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PEDIATRICS Vol. 110 No. 4 October 2002, pp. 820-823

COMMENTARY

Control of Disease Attributable to Haemophilus influenzae Type b and the National Immunization Program

Abbreviations: PRP, polyribosylribitol phosphate • Ig, immunoglobulin

Haemophilus influenzae type b was the most important cause of invasive bacterial disease in young children before introduction of a polysaccharide vaccine in 1985.1 After the availability of conjugated polysaccharide vaccines in 1987, disease caused by H influenzae type b declined by >95% (Fig 1).2 In fact, the reduction in H influenzae type b disease has turned out to be even greater than what many persons predicted, attributable in part to the ability of the vaccine to reduce pharyngeal colonization among vaccinees. This unexpected benefit, which was not fully anticipated from prelicensure clinical trials, stands in contrast to the rare unanticipated adverse event (intussusception) that was not detected in prevaccine trials but occurred after widespread use of the rhesus rotavirus tetravalent vaccine,3 demonstrating that beneficial as well as undesirable consequences may result when new vaccines are used widely. In addition to the remarkable reduction in morbidity and mortality, significant economic benefit has resulted from control of H influenzae type b disease. In this issue of Pediatrics, Zhou et al4 offer an elegant economic analysis of the conjugate vaccine demonstrating that the national H influenzae type b vaccination program offers substantial cost savings from both the direct cost and societal perspectives. Although many current pediatric residents may never treat a child with H influenzae meningitis or epiglottitis because of the rarity of these diseases, more experienced pediatricians readily acknowledge the extraordinary benefits from the significant reduction of invasive disease attributable to H influenzae type b. At a time when immunization programs are being challenged from many nonscientific perspectives, the study by Zhou et al offers important documentation of the cost-effectiveness of one vaccination program.4,5



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  		Fig 1. Estimated incidence of invasive Hib disease, 1987–2000.

 
The bacterium H influenzae was first isolated from respiratory tract secretions of patients who died of pneumonia during the 1889 influenza pandemic. Pfeiffer initially proposed a causal association between the organism and the syndrome of influenza. It was not until 1933 that H influenzae was recognized as a cause of a secondary complication and not the cause of the influenza syndrome. Before the introduction of effective vaccines, ~20 000 persons each year in the United States developed invasive disease attributable to H influenzae. Disease demonstrated a remarkable age predilection, with ~1 in 200 children experiencing invasive disease (meningitis, bacteremia, epiglottitis, pneumonia, cellulitis, arthritis, osteomyelitis, or pericarditis) before 5 years of age. Meningitis was the most common manifestation of infection, occurring in ~60% of young children who experienced invasive disease. The case fatality rate for H influenzae type b meningitis was 5%, resulting in ~600 deaths per year. Among survivors, 15% to 30% suffered severe neurologic complications including unilateral or bilateral hearing deficits, mental retardation, seizure disorders, or paralysis.1

Invasive disease is caused almost exclusively by 1 of the 6 antigenic capsular types (a through f). In the prevaccine era, type b strains caused >95% of invasive disease. Each capsule consists of a biochemically unique polysaccharide, polyribosylribitol phosphate (PRP). This capsule is a key virulence factor that inhibits phagocytosis by blocking opsonization. Antibody to PRP capsule is a major determinant of immunity. Among unvaccinated children, typically 0.5% to 3% of healthy infants and children have nasopharyngeal colonization by H influenzae type b. Asymptomatic colonization of mucous membranes of the upper respiratory tract by unencapsulated or nontypeable strains is more common, occurring in 60% to 90% of young children.6 Unencapsulated stains of H influenzae rarely are associated with invasive disease but are a common cause of otitis media, sinusitis, bronchitis, and less commonly pneumonia and urinary tract infections. Bacteremia resulting from unencapsulated strains is rare.

Encapsulated and unencapsulated strains are transmitted from person to person either by direct contact or by inhalation of droplets of respiratory tract secretions containing the organism. Once the organism makes contact with the nasopharynx, 1 of 3 outcomes is possible—colonization, progression to disease, or eradication. Before vaccines became available, immunity to H influenzae type b was acquired either by asymptomatic infection or by exposure to organisms with antigens that induce cross-reacting antibodies. In addition to preexisting immunity, genetic factors seem to influence susceptibility to infection by H influenzae type b, although this interaction is incompletely understood.7 The presence of a concomitant viral infection also is associated with an increase in risk of disease.8

