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What is the History of Hib Vaccine in America?


History of Hib vaccine

In the 1970’s, scientists began research on a vaccine using a purified polysaccharide, polyribosylribitol phosphate (PRP) for the prevention Haemophilus influenzae type b.1 This polysaccharide vaccine only induced protective antibody levels in children older than 18 to 24 months old and revaccination did not induce a booster effect at any age. As a result, 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.2 Despite the limited effectiveness of Hib polysaccharide vaccines, these vaccines received FDA approval for use in 1985.3 The CDC reported the vaccines to be effective in children older than two and in adults, however, acknowledged their ineffectiveness in children under the age of 18 months. In children between the ages of 18 and 23 months, the immune response following vaccination was noted to be lower than in persons aged two years and older.4

When the FDA approved the first Hib polysaccharide vaccines in 1985, the duration of vaccine acquired immunity was not known but estimated to be at only 1.5 to 3.5 years. Children between the ages of 6 months and 1 year of age were considered to be the most susceptible to Haemophilus influenzae invasive disease and only 35 to 40 percent of Hib cases occurred in children 18 months of age and older. In 1985, the CDC recommended that all children receive a single dose of polysaccharide vaccine at 24 months, but stated that vaccination could begin at 18 months of age if a child was considered at a high risk for developing Hib invasive disease. Children attending daycare, children with immunosuppression related to cancer, and children with asplenia were reported to be at a higher risk for Hib invasive disease. The CDC, however, cautioned that while the vaccine could be administered in children as young as 18 months of age, it may not effective in children between the ages of 18 and 24 months.5 Three Hib polysaccharide vaccines received approval in 1985: b Capsa 1 manufactured by Praxis; HibImmune, manufactured by Lederle; and HibVAX, manufactured by Connaught.6

Studies on the effectiveness of polysaccharide Hib vaccines for the prevention of invasive H. influenzae type b disease varied significantly with vaccine effectiveness reported to be between 88 and -69 percent (with the negative efficacy indicating that vaccination increased the likelihood of Hib infection).7 Additional studies also noted an increased risk for the development of invasive Hib disease within 7 days following the administration of the polysaccharide Hib vaccine.8 In the 1994 review of vaccine adverse events completed by the Institute of Medicine (IOM), a causal association was favored by the committee between an increased risk of early onset H. influenzae disease in children older than 18 months who received an unconjugated PRP vaccine as their first Hib vaccine.9 All Hib polysaccharide vaccines were discontinued in 1989, 4 years following their initial FDA approval.10

After researchers discovered that a conjugation process resulted in a better immune response, the first conjugated Hib vaccine, ProHIBIT, was introduced in the U.S. in December 1987.11 12 This first conjugated Hib vaccine linked the Haemophilus b capsular polysaccharide to a diphtheria toxoid, and in January 1988, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended routine use of the vaccine for all children beginning at 18 months of age.13 At the time of this recommendation, however, ACIP acknowledged that “the efficacy of conjugate vaccine in children 18 months of age or older has not been determined in field trials.”14 The approval was based on studies that compared Hib antibody levels in children who received the newly approved conjugated Hib vaccine, against those who were administered the previously approved Hib polysaccharide vaccine. Study results suggested that the conjugated Hib vaccine would offer greater protection than Hib polysaccharide vaccines.15 In December of 1988, HibTITER, a second Hib conjugated vaccine, received FDA approval for use in children 18 months of age and older.16 17 However, prior to the FDA approval, Praxis, the manufacturer of HibTITER, was found to have engaged in misleading promotional activities. Praxis had claimed HibTITER to be superior in quality and purity, and would offer a greater immune response than the currently available Hib vaccines and the statements resulted in four separate warning letters from the FDA. As well, following FDA approval of HibTITER for use in children 18 months of age and older, Praxis was found to be in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act) on five separate occasions. In particular, Praxis had released a draft scientific article written by five of the company’s scientists in December of 1988 reporting on the use of the vaccine in young infants, despite the fact that the vaccine was not yet approved for use in children under the age of 18 months.18 HibTITER was not FDA approved for use in infants aged 2 months and older until October of 1990.19

