PEDIATRICS Edited by Michael D. Reed

HAEMOPHILUS INFLUENZAE TYPE B CONJUGATE VACCINES Rex W. Force, Ralph A. Lugo, and Milap C. Nahata

OBJECTIVE:

To review the epidemiology of Haemophilus injluenzae

type b (Hib) disease, the first Hib vaccine and its limitations, the

characteristics and clinical efficacy of the newer conjugate vaccines, and the current recommendations for administration of Hib vaccmes. DATA SOURCFB: Pertinent literature was identified via a MEDLINE search. Additionally, references cited in published articles were used as data sources.

Studies describing the epidemiology of Hib disease and the efficacy and/or immunogenicity of the Hib vaccines are reviewed.

STUDY SELECTION:

DATA SYNTHESIS: Serious invasive disease secondary to Hib infection causes significant morbidity and mortality in children between the ages of three months and five years. The original Hib vaccine was found to be ineffective in stimulating an adequate immune response in children younger than two years of age. The new Hib conjugate vaccines provide superior efficacy and immunogenicity compared with the original unconjugated vaccine. They stimulate an immune response that is distinctly different from that elicited by the original vaccine. Two vaccine products are currently licensed for use in children as young as two months of age, thus conferring immunity to those children at highest risk for Hib disease. CONCLUSIONS: The new Hib conjugate vaccines provide excellent efficacy and, when used as recommended, may significantly reduce the incidence of invasive Hib disease and its sequelae.

Ann Pharmacother 1992;26: 1429-40.

(Hib), a pleomorphic gramnegative bacterium, causes a variety of infections leading to significant morbidity and mortality in infants and children. The Food and Drug Administration (FDA) has approved three conjugate vaccines to prevent invasive Hib disease. The new Hib vaccines possess enhanced immunogenicity and efficacy in young children compared with

HAEMOPHlLUS INFLUENZAETYPE B

REX W. FORCE, Pharm.D.. is a Fellow in Infectious Disease Pharmacotherapy: RALPH A. LUGO, Pharm.D.. is a Fellow in Pediatric Pharmacotherapy: and MI· LAP C. NAHATA, Pharm.D., is a Professor of Pharmacy and Pediatrics, Colleges of Pharmacy and Medicine, Ohio Slate University, and Wexner Institute for Pediatric Research, Children's Hospital, Columbus, OH. Reprints: Milap C. Nahata, Pharm.D .. College of Pharmacy, Ohio State University, 500 W. 12th Ave.. Columbus, OH 43210. MICHAEL D. REED, Pharm.D.. is an Associate Professor of Pediatrics, Division of Pediatric Pharmacology and Critical Care, Rainbow Babies and Childrens Hospital, Case Western Reserve University, Cleveland, OH 44106.

This article is approved for continuing education credit.

the first Hib vaccine, thereby significantly reducing the potential for severe Hib infections. At our institution, the number of Hib isolates decreased from 112 in 1988 to 24 in 1991 (personal communication, Harold J. Cannon, Jr., RM, SM(AAM), Microbiology Laboratory, Children's Hospital, Columbus, OH, January 31, 1992). The lack of adequate comparative information in the literature justifies the need for a comprehensive review of currently available Hib vaccines. The purpose of this article is to discuss the epidemiology of Hib infection, the first Hib vaccine and its limitations, the immunology and clinical efficacy of the newer conjugate vaccines, and the current recommendations for the administration of these vaccines. Background and Epidemiology

Some strains of H. influenzae possess a polysaccharide capsule; others do not. Encapsulated organisms are designated types a through f on the basis of specific capsular polysaccharides. I Nonencapsulated organisms typically are responsible for many childhood infections including otitis media, sinusitis, and conjunctivitis; in contrast, the encapsulated organisms usually cause invasive, systemic infections. More than 95 percent of the serious, invasive infections are caused by Hib.2,3 Nearly all cases of invasive Hib disease in children occurs in those between the ages of 3 months and five years. One in 200 children develops Hib disease by the age of five, with up to 75 percent of infections occurring in children younger than 24 months of age.2,4·8 Meningitis accounts for approximately half of these cases and occurs in up to 15000 children annually.' Hib is the most common cause of bacterial meningitis in preschool children with a peak incidence occurring at 6 to 7 months of age. 509 Epiglottitis occurs in 10-36 percent of patients with invasive disease with a peak incidence at three years of age.":" Pneumonia, cellulitis, septic arthritis, and bacteremia account for the remaining invasive Hib infections. tO,lI oB Several factors predispose infants and children to the development of invasive Hib disease. One of the most important is age. As early as 1933 it was reported that infants up to two months of age are protected from disease." The incidence of invasive Hib disease then increases with age, reaching a peak between the ages of six and nine months. This peak is followed by a gradual decline in incidence until the age of five years. Most children possess protective

