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Prohibit

CLINICAL PHARMACOLOGY

Haemophilus influenzae type b (Haemophilus b) was a leading cause of serious systemic bacterial disease in the United States. Prior to licensure of Haemophilus b Conjugate Vaccines, it was the most common cause of bacterial meningitis, accounting for an estimated 12,000 cases annually, primarily among children under five years of age. The mortality rate was 5%, and neurologic sequelae were observed in as many as 25%-35% of survivors1. Most cases of Haemophilus influenzae meningitis among children are caused by capsular strains of type b, although this capsular type represents only one of the six types known for this species. In addition to bacterial meningitis, Haemophilus b is responsible for other invasive diseases, including epiglottitis, sepsis, cellulitis, septic arthritis, osteomyelitis, pericarditis, and pneumonia.1

In the United States prior to licensure of Haemophilus b Conjugate Vaccines, approximately one of every 1000 children under five years of age developed systemic Haemophilus b disease each year, and a child's cumulative risk of developing systemic Haemophilus b disease at some time during the first five years of life was approximately one in 200. Attack rates peaked between six months and one year of age and declined thereafter.1

Approximately 75%-85% of Haemophilus b disease occurs among children less than 24 months of age.2,3,4 Incidence rates of Haemophilus b disease are increased in certain high-risk groups, such as native Americans (both American Indian and Eskimos), blacks, individuals of lower socioeconomic status, and patients with asplenia, sickle cell disease, Hodgkin's disease, and antibody deficiency syndromes.1,4 Recent studies also have suggested that the risk of acquiring primary Haemophilus b disease for children under five years of age appears to be greater for those who attend day-care facilities.5,6,7,8

The potential for person-to-person transmission of the organism among susceptible individuals has been recognized. Studies of secondary spread of disease in household contacts of index patients have shown a substantially increased risk among exposed household contacts under four years of age.9 Adults can be colonized with Haemophilus influenzaetype b from children infected with 10 the organism.

In 1974, a randomized controlled trial was conducted in Finland, which allowed the evaluation of clinical efficacy of a non-conjugated Haemophilus type b polysaccharide vaccine in children 3 to 71 months of age.11 Approximately 98,000 children, half of whom received the Haemophilus b vaccine, were enrolled in the field trial and followed for a four-year period for the occurrence of Haemophilus b disease. Among children 18 to 71 months of age, 90% protective efficacy (95% confidence limits, 55%-98%) was demonstrated for the four-year follow-up period in prevention of all forms of invasive Haemophilus b disease.

Based on evidence from this 1974 Finnish efficacy trial, from passive protection in the infant rat model, and from experience with agammaglobulinemic children, an antibody concentration of ≥ 0.15 g/mL has been correlated with protection.11,12,13,14 Antibody levels of ≥ 1 g/mL were correlated with long-term protection in three-week post-vaccination serum. Anti-capsular antibodies induced by ProHIBiT (haemophilus b conjugate vaccine) ® in children 18 months of age and older had bactericidal activity, opsonic activity and were also active in passive protection assays.15,16,17

The development of stable humoral immunity requires the recognition of foreign material by at least two separate sets of lymphocytes. These sets are the B-lymphocytes which are precursors of antibody forming cells, and the T-lymphocytes which modulate the function of B-cells. Some antigens such as polysaccharides are capable of stimulating B-cells directly to produce antibody (T-independent). The responses to many other antigens are augmented by helper T-lymphocytes (T-dependent).18

The manufacturing process utilizes a technology of covalent bonding the capsular polysaccharide of Haemophilus influenzae type b to diphtheria toxoid, to produce an antigen which is postulated to convert a T-independent antigen into a T-dependent antigen.19,20 The protein carries both its own antigenic determinants and those of the covalently bound polysaccharide. As a result of the conjugation to protein, the polysaccharide is presented as a T-dependent antigen resulting in both an enhanced antibody response and an immunologic memory.

In studies conducted with ProHIBiT (haemophilus b conjugate vaccine) ® in several locations throughout the US, the antibody responses of 18- to 26-month-old children were measured (Table 1).15 In other studies, the antibody responses to licensed Haemophilus b polysaccharide vaccines were measured in a comparable age group (Table 1).15 The data shown in Table 1 were obtained from sera tested in one laboratory using a single radioimmunoassay (RIA). Mean antibody levels induced by ProHIBiT (haemophilus b conjugate vaccine) ® in children 18 to 20 months of age are 30-fold higher than those induced by polysaccharide vaccines in the same age group.15

The RIA procedure used by Connaught Laboratories, Inc. to estimate antibody responses to the Haemophilus b vaccines has been shown to correlate with the assay used by the Finland National Public Health Institute.21 Antibody levels ( ≥ 1.0 g/mL) estimated by the Finnish assay were correlated with protection.11

TABLE 115: Immunogenicity Studies of ProHIBiT (haemophilus b conjugate vaccine) ® and Polysaccharide Vaccines*

Vaccine Age Group No. of Subjects Anti-Polysaccharide GMT (g/mL) % Subjects Responding with ≥ 1.0 g/mL**
Pre Post
ProHIBiT® 15 to 17 Mo. 43 0.017 1.12 53%
18 to 21 Mo. 173 0.025 2.85 75%
22 to 26 Mo. 37 0.021 2.96 73%
POLYSACCHARIDE 18 to 20 Mo. 51 0.021 0.100 24%
24 to 27 Mo. 84 0.035 0.520 43%
* Only subjects whose sera had preimmunization levels ≤ 0.60 g/mL were included in this analysis.
** A subset of these data was obtained from a randomized comparison of the two vaccines, in which the percentage of children 18 to 20 months of age responding with ≥ 1.0 g/mL was 75% for ProHIBiT (haemophilus b conjugate vaccine) ® (n=12) and 27% for the polysaccharide (n=11).