In December of 1989, PedvaxHIB, a conjugated Hib vaccine bound to a meningococcal protein (PRP-OMP) manufactured by Merck, Sharpe, and Dohme, received FDA approval for use in children 18 months of age and older. The FDA, as well, gave approval for the vaccine to be used in children as young as 15 months of age if it were determined that the child would not return at 18 months of age to be vaccinated.  In April of 1990, the CDC’s Advisory Committee on Immunization practices (ACIP) issued a recommendation for the routine use of Hib vaccination beginning at 15 months of age.20 In October of 1990, the FDA expanded the use of HibTITER in children under the age of 18 months by approving the vaccine for use in infants beginning at 2 months of age.21 HibTITER was recommended to be administered as a 3 dose primary vaccine series, at 2, 4, and 6 months of age. The CDC also recommended that previously unvaccinated infants between 7 and 11 months of age receive 2 doses of the vaccine, 2 months apart. Previously unvaccinated children between 12 and 14 months of age were recommended to receive a single dose, with a booster dose after 15 months and unvaccinated children between 15 and 60 months were recommended to receive a single dose of the vaccine. 22 Two months later, in December of 1990, the FDA expanded the use of Merck’s PedvaxHIB, for use in infants beginning at 2 months of age. PedvaxHIB was recommended to be administrated as a 2-dose primary series at 2 and 4 months, with a booster dose at 12 months.23 Two year later, in November of 1992, Merck reported that 16 PedvaxHIB lots, or 366,000 doses “may have lower than expected immunogenicity.”24 Merck stated that it would be contacting physicians who received doses of the vaccines from these lots to suggest that certain vaccine recipients receive an additional Hib dose.25

On March 30th, 1993, the FDA approved two more Hib conjugated vaccines for use in infants as young as 2 months of age. ActHIB, a polyribosylribitol phosphate-tetanus toxoid conjugate Haemophilus b vaccine, (PRP-T), manufactured by Pasteur Merieux Serum et Vaccins (now Sanofi Pasteur) and distributed in the U.S. by Connaught Laboratories and TETRAMUNE, a combined diphtheria and tetanus toxoid, whole cell pertussis and Haemophilus b conjugate vaccine, made available by Lederle-Praxis Biologicals. TETRAMUNE combined the previously licensed DTP vaccine, TRI-IMMUNOL, with HibTITER, a Haemophilus b conjugate vaccine.26

In September 1993, the CDC’s Advisory Committee on Immunization Practices (ACIP) issued recommendations for the use of both the available Haemophilus b conjugate vaccine as well as the combined diphtheria, tetanus, whole cell pertussis, and Haemophilus b conjugate vaccine. At the time of this recommendations, there were five FDA approved Hib containing vaccines, with four vaccines approved for use in children beginning at 2 months of age (HibTITER, PedvaxHIB, ActHIB, and the combined DTP-Hib vaccine, TETRAMUNE). The fifth vaccine, ProHIBIT, was approved for use only as a booster dose following completion of a primary 2 or 3 dose vaccine series, or as single dose in children between the ages of 15 and 59 months.27

On September 27, 1996, the first combined diphtheria, tetanus, acellular pertussis, and Haemophilus b vaccine, TriHIBit, received FDA approval for use as the fourth dose of the vaccine series to be administered to children between the ages of 15 and 18 months. TriHIBit combined Tripedia, a newly approved diphtheria and tetanus toxoid and acellular pertussis vaccine, with the Hib conjugated vaccine, ActHIB.28 In late July of 1996, Tripedia became the first DTaP vaccine approved by the FDA for use in infants beginning at 2 months of age, and was recommended for use by the CDC’s Advisory Committee on Immunization Practices, in lieu of the highly reactive whole cell DTP vaccine.29 Prior to this July 1996 recommendation, the DTaP vaccine was approved only for use in children who had previously received three doses of DTP, at 2, 4, and 6 months of age.30 However, as Tripedia was approved for use in infants as young as 2 months of age, confusion resulted in regards to the use of TriHIBIT. TriHIBIT was only FDA approved for use as the fourth Hib dose, to be administered between 15 and 18 months, however, health care providers were found to be using TriHIBIT in children as young as 2 months. As a result, the CDC was required to issue a warning in September of 1988 in regards to the unlicensed use of TriHIBIT.31

In October 1996, Merck’s Comvax, a vaccine combining PedvaxHIB with RECOMBIVAX HB, a previously approved recombinant hepatitis B vaccine, received FDA approval for use in infants and children, and was recommended by the CDC to be administered at 2, 4, and 12-15 months of age. Infants receiving a birth dose of Hepatitis B vaccine, as recommended by the CDC’s Advisory Committee on Immunization (ACIP), would receive an additional fourth dose of Hepatitis B vaccine between 12 and 15 months of age, if administered the three recommended Comvax doses.32 Merck discontinued Comvax in 2014.