In 1985 a first-generation vaccine consisting of purified polysaccharide antigen was licensed by the Food and Drug Administration and was available until 1988. This pure polysaccharide vaccine demonstrated characteristics similar to those of other nonconjugated polysaccharide vaccines (pneumococcal, meningococcal): the immune response was T-cell independent (B lymphocyte produces antibody without involvement of T cells), resulting in poor immunogenicity in children <24 months old, absence of a booster response with subsequent vaccinations, and an immune response consisting primarily of low-affinity immunoglobulin M (IgM) antibody.9,10

In December 1987 the first of several H influenzae type b conjugate vaccines was licensed. By bonding or conjugating the polysaccharide PRP moiety to a protein carrier (diphtheria toxoid, tetanus toxoid, meningococcal outer membrane protein, or mutant diphtheria protein CRM197), the immune response was converted from a T-cell–independent response to a T-cell–dependent response, improving immunogenicity in young children.11 Furthermore, conjugate vaccines induce immunologic memory so that booster doses induce a long-term IgG response. Antibodies induced by conjugate vaccines bind with increased avidity and demonstrate greater bactericidal activity than those stimulated by pure polysaccharide vaccines.12,13 Finally, recipients of conjugated vaccines demonstrate reduced nasopharyngeal colonization with H influenzae type b, resulting in herd immunity through a reduced likelihood of transmission of the bacterium to unvaccinated children.14 Starting in 1990, 4 additional conjugate H influenzae type b vaccines were licensed by the Food and Drug Administration for use in children and infants as young as 6 weeks of age (Table 1). In addition, 2 combination vaccines containing conjugated H influenzae type b have been licensed, and additional combinations are undergoing testing.


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  		TABLE 1. Haemophilus influenzae Type b Vaccines

 
In 1991, recommendations were issued by the American Academy of Pediatrics Committee on Infectious Diseases and the Advisory Committee on Immunization Practices stating that all children should be immunized with an appropriate conjugate vaccine beginning at 2 months of age.15 From 1989 to 1997, there was a 99% reduction in disease attributable to H influenzae type b among children <5 years of age. This reduction in disease burden occurred as a direct consequence of the immunization program. This decline was documented by the Centers for Disease Control and Prevention-sponsored multistate laboratory-based active surveillance program. Based on data from the US National Immunization Survey obtained between July 2000 and June 2001, >93% of infants in the United States had received 3 doses of vaccine by 18 months of age. One of the objectives of Healthy People 2010is the elimination of all invasive H influenzae type b disease among children younger than 5 years of age by 2010. The availability of effective vaccines and the fact that there are no known reservoirs for H influenzae type b other than humans make this a realistic objective for the United States.

As the remarkable efficacy of the immunization program has become apparent, concern has been raised about a possible shift in serotype causing disease, with encapsulated, non-type b strains emerging to fill the void left by reduction in type b disease.16 Surveillance programs have not detected a significant increase in infections attributable to other serotypes, indicating that to date this has not occurred. Centers for Disease Control and Prevention data from 1998 to 2000 define the incidence of invasive disease attributable to nontype b H influenzae as 0.8 cases per 100 000 children <5 years of age.2 Although occasional reports describe clusters of disease attributable to non-b serotypes, no pattern of serotype shift seems to be emerging.17,18 Nontype b strains seem to be less virulent and therefore less likely to cause widespread disease.

It is important that the serotype of all isolates from cases of invasive H influenzae disease occurring in children <15 years of age be reported to the state health department. Investigation of cases should include information on serotype, immunization status, dates of vaccinations, and vaccine lot numbers. This information will enable determination of whether a case represents a vaccine failure, disease in a person who was not adequately vaccinated, disease in a child too young to be fully protected using the current vaccine schedule, or disease attributable to a nontype b strain. More than 95% of vaccinated children develop a protective titer of anti-PRP antibody after 2 or 3 doses (a titer of 1 µg/mL 3 weeks after vaccination with a polysaccharide vaccine seems to correlate with long-term protection).19 Conjugate vaccines have demonstrated immunogenicity in children with sickle cell disease, congenital asplenia, and bone marrow transplant recipients.20–22 In view of the efficacy of conjugate vaccines in most children, what is the explanation for vaccine failures? Results of several studies suggest that one reason for breakthrough disease is an inadequate serum concentration of anti-PRP antibody. Children with low antibody levels—particularly IgG2, IgA, or IgM levels—constitute a large percentage of vaccine failures.23,24 However, it is important to remember that antibody deficiency in some children may be transient, representing a maturational delay that will resolve in time rather than indicating a child with an immunodeficiency.25 Other data from children for whom vaccines failed suggest that the protective role of antibody to PRP is not only a function of antibody concentration but also related to antibody avidity.26 Additional justification for careful follow-up of cases of invasive H influenzae disease comes from the need to evaluate postexposure prophylaxis in contacts. Household contacts of an index case have a 600-fold increase in risk of disease during the month after exposure if they are not immunized or do not receive antimicrobial prophylaxis. Child care contacts seem to be at slightly higher risk of secondary disease than the general population.