Following immunization of 16 to 24-month-old children with a single dose of ProHIBiT (haemophilus b conjugate vaccine) ®, 89% (109/123) had antibody levels ≥ 0.15 g/mL 12 months post-immunization, compared to 93% one month post-immunization.15

The immunogenicity of ProHIBiT (haemophilus b conjugate vaccine) ® as a booster vaccination administered to children 12 months of age has been studied in the United States, Finland and Canada.15

Based on the study conducted by Drs. Edwards and Decker at Vanderbilt University, it was demonstrated that ProHIBiT (haemophilus b conjugate vaccine) ® induce booster responses in children immunized with any of four different Hib conjugate vaccines as well as or better than the homologous vaccine.15

No impairment of the immune response to ProHIBiT (haemophilus b conjugate vaccine) ® was observed in a group of 36 patients with sickle cell disease (SS, SC, S-thalassemia), aged 1.5 to 5.0 years (mean 3.3 years).15,22,23 Satisfactory immune responses were obtained following administration of ProHIBiT (haemophilus b conjugate vaccine) ® in children 2 to 6 years of age with acute leukemia who had been on chemotherapy < 1 year.24 However, similar children with chemotherapy > 1 year frequently failed to respond to the vaccine.

REFERENCES

1. Recommendations of the Immunization Practices Advisory Committee (ACIP). Polysaccharide vaccine for prevention of Haemophilus influenzae type b disease. MMWR 34: 201-205, 1985

2. Cochi SL, et al. Immunization of US children with Haemophilus influenzae type b polysaccharide vaccine: A cost-effectiveness model of strategy assessment. JAMA 253: 521-529, 1985

3. Murphy TV, et al. Prospective surveillance of Haemophilus influenzae type b disease in Dallas County, Texas, and in Minnesota. Pediatr 79: 173-179, 1987

4. Broome CV. Epidemiology of Haemophilus influenzae type b infections in the United States. Pediatr Infect Dis J 6: 779-782, 1987

5. Istre GR, et al. Risk factors for primary invasive Haemophilus influenzae disease: Increased risk from day care attendance and school-aged household members. J Pediatr 106: 190-195, 1985

6. Redmond SR, et al. Haemophilus influenzae type b disease. An epidemiologic study with special reference to day-care centers. JAMA 252: 2581-2584, 1984

7. Murphy TV, et al. County-wide surveillance of invasive Haemophilus infections: Risk of associated cases in Child Care Programs (CCPs). Twenty-third Interscience Conference on Antimicrobial Agents and Chemotherapy (Abstract #788) 229, 1983

8. Fleming D, et al. Haemophilus influenzae b (Hib) disease – secondary spread in day care. Twenty-fourth Interscience Conference on Antimicrobial Agents and Chemotherapy (Abstract #967) 261, 1984

9. CDC. Prevention of secondary cases of Haemophilus influenzae type b disease. MMWR 31: 672-680, 1982

10. Michaels RH, et al. Pharyngeal colonization with Haemophilus influenzae type b: A longitudinal study of families with a child with meningitis or epiglottitis due to H. influenzae type b. J Infec Dis 136: 222-227, 1977

11. Peltola H, et al. Prevention of Haemophilus influenzae type b bacteremic infections with the capsular polysaccharide vaccine. N Engl J Med 310: 1561-1566, 1984

12. Smith DH, et al. Responses of children immunized with the capsular polysaccharide of Haemophilus influenzae, type b. Pediatr 52: 637-644, 1973

13. Robbins JB, et al. Quantitative measurement of “natural” and immunization-induced Haemophilus influenzae type b capsular polysaccharide antibodies. Pediatr Res 7: 103-110, 1973

14. Robbins JB, et al. A review of the efficacy trials with Haemophilus influenzae type b polysaccharide vaccines. In: Sell, S.H., Wright, P.E. eds. Haemophilus influenzae. New York: Elsevier Biomedical. 255-263, 1982

15. Unpublished data available from Connaught Laboratories, Inc.

16. Granoff DM, et al. Immunogenicity of Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine in adults. J Pediatr 105: 22-27, 1984

17. Cates KL. Serum opsonic activity for Haemophilus influenzae type b in infants immunized with polysaccharide-protein conjugate vaccines. J Infec Dis 152:1076-1077,1985

18. Benacerraf B, et al. Textbook of Immunology. Cellular interactions. Williams and Wilkins, p 22,1979

19. Schneerson R, et al. Preparation, characterization, and immunogenicity of Haemophilus influenzae type b polysaccharide-protein conjugates. J Exp Med 152:361-376,1980

20. Lepow ML, et al. Safety and immunogenicity of Haemophilus influenzae type b-polysaccharide diphtheria toxoid conjugate vaccine in infants 9 to 15 months of age. J Pediatr 106:185-189,1985

21. Greenberg DP, et al. Variability in quantitation of Haemophilus influenzae type b anticapsular antibody (anti-PRP) by radioimmunoassay (RIA). Twenty-sixth Interscience Conference on Antimicrobial Agents and Chemotherapy (Abstract #209) 133,1986

22. Frank AL, et al. Haemophilus influenzae Type b immunization of children with sickle cell diseases. Pediatr 82:571-575,1988

23. Plotkin SA, et al. Vaccines. Haemophilus influenzae vaccines. W.B. Saunders Co. p 318,1988

24. Gigliotti F, et al. Response of children with acute lymphoblastic leukemia (ALL) to H. influenzae type b (Hib) conjugate vaccine. The Society for Pediatric Research (Serial #11595), 1988

Last reviewed on RxList: 3/9/2009
This monograph has been modified to include the generic and brand name in many instances.

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