The Haemophilus influenzae type b (Hib) polysaccharide (PS) vaccine was first licensed in the United States in April 1985 and use of this vaccine has been reviewed in detail previously.1 In this article, the author will briefly review: 1) the rationale for an Hib vaccine program; 2) the licensed Hib PS vaccine; 3) recommendations for its use; 4) limitations of this vaccine; and 5) strategies for developing more effective vaccines.
RATIONALE FOR AN HIB VACCINE PROGRAM
Each year in the United States, approximately 12,000 children develop Hib meningitis and another 6,000 develop other invasive Hib infections. About one in 250 children develops serious Hib disease by the age of 5 years. The peak attack rate is in children 6 months to 1 year of age, with about two-thirds of cases occurring in children less than 18 months, and 75% to 85% in children less than 24 months.2'3 Children who have been identified as being at increased risk for developing Hib disease include native Americans (ie, Eskimos and American Indians), Blacks, those from low socioeconomic groups, immunocompromised hosts (including children with antibody deficiency, asplenia, sickle cell disease), and Hodgkin's disease; household contacts of patients with Hib disease, and patients recovered from Hib disease. In addition, it has been found that children who attend day care are at increased risk of developing Hib infections.
Despite advances in antimicrobial therapy, the mortality rate from Hib meningitis and other serious Hib infections remains approximately 5% and Hib meningitis is one of the leading causes of acquired mental retardation. This organism has become increasingly resistant to standard antibiotic regimens, and there is every reason to believe that it will continue to develop resistance to new antimicrobials. Although rifampin prophylaxis has been recommended for prevention of subsequent cases of Hib disease,4 this approach clearly is inadequate to control Hib disease since only an estimated 1% to 2% of all cases have a history of previous exposure to a patient with disease. Prevention of Hib disease by means of immunization appears to be the most promising means of preventing disease caused by this organism.
THE HAEMOPHILUS INFLUENZAR TYPE B POLYSACCHARIDE VACCINE
The Hib PS vaccines licensed in the United States by Praxis Biologies (Rochester, NY), Connaught Laboratories, Inc. (Swiftwater, PA) and Lederle Laboratories (Pearl River, NY) are derived from cultures of Hib. They consist of the purified type b capsular polysaccharide, which is a polymer of ribose, ribitol and phosphate. They contain no live bacteria.
The only study which has demonstrated efficacy of this type of vaccine was performed in approximately 100,000 children in Finland.5 It demonstrated that, among children 24 to 71 months of age, the vaccine was approximately 90% effective.5'6 This vaccine was not effective in preventing Hib disease in children less than 18 months of age, and the number of children immunized between 18 and 23 months was too small to permit conclusions to be drawn about efficacy in this age group.
RECOMMENDATIONS FOR ADMINISTRATION OF THE HAEMOPHlLUS INFLUENZAR TYPE B POLYSACCHARIDE VACCINE
The Committee on Infectious Diseases of the American Academy of Pediatrics (AAP)7 and the Immunization Practices Advisory Committee (ACIP) of the Centers for Disease Control,8 independently have developed guidelines for the use of the Hib PS vaccine in the United States. Both recommend: 1) that all children be immunized at 24 months of age; and 2) that children under 18 months of age not be immunized. The AAP recommends immunizing all children 24 to 59 months, and the ACIP that children in this age group be immunized based on risk of disease (eg, immunodeficiency, asplenia, sickle cell disease, malignancies, day care). The major difference between the recommendations of the two advisory groups is that, whereas, the AAP states that there are insufficient data upon which to base a recommendation regarding vaccine administration in infants 18 to 23 months of age,7 the ACIP recommends that immunization for 18to 23-month-old children who are in high-risk groups "may be considered."8
The incidence of adverse reactions to the Hib PS vaccine has been, extremely low. Fewer than 2% of vaccinées develop local side effects (ie, erythema, induration and/or pain at the injection site) or systemic reactions such as fever. Anaphylaxis has occurred in two children (one in Finland and one in the United States), but was reversed with epinephrine in both children. One 3-year-old child died on the same day as receiving the vaccine (personal communication, Praxis Biologies), but it is unclear whether or not the death was vaccine-related. The vaccine is contraindtcated in individuals who have hypersensitivity to any component of the vaccine (such as the thimerosal preservative). Overall, even if it were assumed that the one death was directly attributable to the vaccine, since an estimated two to three million doses of vaccine have been administered (personal communication, Praxis Biologies), the incidence of serious adverse reactions is extremely low.
The diphtheria, tetanus and pertussis (DTP) vaccine can be administered at the same time as the Hib PS vaccine, but at a separate site.
