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Pediatric Infectious Disease Journal:
Haemophilus Influenzae Type B Vaccines

Haemophilus influenzae type b vaccines: history, choice and comparisons

DECKER, MICHAEL D. MD, MPH; EDWARDS, KATHRYN M. MD

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From the Departments of Preventive Medicine (MDD), Medicine (Infectious Diseases) (MDD) and Pediatrics (KME), Vanderbilt University School of Medicine, Nashville, TN.

Address for reprints: Association pour l'Aide à la Médicine Préventive, 3 avenue Pasteur, 92430 Marnes-la-Coquette, France.

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Abstract

The conjugate Haemophilus influenzae type b (Hib) vaccines are safe and far more immunogenic among infants and young children than is the unconjugated H. influenzae type b polysaccharide. The vaccines differ in their immunogenicity when used for primary immunization of infants, and these differences appear to be predictive of efficacy, such that some vaccines might be more suitable than others in certain populations.

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INTRODUCTION

Infections caused by Haemophilus influenzae type b (Hib) have been a major cause of severe morbidity and mortality among infants and young children worldwide.1-4 The essential virulence factor of Hib is its capsular polysaccharide, polyribosylribitol phosphate (PRP), and antibody to PRP confers protection from disease.5, 6 Unfortunately PRP is a T cell-independent antigen, to which the immature immune system of infants cannot mount an adequate protective antibody response.7 Although vaccines consisting solely of PRP showed early promise for the prevention of invasive Hib disease in Finnish children older than 18 months of age,8 vaccine failures were observed in US children younger than 24 months.9 Efficacy has not been shown for PRP vaccine for children younger than 18 months, who are at the greatest risk of developing invasive Hib disease.8

The coupling of PRP to a protein produces a conjugate that can stimulate T cell-dependent immune responses, even among infants, enhancing production of antibody to the polysaccharide and priming memory cells.9 As detailed by Heath10 in this issue, the systematic use of conjugate Hib vaccines in infancy can essentially eradicate Hib disease among infants and children.

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THE CONJUGATE VACCINES

Four basic types of conjugate Hib vaccines have been licensed in various countries. These vaccines differ in their carrier proteins, in the structure and length of the polysaccharide molecule(s) bound to the carrier protein, in the method of coupling the protein to the carbohydrate and in the ratio of protein to polysaccharide (Fig. 1; Table 1).

Fig. 1
Fig. 1
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Table 1
Table 1
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PRP-D. The first conjugate Hib vaccine to be licensed, PRP-D, was marketed as ProHIBIT® by Connaught Laboratories [now Pasteur Mérieux Connaught (PMC)]. Licensed in the United States in December, 1987, PRP-D contains medium length polysaccharide conjugated with a 6-carbon spacer to diphtheria toxoid. Each 0.5-ml dose is formulated to contain 25 μg of polysaccharide, 18 μg of protein, thimerosal 1:10 000 and sodium phosphate buffer.

PRP-CRM. The second conjugate Hib vaccine, PRP-CRM (also commonly referred to as HbOC, for Haemophilus b oligosaccharide conjugate) was marketed as HibTITER® by Praxis Laboratories (now Wyeth Lederle Pediatrics and Vaccines). Licensed in the United States in December, 1988, PRP-CRM contains PRP oligosaccharide conjugated to CRM197 [CRM197 is a nontoxic variant of diphtheria toxin isolated from cultures of Corynebacterium diphtheriae C7 (beta 197)]. Each 0.5-ml dose is formulated to contain 10 μg of polysaccharide, 25 μg of protein, thimerosal 1:10 000 and saline.

PRP-OMP. The third conjugate Hib vaccine, PRP-OMP, was developed by Merck & Co. and marketed as PedvaxHIB® after US licensure in December, 1989. PRP-OMP contains medium length polysaccharide chains conjugated via a thioether spacer to the outer membrane protein complex of the B11 strain of Neisseria meningitidis serogroup B. Each 0.5-ml dose is formulated to contain 7.5 μg of polysaccharide, 125 μg of protein, 225 μg of aluminum hydroxide and saline.