On December 13th, 2007, Merck announced a voluntary recall of several vaccine lots of both PedvaxHIB (Hib conjugate vaccine) and Comvax (Hib conjugate/Hepatitis B vaccine) related to a manufacturing issue. Merck reported that it could not guarantee the sterility of the equipment used to manufacture certain lots of the vaccines and as a result, issued the recall. The recall and anticipated Hib vaccine shortage prompted the CDC to recommend that healthcare providers defer the booster dose of Hib vaccine typically administered between 12 and 15 months of age in children not considered to be at high risk for invasive Hib disease.33 It was late June 2009 before the CDC recommended that the booster dose of Hib vaccine be reinstated for all children.34

In response to the shortage of available Hib vaccines resulting from Merck’s vaccine sterility issues, the FDA allowed GlaxoSmithKline HIBERIX, an additional Haemophilus b conjugate vaccine, to receive approval under the Accelerated Approval Regulations.35 The Accelerated Approval process allows drugs and vaccines targeting serious conditions that fill an unmet medical need to be approved based on a surrogate endpoint. A surrogate endpoint is a marker such as radiographic image, a physical sign, a laboratory measurement, or other tool of measurement that is thought to predict clinical benefit of the product, but is not actually a measure of clinical benefit. By using this surrogate endpoint, the FDA can accelerate approval of drugs and vaccines.36 HIBERIX initially received FDA approval in August of 2009 for use in children between the ages of 15 months and 4 years of age,37 however, in January of 2016, the FDA expanded the use of HIBERIX, allowing the vaccine to be used as the primary 3-dose Hib series in children as young as 6 weeks of age.38

In June of 2008, Pentacel, a combination diphtheria and tetanus toxoid and acellular pertussis (DTaP), inactivated poliomyelitis, and Haemophilus influenzae type b conjugate vaccine manufactured by Sanofi Pasteur, was FDA approved for use as a four dose series at 2, 4, 6, and 12-15 months.39 Pentacel combined ActHIB Hib vaccine with the polio vaccine, Poliovax, and the DTaP vaccine Daptacel, however, Pentacel contained twice as much detoxified PT and four times as much FHA as Daptacel.40 41

On June 14, 2012, MenHibrix, a Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine manufactured by GlaxoSmithKline received FDA approval for use in infants and children between 6 weeks and 18 months of age.42 At the October 2012 Advisory Committee on Immunization Practices (ACIP) meeting, MenHibrix was recommended exclusively for use in infants and children determined to be at higher risk for meningococcal disease. Included in this recommendation were infants found to have anatomical or functional asplenia, including sickle cell disease, and those with persistent complement pathway deficiencies. MenHibrix was also approved for use in communities dealing with outbreaks of meningococcal group C and Y, but not recommended for routine use due to the low number of cases of group C and Y meningococcal disease in the United States.43 In October 2016, citing low demand for the product, GlaxoSmithKline announced the discontinuation of MenHibrix vaccine in the United States.44

In December of 2016, a small Pennsylvania newspaper reported that between 2013 and 2015, Sanofi Pasteur had permitted two glass contaminated ActHIB vaccine lots to be administered to infants and young children. The Morning Call pieced together information acquired through the Freedom of Information Act (FOIA) and reported that Sanofi Pasteur, who became aware of the glass contaminated lots on April 2, 2013, had declined to issue a recall. The two contaminated vaccine lots had already been shipped and would remain available for use until their expiration dates of September 5 and 6, 2014.45