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concentrations of antibody by five years of age. 7•IS The mechanism for the increase in antibody concentration is unclear, particularly in those who do not develop invasive Hib disease. It is theorized that colonization with antigenically similar commensal bacteria, including some strains of Escherichia coli, may stimulate the production of antibodies that crossreact with Hib." Additionally, asymptomatic nasopharyngeal colonization with Hib is common and may aid in stimulating antibody production.P:" Another well-recognized predisposing factor to the development of invasive Hib disease is ethnic heritage. Ward et al. reported that native Alaskans have a ten-fold higher risk compared with the general US population for contracting Hib meningitis. These investigators found that 2.4 percent of native Alaskan infants developed Hib meningitis in the first year of life." Although native Alaskans make up only 16 percent of the state's population, they account for 51 percent of the state's cases of invasive Hib disease.' Navajo and Apache Indians are also at high risk for developing invasive Hib disease. 2,18,' 9 Additionally, reports indicate that there is a higher incidence of invasive Hib disease in African and Hispanic Americans than in the general US population; however, socioeconomic factors may confound these data. 2,s,2o Daycare center attendance and crowded housing conditions are reported to predispose children to Hib disease. In one study, children attending daycare were 3.9 times more likely to develop disease than were those not attending.P Other high-risk populations include patients with sickle cell anemia, splenic dysfunction, and immunodeficiency disorders.' Hib meningitis is reported to be fatal in up to 10 percent of patients," Permanent neurologic dysfunction occurs in 20-45 percent of survivors.v--" The neurologic sequelae of Hib meningitis range from minor hearing loss and behavior problems to seizure disorders, hemiparesis, blindness, quadriplegia, profound mental retardation, and cerebral palsy. Even minor hearing loss is associated with poor school performance and difficult social adjustment. Decreased school readiness and achievement as well as lower intelligence quotients may occur in children with a history of meningitis compared with matched controls or siblings without disease.' Although the use of third-generation cephalosporins and corticosteroids has reduced the morbidity and mortality associated with invasive Hib disease, the pre-immunization incidence of this disease had been unacceptably high. 22-24 Thus, the need for a safe and effective Hib vaccination was critical.

Host defenses against encapsulated Hib are quite complex. The polysaccharide capsule is composed of repeating units of ribose, ribitol, and phosphate (PRP). The capsule serves to inhibit efficient phagocytosis, thus providing a crucial virulence factor in the pathogenesis of disease." The most important host defense factors include the production of H. influenzae type-specific anticapsular (antiPRP) antibodies and the activation of complement. A close correlation between serum opsonic activity and anti-PRP antibody concentrations has been reported." The humoral immune response to antigens can be classified either as T-cell dependent or T-cell independent. Most protein antigens elicit a T-cell- dependent antibody response. T-helper lymphocytes are activated by the antigen to initiate antibody synthesis in B lymphocytes. Response intensity is regulated by the balance between Thelper and T-suppressor cells. Additionally, T-cell-dependent immunity causes the production of B-memory cells, thus providing the capability for a booster or anamnestic antibody response when the host is rechallenged with the antigen (Figure 1). In contrast, bacterial capsular polysaccharides, such as those produced by Hib, do not require T lymphocytes for antibody synthesis and thus stimulate a Tcell-independent immune response. These antigens directly trigger B-cell production of antibodies without the aid of T-helper cells. T-cell-independent antigens result in the production of few B-memory cells; therefore, an appreciable anamnestic antibody response is not elicited upon rechallenge with the antigen (Figure 2).27.28 Children younger than two years of age exhibit a poor T-cell-independent antibody response to bacterial polysaccharides. Studies in animals have led to several hypotheses for this observation. Delayed development of T-cell-independent responsiveness has been reported in neonatal mice.28-30 This may be caused, in part, by a deficiency in a subset of mature B cells during the early months of life. Consequently, there is inadequate antibody production in response to a T-cell-independent antigenic challenge. In addition, a T-cell imbalance caused by excessive T-suppressor-cell activity may further impair antibody response to bacterial polysaccharides. The delayed development of T-cell-independent responsiveness in mice may provide a model for the delayed immunologic development observed ~

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Haemophilus influenzae Type B Immunity Antibody assays using radiolabeled polyribosylribitol phosphate (PRP) have documented an inverse relationship between plasma antibody concentration and invasive Hib disease.' At birth, infants are protected from Hib disease by maternally acquired antibodies. Infants are also protected by antibodies acquired through breastfeeding.F' Antibody concentrations decline during the first three to six months of life and remain low in children younger than two to three years of age. The inverse relationship between serum antibody concentration and the incidence of invasive disease is a manifestation of the inability of children less than two years of age to effectively mount an antibody response against the polysaccharide capsule of Hib,? 1430 •

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1992 November, Volume 26

Hib Vaccines

in human infants." If this model is representative of the immune system in infants, the production of protective antibodies is unlikely given any T-cell-independent capsular polysaccharide challenge. This has been substantiated by the poor antibody responses to polyvalent pneumococcal and meningococcal groups A and C polysaccharide vaccines in young children,"