PRP-T. The fourth conjugate Hib vaccine to be licensed in the United States in 1993 was among those developed by Schneerson et al.9 at the National Institutes of Health (NIH). It is manufactured by PMC for worldwide distribution as ActHIB® and is also distributed by SmithKline Beecham (SB) in the United States as OmniHIB®. Another preparation of PRP-T is manufactured by SB as Hiberix®, for distribution outside the United States. PRP-T is composed of large polysaccharide chains conjugated via a 6-carbon spacer to tetanus toxoid. Each 0.5-ml dose contains 15 μg of polysaccharide, 24 μg of protein, 8.5% sucrose and saline diluent ((Hiberix® contains 10 μg of polysaccharide and 20 to 40 μg of protein).

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ADVERSE REACTIONS

Adverse reactions after any of the conjugate Hib vaccines are uncommon, are typically mild and usually resolve within 12 to 24 h.12 A randomized, blinded, comparative study found only minor differences among the four vaccines in the frequency and duration of adverse reactions.13

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IMMUNOGENICITY

All four conjugate Hib vaccines are highly immunogenic in adults and older children. However, they differ markedly in the immune responses they stimulate among infants.13-16

As shown in Figure 2, PRP-D has the lowest immunogenicity among infants, even after three doses. Although it has proved capable of eradicating Hib disease in Finland,17 a country in which the majority of Hib disease occurs after the first year of life,18 it has shown poor efficacy in populations with early and intense disease, such as Native Alaskan infants,19 and is not licensed for infant use in the US. In contrast PRP-D is highly immunogenic when used as a booster at ages 12 to 18 months after primary immunization with any of the other conjugate Hib vaccines.20

Fig. 2
Fig. 2
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PRP-T and PRP-CRM produce similar antibody responses among infants.13 As shown in Figure 2 the first injection of either vaccine stimulates very little antibody, and geometric mean antibody concentrations 1 month after the second injection remain well below 0.1 μg/ml. However, the third injection of the primary series stimulates high antibody concentrations, with most children developing more than 1.0 μg/ml (the concentration generally accepted as providing long term protection from invasive Hib disease). A fourth dose of either vaccine, given as a booster immunization at 12 to 18 months, produces very high mean concentrations of antibody (typically >20 μg/ml), with essentially all recipients developing protective levels.20 The PRP-T vaccines produced by PMC (ActHIB® and OmniHIB®) and by SB (Hiberix®) do not appear to differ materially in immunogenicity.

PRP-OMP is unique among the conjugate Hib vaccines in producing substantial antibody rises after the first dose, given at 2 months of age.13 However, there is only a modest further increase in antibody after the second dose (or after a third dose).13 Consequently PRP-OMP is licensed in the United States as a two-dose primary series, whereas PRP-CRM and PRP-T are licensed as a three-dose primary series.

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INTERCHANGEABILITY

The distinct immunologic characteristics of PRP-OMP vs. PRP-CRM and PRP-T led initially to the recommendation that the former vaccine be used preferentially in populations experiencing high levels of Hib disease early in life (e.g. Native Americans or Native Alaskans) to provide some protection as early as possible. In contrast the latter vaccines were thought preferable for populations with less intense Hib exposure, such as most middle class US or European populations, because they produced substantially higher final antibody concentrations.

A number of studies21-23 have evaluated the effect of beginning primary Hib immunization with one conjugate vaccine and concluding with another. In every case concluding the primary immunization series with a different vaccine produced antibody concentrations at least as high as those observed when the series was concluded with the vaccine with which it was begun (Table 2). Uniformly the highest antibody concentrations were obtained by initiating the vaccine series with one dose of PRP-OMP and concluding with two doses of PRP-T or PRP-CRM.