Sanofi Pasteur placed blame on the vaccine’s vial manufacturer and promptly changed suppliers, however, the company waited over two months before notifying the FDA. Despite noting fifteen shortcomings in regards to Sanofi’s response to the glass contamination, the FDA also declined to issue a recall of the contaminated vaccines. By November of 2014, the FDA had completed its investigation and stated that Sanofi had “acted responsibly”46 by correcting the problem. In addition to the 2013 contamination, Sanofi Pasteur notified the FDA on two separate occasions in January 2015 and again in March of 2015, of other contaminated ActHIB lots. In January of 2015, Sanofi reported that a previously distributed lot that had expired in March of 2014, had contained stainless steel particulates. On March 30th, 2015, the FDA was again notified of glass contamination involving another lot of ActHIB vaccine, with an expiration date of August 5th, 2014. While no adverse events have been reported to be directly associated with the administration of the glass contaminates, the FDA has warned that blood clots and other serious vascular events can occur when glass is administered subcutaneously.47

Currently there are four Haemophilus influenzae type b (Hib) vaccines available for use in the United States: ActHIB; HIBERIX; PedvaxHIB; and Pentacel (Hib vaccine combined with diphtheria and tetanus toxoids, acellular pertussis adsorbed, and inactivated poliovirus).48 On December 21, 2018, the FDA approved VAXELIS, a 6 in 1 (hexavalent) 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.49 Manufactured in a partnership between Sanofi Pasteur and Merck, VAXELIS combines the diphtheria and tetanus toxoids, acellular pertussis and inactivated poliomyelis antigens manufactured by Sanofi Pasteur with the Haemophilus influenzae type b conjugate and hepatitis B recombinant vaccines, manufactured by Merck. VAXELIS, approved for use in infants and children between 6 weeks and 4 years of age and recommended to be administered at 2, 4, and 6 months of age, is expected to become available for use in the United States in 2020.50 The CDC’s Advisory Committee on Immunization Practices (ACIP), however, has not made any recommendations regarding the use of VAXELIS at this time.

The CDC’s Advisory Committee on Immunization Practices (ACIP) recommends that all infants and young children receive Hib vaccine at 2, 4, and 6 months of age with an additional booster dose between 12 and 15 months of age. Hib vaccine is also recommended by the CDC for use in older children, adolescents and adults with certain medical conditions,51 however, no Hib vaccines are currently FDA approved for use in persons over five years of age.52

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 Institute of Medicine Committee to Review Adverse Effects of Vaccines. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. 1994 Chap. 9 Haemophilis influenzae Type b vaccines. P 236-273

2 Schneerson R, Barrera O, Sutton A, Robbins JB. Preparation, Characterization, and Immunogenicity of Haemophilus Influenzae Type b Polysaccharide-Protein Conjugates. J Exp Med. 1980 Aug 1;152(2):361-76.

3 CDC MMWR. Morbidity and mortality weekly report` MMWR Apr. 19, 1985; 34 (15); 201-205

4 Ibid

5 Ibid

6 Institute of Medicine Committee to Review Adverse Effects of Vaccines. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. 1994 Chap. 9 Haemophilis influenzae Type b vaccines. P 236-273

7 CDC Haemophilus influenzae type b – Haemophilus influenzae type b Vaccines Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.

8 Institute of Medicine Committee to Review Adverse Effects of Vaccines. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. 1994 Chap. 9 Haemophilis influenzae Type b vaccines. P 236-273

9 Ibid

10 CDC Selected Discontinued U.S. Vaccines Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). August 2011

11 CDC MMWR. Morbidity and mortality weekly MMWR Jan. 1, 1988; 36(50/51): 832

12 Institute of Medicine Committee to Review Adverse Effects of Vaccines. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. 1994 Chap. 9 Haemophilis influenzae Type b vaccines. P 236-273

13 CDC MMWR. Morbidity and mortality weekly report MMWR Jan. 22, 1988; 37(2): 13-16

14 Ibid

15 Ibid

16 Institute of Medicine Committee to Review Adverse Effects of Vaccines. Adverse Events Associated with Childhood Vaccines: Evidence Bearing on Causality. Washington, DC: The National Academies Press. 1994 Chap. 9 Haemophilis influenzae Type b vaccines. P 236-273

17 CDC MMWR Morbidity and mortality weekly report MMWR Jan. 13, 1989; 38(1): 14

18 The Pink Sheet PRAXIS HIBTITER HISTORY OF MISLEADING PROMOTIONAL ACTIVITIES CITED Pharma Intelligence Apr. 1, 1991

19 CDC MMWR. Morbidity and mortality weekly report. MMWR Oct. 5, 1990; 39(39): 698-699

20 CDC Recommendations of the Immunization Practices Advisory Committee Supplementary Statement: Change in Administration Schedule for Haemophilus b Conjugate Vaccines MMWR Apr. 13, 1990; 39(14);232-233