The H influenzae type b vaccine has now been added to a list of remarkably successful vaccines that have improved dramatically the health of children in many countries. Over the past 15 years, disease attributable to H influenzae type b has evolved from the most common cause of bacterial meningitis into a disease which is almost never encountered in vaccinated persons and soon may be eliminated. Seven other potentially fatal infectious diseases of childhood have experienced more than a 97% reduction in incidence from 20th century annual morbidity. This list includes polio, measles, rubella, tetanus, diphtheria, mumps, and pertussis. Annual deaths in the United States resulting from these diseases now have declined to near zero. Currently, we are witnessing a dramatic reduction in incidence of 2 other infectious diseases of childhood because of the availability of recently licensed vaccines—varicella and pneumococcal disease. Because each infectious disease has its own epidemiologic characteristics, the final impact of varicella and pneumococcal vaccines may not be as great as that of the H influenzae type b vaccine, but reduction in morbidity and mortality will be significant. Other common scourges of children and adults that may soon succumb to the control of vaccines include groups A and B streptococci, malaria, human papillomaviruses (cause of cervical cancer), influenza virus, respiratory syncytial virus, parainfluenza virus, Epstein-Barr virus, chlamydia, herpes simplex virus, and human immunodeficiency virus.

The price of new vaccines being added to the recommended childhood immunization schedule is escalating, and the benefit-cost ratios of future vaccines may not always exceed one as it did in the study by Zhou and associates. If this trend continues, the cost of additional vaccines eventually may not be absorbed under the current system of paying for vaccines. Inadequate financing of vaccines looms as a major impediment to delivery of vaccines recommended for all children. The issue of whether children, regardless of their socioeconomic status, should have access to all recommended childhood vaccines and, if so, how the cost of these vaccines will be supported must be addressed. Vaccine finance issues are being considered by several groups including the National Vaccine Advisory Committee, the Institute of Medicine, the American Academy of Pediatrics, and others. The challenges now are to maintain the vaccine supply, to continue funding for research and development of novel vaccines, to ensure stability of vaccine financing, and to ensure that each child is fully immunized.

H. Cody Meissner, MD

Division of Pediatric Infectious Disease
New England Medical Center
Tufts University School of Medicine
Boston, MA 02111

Larry K. Pickering, MD

National Immunization Program
Centers for Disease Control and Prevention
Atlanta, GA 30333

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FOOTNOTES

Received for publication Jun 12, 2002; Accepted Jun 13, 2002.

Address correspondence to H. Cody Meissner, MD, Pediatric Infectious Disease Division, Tufts-New England Medical Center, 750 Washington St, Boston, MA 02111. E-mail: cmeissner{at}lifespan.org

