Recommendations of the Immunization Practices Advisory Committee Update: Prevention of Haemophilus influenzae Type b Disease

Haemophilus b Conjugate Vaccine (Diphtheria Toxoid-Conjugate) has recently been licensed for use in children 18 months of age or older for the prevention of Haemophilus influenzae type b (Haemophilus b) disease. This vaccine consists of Haemophilus b capsular polysaccharide covalently linked to diphtheria toxoid (conjugate vaccine).

A previously developed vaccine consisting of the Haemophilus b capsular polysaccharide alone (polysaccharide vaccine) was shown to be effective in Finnish children over 24 months of age (1), the age group in which approximately 20% of all invasive Haemophilus b infections among U.S. children less than 5 years of age can be expected to occur (2). A similar, but not identical, polysaccharide vaccine was licensed for use in the United States in April 1985 on the basis of data demonstrating biochemical characteristics and immunogenicity comparable to the vaccine used in the original Finnish trial (3). In that Finnish trial, polysaccharide vaccine was not effective in children less than 18 months of age. Because of the small sample size, efficacy could not be demonstrated in children 18 to 23 months of age. Polysaccharide vaccine was immunogenic (as measured by antibody production) in children 18 to 23 months old, but less so than it was in older children (1).

Conjugate vaccine was developed with the ultimate goal of providing an effective vaccine for infants and younger children. Preliminary data from a new Finnish study suggest that conjugate vaccine was 87% effective in preventing Haemophilus b disease when administered in a three-dose regimen to infants 3 to 6 months of age (4). However, licensure of conjugate vaccine for use in infants in the United States cannot be considered until this and other efficacy trials are further evaluated. Since antibody production after vaccination with conjugate vaccine in children 18 months of age or older is substantially greater than that after vaccination with polysaccharide vaccine, conjugate vaccine has been licensed for use in these children.

Safety

When conjugate vaccine alone was given to over 1,000 adults and vaccination with conjugate vaccine in children 18 months of age or older is substantially greater than that after vaccination with polysaccharide vaccine, conjugate vaccine has been licensed for use in these children.

Safety

When conjugate vaccine alone was given to over 1,000 adults and children, no serious adverse reactions were observed (5-12). When conjugate vaccine was given with diphtheria and tetanus toxoid and pertussis vaccine (DTP) and inactivated polio vaccine (IPV) to 30,000 infants, the rate and extent of serious adverse reactions did not differ from those seen when DTP was administered alone (4). In one study of over 500 children 15 to 24 months of age, no significant difference in local or systemic side effects occurred between groups of children vaccinated with either polysaccharide vaccine or conjugate vaccine (7). Local reactions were noted for 10.3% of children receiving polysaccharide vaccine and 12.5% of children receiving conjugate vaccine, while moderate fever (temperature greater than 39.0 degrees C (greater than 102.2 degrees F) occurred in 1.4% of children vaccinated with polysaccharide vaccine and 0.7% of children vaccinated with conjugate vaccine.

Immunogenicity

In several studies using different regimens of vaccine administration, conjugate vaccine has shown greater immunogenicity than polysaccharide vaccine (5-9,11,12). Response to a single dose of either polysaccharide vaccine or conjugate vaccine in children 15 to 24 months of age was specifically addressed in a randomized, double- blind study recently completed in the United States (7). More than 90% of children vaccinated with conjugate vaccine responded with antibody levels considered to be protective (0.15 ug/mL), whereas less than 50% of children vaccinated with polysaccharide vaccine had such a response. Over 60% of children vaccinated with conjugate vaccine, but less than 30% of those vaccinated with polysaccharide vaccine, produced levels of antibody considered to be indicative of long-term protection (1.0 ug/mL).* Children given conjugate vaccine at 15 to 24 months of age had significantly higher levels of antibody to Haemophilus b polysaccharide 1 year after vaccination than did children receiving polysaccharide vaccine (8). Conjugate vaccine recipients responded to a booster dose of either polysaccharide vaccine or conjugate vaccine with higher geometric mean antibody levels than did those initially vaccinated with polysaccharide vaccine (8).