21 CDC MMWR. Morbidity and mortality weekly report. MMWR Oct. 5, 1990; 39(39): 698-699

22 Ibid

23 CDC MMWR. Morbidity and mortality weekly report MMWR Dec. 19, 1990; 39(50): 925-926

24 CDC Advisory Committee on Immunization Practices Update: Report of PedvaxHIB Lots with Questionable Immunogenicity MMWR Nov. 20, 1992; 41(46);878-879

25 Ibid

26 CDC FDA Approval of Use of a New Haemophilus b Conjugate Vaccine and a Combined Diphtheria-Tetanus-Pertussis and Haemophilus b Conjugate Vaccine for Infants and Children. MMWR Apr. 23, 1993; 42(15);296-298

27 CDC Recommendations for Use of Haemophilus b Conjugate Vaccines and a Combined Diphtheria, Tetanus, Pertussis, and Haemophilus b Vaccine Recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Sep. 17, 1993; 42(RR-13)

28 CDC Notice to Readers FDA Approval of a Haemophilus b Conjugate Vaccine Combined by Reconstitution with an Acellular Pertussis Vaccine MMWR Nov. 15, 1996; 45(45);993-995

29 CDC Notice to Readers Food and Drug Administration Approval of an Acellular Pertussis Vaccine for the Initial Four Doses of the Diphtheria, Tetanus, and Pertussis Vaccination Series MMWR Aug. 09, 1996; 45(31);676-7

30 CDC Food and Drug Administration Approval of a Second Diphtheria and Tetanus Toxoids and Acellular Pertussis Vaccine MMWR Aug. 28, 1992; 41(34);630-631

31 CDC Notice to Readers Unlicensed Use of Combination of Haemophilus influenzae type b Conjugate Vaccine and Diphtheria and Tetanus Toxoid and Acellular Pertussis Vaccine for Infants MMWR Sep. 25, 1998; 47(37);787

32 CDC Notice to Readers FDA Approval for Infants of a Haemophilus influenzae Type b Conjugate and Hepatitis B (Recombinant) Combined Vaccine MMWR Feb. 7, 1997; 46(05);107-109

33 CDC Interim Recommendations for the Use of Haemophilus influenzae Type b (Hib) Conjugate Vaccines Related to the Recall of Certain Lots of Hib-Containing Vaccines (PedvaxHIB® and Comvax®) MMWR Dec. 21, 2007; 56(50);1318-1320

34 CDC Updated Recommendations for Use of Haemophilus influenzae Type b (Hib) Vaccine: Reinstatement of the Booster Dose at Ages 12--15 Months MMWR Jun. 26, 2009; 58(24);673-674

35 CDC Food and Drug Administration Approval for Use of Hiberix as a 3-Dose Primary Haemophilus influenzae Type b (Hib) Vaccination Series MMWR Apr. 29, 2016; 65(16);418–419

36 FDA Accelerated Approval Jan. 4, 2018

37 FDA August 19, 2009 Approval Letter – Hiberix Aug. 19, 2009

38 FDA January 14, 2016 Approval Letter – HIBERIX Jan. 14, 2016

39 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

40 CDC Daptacel – Product Insert Sep. 14, 2016

41 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

42 FDA June 14, 2012 Approval Letter – MenHibrix Jun. 14, 2012

43 CDC Infant Meningococcal Vaccination: Advisory Committee on Immunization Practices (ACIP) Recommendations and Rationale MMWR Jan. 25, 2013; 62(03);52-54

44 GSK.com MenHibrix Discontinuation Notice. Oct. 2016

45 Kennedy S. No recall for glass found in vaccines made in Monroe County. The Morning Call Dec. 10, 2016.

46 Ibid

47 La Vigne P ActHIB Vaccine Found to Contain Pieces of Glass Between 2013 and 2015 The Vaccine Reaction Jan. 12, 2017

48 FDA Vaccines Licensed for Use in the United States Mar. 29, 2018

49 FDA VAXELIS Product Insert Dec. 21, 2018

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

51 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

52 FDA Vaccines Licensed for Use in the United States Nov. 16, 2018


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