMWR Oct. 3, 2008; 57(39);1079-1080

11 Jacobs JP The status of human diploid cell strain MRC-5 as an approved substrate for the production of viral vaccines. J Biol Stand. 1976 Apr;4(2):97-9.

12 FDA Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate (Tetanus Toxoid Conjugate) Vaccine Mar. 16, 2017

13 FDA VAXELIS Product Insert Dec. 21, 2018

14 CDC Prevention and Control of Haemophilus influenzae Type b Disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Feb. 28, 2014; 63(RR01);1-14

15 CDC Recommended Immunization Schedule for Adults Aged 19 Years or Older, United States, 2018 - Haemophilus influenzae type b vaccination. Mar. 5, 2018


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