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First-Generation Polysaccharide Vaccine The first Hib vaccine, aT-cell-independent purified polysaccharide (PRP) vaccine, was licensed in the US in 1985.31 FDA approval was based on the results of a large randomized trial performed in Finland. The protective efficacy rate of the vaccine was 90 percent (95 percent confidence interval [CI], 56-96 percent) in Finnish children vaccinated after 18 months of age. No protection was conferred to children vaccinated before 18 months of age. 3 1_12 This was a significant limitation, as 75 percent of all Hib infections in the US occur in children younger than two years of age. 2•7,8 Consequently, the Immunization Practices Advisory Committee (ACIP) of the Centers for Disease Control recommended universal immunization for children aged 24-60 months and those aged 18-24 months at high risk for developing infection." Despite early reports suggesting that anti-PRP antibody concentrations of 0.15 llg/mL are required to provide protection against Hib in nonimmunized people.r'-" concentrations of 1.0 ug/ml, measured three weeks after vaccination were associated with protection in the Finnish study.P-" Children failing to achieve protective concentrations were those younger than 18 months of age in whom no vaccine efficacy was seen.P It is important to note that immunogenicity data are reported two different ways: as geometric mean concentration of anti-PRP antibody or as the percentage of vaccine recipients who develop a geometric mean antibody concentration of at least 1.0 ug/ml., Antibody concentrations reported to be protective must be interpreted with caution. Poor standardization and significant interlaboratory variability in antibody measurement may occur.3 1,37 Additionally, differences may exist in the functional affmity and activity of anti-PRP antibodies, thus yielding any reports of protective concentrations unreliable.P-" Reports of PRP vaccine failure in the US began to appear soon after its FDA approval." Results of large trials conducted in this country were less promising than those performed in Finland. Five case-control studies and one retrospective cohort study reported widely varying and generally lower protective efficacy rates compared with those in the Finnish study (Table 1).41-45 Osterholm et al. reported markedly differing results compared with those of the other four case-control studies." Thus, although their investigation was originally part of a larger multicenter study," these data were published separately. Osterholm et al. reported a protective PRP vaccination efficacy rate of -55 percent (95 percent CI, -238 to 29 percent). This suggests that the vaccinated group of patients that they evaluated was at higher risk for developing Hib disease compared with a placebo group. However, there was no statistical difference between the two groups, as evidenced by the fact that the 95 percent CI crossed O. The authors concluded that the vaccine was not effective in preventing Hib disease in their patients." In contrast, Shapiro et al. report-

Secondary Antigen Challenge

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Figure 2. Simplified schematic ofT-ceil-independent immune response.

Table I. United States Polyribosylribitol Phosphate (Unconjugated) Vaccine Efficacy Studies PATIENT AGES" (mo)

STUDY

Retrospective cohort Kaiser' Case-control Kaiser' CDC Multicenter Minnesota CDC

23-72 23-72 18-59 24-72 24-71 24-59

PROTECTIVE EFFICACyb (%)

68 (4 to 89) 62 (-44 to 90) 45 (-I to 70) 88 (74 to 96) -55 (-238 to 29) 62 (0 to 85)

REF.

41 41 42 43 44 45

CDC = Centers for Disease Control. "Age at the time of Haemophilus influenzae type b disease. b95 percent confidence interval in parentheses. C Assignments of control populations differed between analyses.

ed an overall protective efficacy rate of 88 percent (95 percent CI, 74-96 percent) with the vaccine in their multicenter trial." There is no proven explanation for these discrepant results. Weinberg and Granoff have suggested that genetic differences among populations may be responsible for differing vaccine efficacies." Another possible explanation may be a regional difference in the exposure to crossreactive, enteric organisms that may prime the immune system against Hib. 16,20 These controversial results eventually led to a revision in the recommendations for Hib vaccination set forth by the American Academy of Pediatrics stating that immunization with PRP vaccine may be deferred in areas where the vaccine has not been shown to be effective."

Second-Generation Conjugate Vaccines Despite the demonstrated efficacy of the PRP vaccine in many children older than 18-24 months of age, there still remained a need for a highly immunogenic and consistently effective vaccine in children younger than 24 months of age. In December 1987, the first of the second-generation conjugate vaccines was licensed." Conjugating (covalent coupling) a polysaccharide to a carrier protein molecule increases the immunogenicity of a vaccine by eliciting a Tcell-dependent immune response." Characteristics of the Hib conjugate vaccines include: (1) enhanced immunogenicity, resulting in increased antibody production (including in children younger than 18 months of age) and (2) ability to produce an anamnestic antibody response upon re-exposure to the antigen." There are three carrier pro-

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teins used in the Hib conjugate vaccines that are currently marketed in the US: diphtheria toxoid, CRM 197 (a nontoxic mutant diphtheria toxin), and meningococcal outer membrane protein (OMP) (Figure 3).22 A fourth conjugate vaccine using tetanus toxoid as the carrier protein is being investigated. Table 2 briefly compares these four vaccines. Each vaccine's polysaccharide-protein complex has different immunogenic properties that depend on the type of carrier protein and the method used for complexation.Pv" Consequently, antibody production in vaccinated children differs among the products. As previously noted, however, it is difficult to interpret and compare anti-PRP antibody concentrations. Specifically, the following factors must be considered: (I) the length of time after vaccination, (2) the type of antibody assay performed, (3) functional differ-

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