In another study, children with sickle cell syndromes who received conjugate vaccine had higher postvaccination levels of antibody to Haemophilus b polysaccharide than did similar children given polysaccharide vaccine (13). The studies to date showing increased immunogenicity in children less than 18 months of age (5,6,9,11) suggest that conjugate vaccine may be functioning as a T-cell dependent antigen. This finding contrasts with the lack of immunogenicity in infants and the absence of immunologic memory characteristic of T-cell independent polysaccharide vaccines.

Biological Activity

Several investigators have demonstrated that conjugate vaccine produces functional activity against Haemophilus b similar to that produced by polysaccharide vaccine. In one randomized, double-blind study, adults vaccinated with conjugate vaccine had serum bactericidal titers for Haemophilus b at least as high as those of adults receiving polysaccharide vaccine (12). In addition, sera from adults vaccinated with conjugate vaccine were protective in an infant rat model of Haemophilus b disease, whereas similarly diluted sera from persons receiving polysaccharide vaccine showed no protective activity. In a separate study, sera from 9- to 14-month-old children given conjugate vaccine showed greater opsonic activity against Haemophilus b organisms than did sera from children vaccinated with polysaccharide vaccine (14). Both studies showed a correlation between functional activity and serum levels of antibody to Haemophilus b polysaccharide and suggest that antibody produced in response to conjugate vaccine is biologically equivalent to that produced in response to polysaccharide vaccine.

Immunization Practices Advisory Committee (ACIP) Recommendations

1. The ACIP recommends that all children receive conjugate vaccine at 18 months of age. The efficacy of conjugate vaccine in children 18 months of age or older has not been determined in field trials. However, studies comparing antibody production in children receiving conjugate vaccine with that in children receiving polysaccharide vaccine suggest that conjugate vaccine is likely to be more effective than polysaccharide vaccine. The ACIP therefore recommends use of conjugate vaccine in all children vaccinated against Haemophilus b disease.

2. While the duration of immunity after a single dose of conjugate vaccine is unknown at this time, it is expected to be at least 1.5 to 3 years. Until further information is available, revaccination is not recommended for children receiving conjugate vaccine at 18 months of age or older.

3. Vaccination of children more than 24 months of age who have not yet received Haemophilus b vaccine should be based on risk of disease. Children considered at high risk for Haemophilus b disease, including those attending day-care centers, those with anatomic or functional asplenia (i.e., sickle cell disease or splenectomy), and those with malignancies associated with immunosuppression, should receive the vaccine. Although risk of disease decreases with increasing age, physicians may wish to vaccinate previously healthy children between 2 and 5 years of age to prevent disease that can occur in this group.

4. Because many children who received polysaccharide vaccine between the ages of 18 and 23 months may have had a less than adequate response to the vaccine, they should be revaccinated with a single dose of conjugate vaccine. Revaccination should take place a minimum of 2 months after the initial dose of polysaccharide vaccine.

5. There is no need to routinely revaccinate children who received polysaccharide vaccine at 24 months of age or older.

6. Children who had invasive Haemophilus b disease when they were less than 24 months of age should still receive vaccine according to the above recommendations since most children less than 24 months of age fail to develop adequate immunity following natural infection (15).

7. Although increases in serum diphtheria anti-toxin levels can follow administration of conjugate vaccine, this vaccine should not be considered an immunizing agent against diphtheria. No changes in the schedule for administration of diphtheria toxoid, customarily given as DTP, should be made secondary to the use of conjugate vaccine.

8. Vaccination with either polysaccharide vaccine or conjugate vaccine probably does not inhibit asymptomatic carriage of Haemophilus b organisms. Although vaccinated children may be protected from invasive disease, they may pass the organism on to susceptible children. In addition, no vaccine is 100% effective. Therefore, chemoprophylaxis of household or day-care contacts of children with Haemophilus b disease should be directed at vaccinated as well as unvaccinated contacts. Because of the length of time necessary to generate an immunologic response to the vaccines, vaccination does not play a major role in the management of patients with Haemophilus b disease or their contacts. Vaccine may be given to previously unvaccinated children of appropriate age to provide protection against future exposure.

9. Conjugate vaccine and DTP may be given simultaneously at different sites. Data are lacking on concomitant administration of conjugate vaccine and measles- mumps-rubella (MMR) or oral polio (OPV) vaccines. However, if the recipient is unlikely to return for further vaccination, simultaneous administration of all vaccines appropriate to the recipient's age and previous vaccination status is recommended (including DTP, OPV, MMR, and conjugate vaccine).