LIMITATIONS OF THE HAEMOPHILUS INfLUENZAE TYPE B POLYSACCHARlDE VACCINE
Because the Hib PS vaccine consists of purified type b capsular material, the capsule is the only Hoemophilus antigen to which vaccine-induced antibody is directed. For this reason, the vaccine will not provide protection against infections usually caused by nontypable H. influenzae (eg, otitis media, sinusitis and bronchitis). Although the AAP (but not the ACIP) recommends that immunodeficient patients (including those over 59 months of age) be immunized with the Hib PS vaccine,7 these individuals may not have a sufficient antibody response to afford protection. Studies currently are in progress to determine the feasibility of immunizing such patients.
The Hib PS vaccine is unlikely to help prevent subsequent cases of disease in contacts of patients with Hib disease. First, over 50% of subsequent cases occur within 1 week of hospitalization of the index case; thus, there is not enough time to mount a protective antibody response to the vaccine. Second, most subsequent cases are in children who are less than 18 months of age and, therefore, are unlikely to be able to respond to the vaccine. Similarly, the vaccine is unlikely to help prevent relapses OT recurrences of Hib disease, since most children's initial episodes are at less than a year of age, and relapses and recurrences usually occur within 1 year. In addition, young children who have had Hib disease often have a poorer response to Hib PS than age-matched control children.
The duration of immunity induced by immunization with Hib PS has been estimated by comparing serum antibodies directed at the Hib PS in children who received the vaccine with those in age-matched children who had not received the vaccine.9 Children immunized at 36 months of age still had significantly higher antibody levels than controls 3.5 years after immunization. Those immunized at 18 to 35 months had higher levels 1.5, but not 3.5 years later. Those immunized at 18 months had levels comparable to those of controls both at 1.5 and 3.5 years. This finding suggests that, although it is unlikely that children immunized at 36 months will need to receive a second dose of vaccine, those immunized initially at 18 months probably will need a second dose. Further data are needed to determine the need for re immunization of the inbetween age group.
Another possible problem with administering the vaccine too early, other than the probable need to reimmunize, is the theoretical possibility of inducing immune tolerance. Studies have shown that when the pneumococcal capsular PS was given to young mice, they had a poorer response to subsequent challenge with the vaccine than mice who had not been immunized previously. Thus, too early exposure to polysaccharide antigens may impair later immune response and, perhaps, even increase susceptibility to disease. Although one report states that there is no evidence for tolerance9 after immunization of young children with Hib PS, the numbers of children reported are small and this work needs to be expanded to a larger group of children.
Genetic factors have been found to be associated with ability to mount an antibody response to the Hib PS vaccine and susceptibility to Hib disease. In one study it was found that black children who are positive for Km (1) (a genetic marker on the Kappa light chain of the IgG molecule) have a higher antibody response to Hib PS vaccine and a lower risk of Hib disease than do black children who are Km (1) negative.10 Also, young siblings of patients who had Hib disease have poorer antibody response to the Hib PS-pertussis vaccine, but not to the Hib PS without pertussis (personal communication) than age-matched control subjects. These studies suggest that it is possible that children at the greatest risk for developing Hib disease may be the group least likely to be protected by immunization.
The most important limitation of the currently licensed Hib PS vaccine is its failure to induce protective levels of antibody in children less than 18 to 23 months of age, the age group at highest risk for developing serious Hib disease. Although one report from Finland suggested that up to 60% of all invasive Hib bacteremic infections chould be prevented by immunization of children beginning at 18 months6 (because of geographic differences in the age distribution of Hib disease in Finland versus the United States),2'3 at most, 30% of cases of Hib meningitis in the United States could be prevented with immunization at 18 months, and 15% to 20% with immunization at 24 months. However, unlike meningitis, the mean age of children who develop epiglottitis is greater than 24 months, and most cases of epiglottitis potentially could be prevented by immunization with this vaccine.
At the time of this writing, Hib PS vaccine has been licensed for less than a year. More than 50 cases of Hib PS vaccine failures (ie, children who develop invasive Hib disease after having been immunized) have been reported in children immunized at 24 months of age or older. It is unclear whether or not the number of failures exceeds those to be anticipated from results of the Finnish vaccine trial.5'6 Such analysis awaits further data collection. In the meantime, however, it is clear some children will not be protected by the vaccine, especially when they are immunized between 18 and 23 months. In fact, it is possible that the vaccine is ineffective in this age group. Therefore, it is important for pediatricians to include coverage for Hib when selecting antimicrobial therapy for immunized young children who develop a clinical picture compatible with Hib disease (eg, meningitis, septic arthritis, epiglottitis, cellulitis, etc.) until the infecting organism has been identified.