REFERENCES

  1. Broome CV. Epidemiology of H influenzae type b in the United States. Pediatr Infect Dis J.1987; 6 :779 –782[Web of Science][Medline]
  2. Centers for Disease Control and Prevention. Progress toward elimination of Haemophilus influenzae type b invasive disease among infants and children–United States, 1998–2000. MMWR Morb Mortal Wkly Rep.2002; 51 :234 –237[Medline]
  3. Murphy TV, Gargiullo PM, Massoudi MS, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med.2001; 344 :564 –572[Abstract/Free Full Text]
  4. Zhou F, Bisgard KM, Yusuf HR, Deuson RR, Bath SK, Murphy TV. Impact of universal Haemophilus influenzae type b vaccination starting at 2 months of age in the United States: an economic analysis. Pediatrics.2002; 110 :653 –661[Abstract/Free Full Text]
  5. Abramson JS, Pickering LK. US immunization policy. JAMA.2002; 287 :505 –509[Free Full Text]
  6. American Academy of Pediatrics. Haemophilus influenzae infections. In: Pickering LK, ed. 2000 Red Book: Report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, IL: American Academy of Pediatrics;2000 :262 –272
  7. Petersen GM, Silimeri DR, Rotter JI, et al. Genetic factors in H influenzae type b disease susceptibility and antibody acquisition. J Pediatr.1987; 110 :229 –233
  8. Takala AK, Mourman O, Kleemoia M, et al. Preceding respiratory infection predisposing for primary and secondary invasive Haemophilus influenzae type b disease. Pediatr Infect Dis J.1993; 12 :189 –195[Web of Science][Medline]
  9. Anderson P, Smith DH, Ingram DL, Wilkins J, Wehrle PF, Howie VM. Antibody of polyribophate of H influenzae type b in infants and children: effect of immunization with polyribophosphate. J Infect Dis.1977; 136(suppl) :S57 –S62
  10. Ada G. Vaccines and vaccination. N Engl J Med.2001; 345 :1042 –1053[Free Full Text]
  11. Heath PT. Haemophilus influenzae type b conjugate vaccines: a review of efficacy data. Pediatr Infect Dis J.1998; 17(suppl) :S117 –S122[CrossRef][Web of Science][Medline]
  12. Schlessinger Y, Granoff DM. Avidity and bactericidal activity of antibody elicited by different H influenzae type b conjugate vaccines. The Vaccine Study Group. JAMA.1992; 267 :1489 –1494[Abstract/Free Full Text]
  13. Amir J, Scott MG, Nahm MG, et al. Bactericidal and opsonic activity of IgG1 and IgG2 anti-capsular antibodies to H influenzae type b. J Infect Dis.1990; 162 :163 –171[Web of Science][Medline]
  14. Murphy TV, Pastor P, Medley F, et al. Decreased Haemophilus colonization in children vaccinated with H influenzae type b conjugate vaccine. J Pediatr.1993; 122 :517 –523[Web of Science][Medline]
  15. Centers for Disease Control and Prevention. Haemophilus b conjugate vaccines for prevention of H influenzae type b disease among infants and children two months of age and older. MMWR Morb Mortal Wkly Rep.1991; 40 :1 –7[Medline]
  16. Heath PT, Booy R, Azzopardi HJ, et al. Non-type b Haemophilus influenzae disease: clinical and epidemiologic characteristics in the H influenzae type b vaccine era. Pediatr Infect Dis J.2001; 20 :300 –305[CrossRef][Web of Science][Medline]
  17. Urwin G, Krohn JA, Deaver-Robinson K, Wenger JD, Farley MM. Invasive disease due to Haemophilus influenzae serotype f: clinical and epidemiologic characteristics in the H influenzae serotype b vaccine era. The Haemophilus influenzae Study Group. Clin Infect Dis.1996; 22 :1069 –1076[Web of Science][Medline]
  18. Adderson EE, Byington CL, Spencer L, et al. Invasive serotype a Haemophilus influenzae with a virulence genotype resembling H influenzae type b: emerging pathogen in the vaccine era? Pediatrics.2001; 108(1) . Available at: URL: http://www.pediatrics.org/cgi/content/full/108/1/e18
  19. Kayhty H, Peltola H, Karanko V, Makela PH. The protective level of serum antibodies to the capsular polysaccharide of H influenzae type b. J Infect Dis.1983; 147 :1100 –1106[Web of Science][Medline]
  20. Goldblatt D, Johnson M, Evans J. Antibody responses to H influenzae type b conjugate vaccine in sickle cell disease. Arch Dis Child.1996; 75 :159 –161[Abstract/Free Full Text]
  21. Webber SA, Sandor GG, Patterson ME, et al. Immunogenicity of H influenzae type b conjugate vaccine in children with congenital asplenia. J Infect Dis.1993; 167 :1210 –1212[Web of Science][Medline]
  22. Guinan EC, Molrine DC, Antin JH, et al. Polysaccharide conjugate vaccine responses in bone marrow transplant patients. Transplantation.1994; 57 :677 –684[Web of Science][Medline]
  23. Heath PT, Booy R, Griffiths H, et al. Clinical and immunological risk factors associated with H influenzae type b conjugate vaccine failure in childhood. Clin Infect Dis.2000; 319 :73 –80
  24. Breukels MA, Spanjaard L, Sanders LAM, Rijkers GTR. Immunological characterization of conjugated H influenzae type b vaccine failure in infants. Clin Infect Dis.2001; 32 :1700 –1705[CrossRef][Web of Science][Medline]
  25. Meissner C, Reimer CB, Black C, et al. Interpretation of IgG subclass values: a comparison of two assays. J Pediatr.1990; 117 :726 –731[CrossRef][Web of Science][Medline]
  26. Brukels MA, Zijde EMJ, van Tol MJD, Rijkers GT. Concentration and avidity of anti-H. influenzae type b antibodies in serum samples obtained from patients for whom vaccination failed. Clin Infect Dis.2002; 34 :191 –197[CrossRef][Web of Science][Medline]
PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics

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