References

1. Peltola H, Kayhty H, Virtanen M, Makela PH. Prevention of Hemophilus influenzae type b bacteremic infections with the capsular polysaccharide vaccine. N Engl J Med 1984;310: 1561-6.

2. Cochi SL, Broome CV, Hightower AW. Immunization of U.S. children with Hemophilus influenzae type b polysaccharide vaccine: a cost-effectiveness model of strategy assessment. JAMA 1985;253:521-9.

3. Immunization Practices Advisory Committee. Polysaccharide vaccine for prevention of Haemophilus influenzae type b disease. MMWR 1985;34:201-5.

4. Eskola J, Peltola H, Takala AK, et al. Efficacy of Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine in infancy. N Engl J Med 1987;317: 717-22.

5. Lepow ML, Samuelson JS, Gordon LK. Safety and immunogenicity of Haemophilus influenzae type b-polysaccharide diphtheria toxoid conjugate vaccine in infants 9 to 15 months of age. J Pediatr 1985;106:185-9.

6. Kayhty H, Eskola J, Peltola H, Stout MG, Samuelson JS, Gordon LK. Immunogenicity in infants of a vaccine composed of Haemophilus influenzae type b capsular polysaccharide mixed with DPT or conjugated to diphtheria toxoid. J Infect Dis 1987;155:100-6.

7. Berkowitz CD, Ward JI, Meier K, et al. Safety and immunogenicity of Haemophilus influenzae type b polysaccharide and polysaccharide diphtheria toxoid conjugate vaccines in children 15 to 24 months of age. J Pediatr 1987;110:509-14.

8. Berkowitz CD, Ward JI, Hendley JO, et al. Persistence of antibody (AB) to Haemophilus influenzae type b (Hib) and response to PRP and PRP-D booster immunization in children initially immunized with either vaccine at 15 to 24 months (Abstract no. 889). Pediatr Res 1987;21:321A.

9. Eskola J, K|$$|Adayhty H, Peltola H, et al. Antibody levels achieved in infants by course of Haemophilus influenzae type b polysaccharide/diphtheria toxoid conjugate vaccine. Lancet 1985;1:1184-6.

10. Lepow ML, Barkin RM, Berkowitz CD, et al. Safety and Res 1987;21:321A.

11. Eskola J, K|$$|Adayhty H, Peltola H, et al. Antibody levels achieved in infants by course of Haemophilus influenzae type b polysaccharide/diphtheria toxoid conjugate vaccine. Lancet 1985;1:1184-6.

12. Lepow ML, Barkin RM, Berkowitz CD, et al. Safety and immunogenicity of Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine (PRP-D) in infants. J Infect Dis 1987;156:591-6.

13. Lepow ML, Randolph M, Cimma R, et al. Persistence of antibody and response to booster dose of Haemophilus influenzae type b polysaccharide diphtheria toxoid conjugate vaccine in infants immunized at 9 to 15 months of age. J Pediatr 1986;108:882-6.

14. Granoff DM, Boies EG, Munson RS. Immunogenicity of Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine in adults. J Pediatr 1984;105:22-7.

15. Frank AL, Labotka RJ, Frisone LR, et al. H. influenza b immunization of children with sickle cell diseases (Abstract no. 906). Pediatr Res 1987;21:324A.

16. Cates KL. Serum opsonic activity for Haemophilus influenzae type b in infants immunized with polysaccharide-protein conjugate vaccines. J Infect Dis 1985;152:1076-7.

17. Immunization Practices Advisory Committee. Update: prevention of Haemophilus influenzae type b disease. MMWR 1986;35:170-4,179-80. *It should be noted that three of four lots of polysaccharide vaccine used in this study had been heat-sized, a process which may reduce immunogenicity. However, children receiving non-heat- sized polysaccharide vaccine also had postimmunization levels of antibodies to Haemophilus b polysaccharide that were lower than those observed in children vaccinated with conjugate vaccine. In another study in which vaccine recipients were tested at 1 month and again at 1 year after completion of the immunization series, 9- to 15-month-old children who had received two doses of conjugate vaccine had significantly higher titers of antibody to Haemophilus b polysaccharide than did similar children who had received two doses of non-heat-sized polysaccharide vaccine (5).

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