Table 2
Table 2
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With the near-elimination of invasive Hib disease after widespread use of conjugate Hib vaccines in infancy, the three vaccines have been considered interchangeable for primary as well as booster vaccination.24 However, after Alaska's change in 1996 from use of PRP-OMP to use of a combination product containing PRP-CRM plus diphtheria and tetanus toxoids and whole cell pertussis vaccine, the Centers for Disease Control and Prevention noted a 2- to 4-fold increase in invasive Hib disease (1995, 2 cases; 1996, 6 cases; 1997, 7 cases).25, 26 Subsequent evaluation of oropharyngeal carriage of Hib among native Alaskan children found carriage rates ranging from 5.6% among children ages 1 to 2 years, to 13.6% among those age 5 to 6 years.21 Although the rates of invasive Hib disease remain low the rates of carriage do not, and concern has been raised that these findings may be a result of the change from PRP-OMP to PRP-CRM. If so, use of PRP-OMP (at least for the first dose) might be more prudent in particularly high risk populations.

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CONCLUSION

The conjugate Hib vaccines are associated with few and mild adverse reactions in all age groups. All are highly immunogenic in older children and adults; they show differing immunogenicities when used for primary immunization of infants: PRP-D is of low immunogenicity and is not suitable for infant use except in highly immunized populations with low Hib prevalence; PRP-OMP is immunogenic after only a single dose, but antibody concentrations after completion of the primary series are lower than those obtained with PRP-T and PRP-CRM. The latter two vaccines produce little antibody after the first two injections and may not be the best choice in populations characterized by high attack rates of Hib disease early in infancy, but they produce substantially higher final antibody concentrations than PRP-OMP after completion of the primary series and might be preferable in populations not marked by early, intense Hib activity. The vaccines are acceptably interchangeable during the primary series, and indeed a sequence in which one injection of PRP-OMP is used followed by two of PRP-T or PRP-CRM appears to provide the optimum antibody response.

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REFERENCES

1. Funkhouser A, Steinhoff M, Ward J. Haemophilus influenzae disease and immunization in developing countries. Rev Infect Dis 1991;13:S542-54.

2. Bijlmer HA, Van Alphen L, Greenwood BM, et al. The epidemiology of Haemophilus influenzae meningitis in children under five years of age in Gambia, West Africa. J Infect Dis 1990;161:1210-15.

3. Wright PF. Approaches to prevent acute bacterial meningitis in developing countries. Bull WHO 1989;67:479-86.

4. Munson RS, Kabeer MH, Lenoir AA, Granoff DM. Epidemiology and prospects for prevention of disease due to Haemophilus influenzae in developing countries. Rev Infect Dis 1989;11(Suppl):S588-97.

5. Fothergill LD, Wright J. Influenzal meningitis: the relation of age incidence to the bactericidal power of blood against the causal organism. J Immunol 1933;24:273-84.

6. Schneerson R, Rodrigues LP, Parke JC Jr, Robbins JB. Immunity to disease caused by Haemophilus influenzae type b: II. Specificity and some biologic characteristics of "natural," infection-acquired, and immunization-induced antibodies to the capsular polysaccharide of Haemophilus influenzae type b. J Immunol 1971;107:1081-9.

7. Anderson P, Smith DH, Ingram DL, Wilkins J, Wehrle PF, Howie VM. Antibody of polyribophate of Haemophilus influenzae type b in infants and children: effect of immunization with polyribophosphate. J Infect Dis 1977;136(Suppl):S57-62.

8. Peltola H, Käyhty H, Virtanen M, et al. Prevention of Haemophilus influenzae type b bacteremic infections with the capsular polysaccharide vaccine. N Engl J Med 1984;310:1561-6.

9. Schneerson R, Barrera O, Sutton A, Robbins JB. Preparation, characterization, and immunogenicity of Haemophilus influenzae type b polysaccharide-protein conjugates. J Exp Med 1980;152:361-76.