Also, because this vaccine does not prevent nasopharyngeal Hib carriage, rifampin prophylaxis should be administered to immunized children when indicated4 to help prevent transmission of the organism.
Several laboratories are working to develop more effective vaccines for the prevention of Hib disease. The two most promising approaches for inducing protection in young children and, possibly, individuals with poor responses to Hib PS due to genetic factors, include chemically conjugating the Hib PS to a carrier protein. Several carrier proteins are being investigated, including diphtheria toxotd and its derivatives,11 and an outer membrane protein of the group B meningococcus12. Such conjugation is felt to enhance the ability of young children to make antibody to PS by converting it from a "T-cell independent" to a "Tcell dependent" antigen. Whereas, few infants immunized at less than 12 months of age respond to Hib PS vaccine challenge, approximately 50% of infants given three doses of the PS-diphtheria toxoid conjugate vaccine (Connaught Laboratories, Swiftwater, PA) at 3, 5 and 7 months, and 57% of those given 2 doses at 7 and 9 months developed concentrations of antibody to PS of greater than or equal to the 1 µ^??? felt to be needed for protection. n Even more promising are data from a trial of a vaccine consisting of PS conjugated to a group B meningococcal outer membrane protein (Merck, Sharp and Dohme, West Point, PA). This vaccine induced 1 u.g/ml or more of antibody to PS in 73% of infants immunized with 2 doses of vaccine at 2 to 6 months and 80% of those given one dose at 9 to 17 months.12 Trials of safety, immunogenicity and efficacy of those new vaccines are underway.
The other most promising approach to Hib vaccine development is the use of other antigens from Hib, such as Hib outer membrane proteins or lipopolysaccharide, instead of, or in conjunction with, Hib PS. Hib outer membrane proteins, for example, may prove to be the most optimal carrier protein for PS-protein conjugate vaccines.
A vaccine for the prevention of Hib disease has been licensed for about a year. It has been widely accepted by pediatricians and is quite safe, but its impact on lowering the incidence of Hib disease in the United States remains to be determined. New approaches to Hib immunization are being pursued, and preliminary experience suggests that licensure of more effective vaccines will occur in the not too distant future.
1. Granoff DM, Cates KL: Hoemnphilus influence type b polysaccharide vaccines. J Pediatr 1985; 107:330-336.
2. Murphy TV, Breedlove JA, Fritz EH. et al: County-wide surveillance of invasive Haemaphilus infections: Risk of associated cases in child care programs. Abstract of the twenty-third Interscience Conference on Antimicrobial Agents and Chemotherapy, Las Vegas, 1983, 788A.
3. Osterholm MT, Kuritsky JN, Pierson LN, et al: Risk of secondary Haemophilus influemae type b disease in day care, Pediatr Res 1984; 18:282A.
4. American Academy of Pediatrics, Committee on Infectious Diseases: Revision of recommendation for use of rifampin prophylaxis of contacts uf patients with Haemophiins influence infection. Rabanes 1984: 74;301-302.
5. Peltola H. Kayhty H, Sivonen A. et al: Haemophilus mfuemee type b capsular polysaccharide vaccine in children; A double-blind field study of 100,000 vaccinees 3 months to 5 years of age in Finland, ftdiomcs 1977; 60:730-737.
6. Peltola H, Kayhry H, Virtanen M. et al: Prevention of Hemuphilus influenzae type b bactetemic infections with the capsular polysaccharide vaccine. N Engf J Med 1984; 310: 1561-1566.
7. American Academy of Pediatrics, Committee on Infections Diseases. Hemiiphilui type b polysaccharide vaccine, Pediatr 1985; 76:322-324.
8. Recommendation of the Immunization Practices Advisory Committee; Polysaccharide vaccine for prevention of Hoemophilus influence type b disease. MMWR 1985; 34:201-205.
9. Kayhty H, Karanko V, Peltola H. et al: Serum antibodies aftet vaccination with Hoemuphilus influenzae type b capsulai polysaccharide and responses tu reimmunization: No evidence of immunologie tolerance or memory. Pediatrics 1984; 74:857-865.
10. Granoff DM, Pandey JP, Boies E, et al: Response tu immunization with Hoemophilus influence type b polysaccharide- pertussis vaccine and risk of Haemophilus influezae meningitis in children with the Km (1) immunoglobulin allotype. J Clim Invest 1984: 74:1708-1714.
11. Eskola J. Peltola H, Matela PH. et al: Antibody levels achieved in infants by course of Haemophilus influenzae type b polysaccharide/diphtheria toxoid conjugate vaccine. Lancet 1985; 1184-1186.
12. Granoff DM, Munson RS Jr: Prospects for prevention of Haemophilus influenzae type b disease by immunization. J Infect Dis 1986; 153:448-461.