10. Heath PT. Hib conjugate vaccines: a review of efficacy data. Pediatr Infect Dis J 1998;17(Suppl):S123-9.

11. Ward J, Lieberman JM, Cochi SL. Haemophilus influenzae vaccines. In: Plotkin SA, Mortimer EA, eds. Vaccines. 2nd ed. Philadelphia: Saunders, 1994:357.

12. 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 1993;42(RR-13):1-15.

13. Decker MD, Edwards KM, Bradley R, Palmer P. Comparative trial in infants of four conjugate Haemophilus influenzae type b vaccines. J Pediatr 1992;120:184-9.

14. Granoff DM, Anderson EL, Osterholm MT, et al. Differences in the immunogenicity of three Haemophilus influenzae type b conjugate vaccines in infants. J Pediatr 1992;121:187-94.

15. Bulkow LR, Wainwright RB, Letson GW, Chang SJ, Ward JI. Comparative immunogenicity of four Haemophilus influenzae type b conjugate vaccines in Alaska Native infants. Pediatr Infect Dis J 1993;12:484-92.

16. Capeding MR, Nohynek H, Pascual LG, et al. The immunogenicity of three Haemophilus influenzae type B conjugate vaccines after a primary vaccination series in Philippine infants. Am J Trop Med Hyg 1996;55:516-20.

17. Takala AK, Peltola H, Eskola J. Disappearance of epiglottitis during large-scale vaccination with Haemophilus influenzae type B conjugate vaccine among children in Finland. Laryngoscope 1994;104(6 Pt 1):731-5.

18. Peltola H. Haemophilus influenzae type b disease and vaccination in Europe: lessons learned. Pediatr Infect Dis J 1998;17:S134-40.

19. Ward J, Brenneman G, Letson GW, Heyward WL. Limited efficacy of a Haemophilus influenzae type b conjugate vaccine in Alaska Native infants. N Engl J Med 1990;323:1393-401.

20. Decker MD, Edwards KM, Bradley R, Palmer P. Responses of children to booster immunization with their primary conjugate Haemophilus influenzae type B vaccine or with polyribosylribitol phosphate conjugated with diphtheria toxoid. J Pediatr 1993;122:410-13.

21. Anderson EL, Decker MD, Englund JA, et al. Interchangeability of conjugated Haemophilus influenzae type b vaccines in infants. JAMA 1995;273:849-53.

22. Greenberg DP, Lieberman JM, Marcy SM, et al. Enhanced antibody responses in infants given different sequences of heterogeneous Haemophilus influenzae type b conjugate vaccines. J Pediatr 1995;126:206-11.

23. Bewley KM, Schwab JG, Ballanco GA, Daum RS. Interchangeability of Haemophilus influenzae type b vaccines in the primary series: evaluation of a two-dose mixed regimen. Pediatrics 1996;98:898-904.

24. Recommended childhood immunization schedule: United States, 1998. MMWR 1998;47:8-12.

25. Galil K, Singleton R, Levine O, et al. High prevalence of Haemophilus influenzae type b (Hib) carriage among Alaska natives despite widespread use of Hib conjugate vaccine [Abstract]. Presented at the 35th Annual Meeting of the Infectious Diseases Society of America, San Francisco, September 13 to 16, 1997.

26. MMWR Interactive Morbidity Tables. Http:158.111.4.28/mmwr/mmwrmorb.htm; Table III (Part 1) for Alaska, 1995-1997.

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Section Description

FIRST INTERNATIONAL CONFERENCE ON HAEMOPHILUS INFLUENZAE TYPE b INFECTION IN ASIA

The Editors thank the Association pur l'Aide à la Médicine Préventive, the Foundation Mérieux, and the World Health Organization for supporting publication of these proceedsings, and Jennifer Wells for her editorial assistance.

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Keywords:

Haemophilus influenzae; Haemophilus influenzae type b; vaccine

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