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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Appendix D-3 The Prospects for Immunizing Against Hemophilus influenzae Type b DISEASE DESCRIPTION Hemophilus influenzae type b is a major cause of meningitis in young children. Neurological sequelae, including hearing and vision loss, motor abnormalities, seizure disorders, severe mental retardation, and quadriplegia, may follow the meningitis (Norden, 1982). The occurrence and characteristics of meningitis caused by H. influenzae type b in developing countries have been described by Cadoz and coworkers (1981, 1983). Other invasive forms of the disease include epiglottitis, pneumonia, bacteremia, and cellulitis. Very little literature exists on nonmeningitic illnesses caused by H. influenzae type b in the developing world. Much of the following discussion is based on information from the United States and presumes that the disease process is similar throughout the world. Studies indicate that H. influenzae first colonizes the nasopharynx and then penetrates the mucosa. Capsulated H. influenzae strains are responsible for most severe illness, although noncapsulated strains have been associated with some infections, such as otitis media. Of the six encapsulated strains, type b is by far the most common cause of invasive disease (Norden, 1982). Host intervention through the production of anticapsular antibodies can prevent disease. The mechanism by which virulent H. influenzae organisms gain access to the blood is not known, but a bacteremic phase that is generally asymptomatic precedes invasion of the meninges. Whether the organism will go on to cause meningitis depends on its virulence and the immune status of the host. Invasion of the cerebrospinal fluid is followed by the usual symptoms of bacterial meningitis, which if not treated promptly is often fatal. The committee gratefully acknowledges the efforts of C.Frasch, who prepared major portions of this appendix, and the advice and assistance of C.V.Broome, S.L.Cochi, L.K.Gordon, D.M.Granoff, J.M.Griffiss, A.L.Reingold, J.B.Robbins, and J.I.Ward. The committee assumes full responsibility for all judgments and assumptions.
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries A polysaccharide-based vaccine for H. influenzae type b was licensed in the United States in April 1985. An improved vaccine is desirable for the reasons discussed in the last section of this appendix. PATHOGEN DESCRIPTION Noncapsulated H.influenzae strains, although common, are largely avirulent. There are six serotypes of H. influenzae with immunochemically distinct capsular polysaccharides (Egan et al., 1982). They are identified as types a, b, c, d, e, and f. Almost all invasive H. influenzae disease is caused by type b (Norden, 1982). Thus, a vaccination program can be directed against a single type. Studies on the noncapsular surface antigens of H. influenzae type b in several laboratories have revealed a number of distinct strains within type b (Hansen et al., 1982a; Loeb and Smith, 1980). The relative prevalence of these different strains as a cause of disease varies with geographic locale. More than 20 different subtypes have been identified, but 5 or 6 account for most H. influenzae type b illness (Hansen et al., 1982a; Loeb and Smith, 1980). Subtyping is primarily of epidemiologic value, because all type b strains are killed by anti-type b polysaccharide antibodies. The type b polysaccharide has been purified and its structure determined. The repeating unit is → 3)-β-D-ribose-(1 → 1)-ribitol-5-phosphate. HOST IMMUNE RESPONSE Protection against invasive H. influenzae disease is due primarily to humoral immunity (Solotorovsky and Lynn, 1978). Protective antibodies are induced to both the capsular polysaccharide and major outer membrane surface proteins. Classic studies by Fothergill and Wright (1933) demonstrated an inverse relationship between the development of bactericidal antibodies and the age-related incidence of H. influenzae disease. The same inverse relationship has been demonstrated for antibodies directed against the type b capsular polysaccharide (Anderson et al., 1977). Following the decline of maternally acquired immunity between 2 and 3 months of age, bactericidal antibodies generally are not detectable for about 3 years. They then rise slowly, reaching adult levels by about age 8. However, there is considerable individual variability in the pattern of antibody changes. Clinical studies suggest a positive correlation between the presence of anti-type b antibodies and the relative absence of H. influenzae disease in children older than 5 years of age (Peltola et al., 1977). Passive protection studies in animals, primarily the infant rat, provide further evidence for the protective effects of antibodies against type b polysaccharide (Myerowitz and Norden, 1977). There is strong evidence from the Finnish studies of the capsular polysaccharide (polyribophosphate) vaccine for the protective role of
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries antibody in older children (Peltola et al., 1984). However, the committee believes the focus should be directed toward a vaccine that would be effective in younger children because of the distribution of the disease described below. DISTRIBUTION OF DISEASE Geographic Distribution H. influenzae type b disease occurs worldwide. The pattern of disease in developing countries is similar to that in the United States with two exceptions. The first is that the disease occurs at a younger age: 40 to 50 percent of cases occur between 6 and 9 months of age. The second is that the mortality rate for H. influenzae type b meningitis can reach 40 percent even with treatment, in contrast to 5 percent for treated cases in the United States (Cadoz et al., 1983; Cochi, personal communication, 1983; Griffiss, personal communication, 1985; Hill, 1983; Norden, 1982). Also, about 30 to 40 percent of survivors exhibit neurological sequelae (Cadoz et al., 1983; Griffiss, personal communication, 1985). Disease Burden Estimates Very few studies are available on which to base estimates of the burden of disease from H. influenzae type b in developing countries. The most comprehensive reports appear to be those of Cadoz et al. (1981, 1983). These, however, are for a single location, Dakar, Senegal, and reflect a population with access to hospital care. The authors reported that H. influenzae meningitis was most frequent between 6 months and 2 years of age, rarely occurring before 2 months or after 5 years. Ninety-seven percent of cases were caused by type b. The incidence for infants and children under 5 years was 60 cases per 100,000 (Cadoz et al., 1983). This rate is slightly higher than that observed for typical U.S. populations, but lower than that reported for Navajo Indian and Alaskan Eskimo populations (Norden, 1982). For the disease burden calculation, the rate reported by Cadoz et al. (1983) is assumed to be reasonably representative of that in all developing countries. Fatality rates for H. influenzae type b meningitis are assumed to be 33 percent, and neurological sequelae are assumed to occur in 33 percent of survivors (Cadoz et al., 1983; Griffiss, personal communication, 1985). Table D-3.1 shows the disease burden due to meningitis caused by H. influenzae type b. Sequelae are assumed to be distributed in severity in about the same proportion as those in the United States (Institute of Medicine, 1985). The number of cases of nonmeningitic H. influenzae type b invasive disease can be estimated only by analogy with the situation in the United States. Various studies in the United States have reported that nonmeningitic conditions account for 30 to 80 percent of invasive illness caused by all types of H. influenzae (Institute of Medicine,
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-3.1 Morbidity and Mortality Associated with Hemophilus influenzae Type b Meningitisa Cases Number of cases of meningitis (morbidity category C) (60/100,000 infants and children under 5 years of age, i.e., 498.6 million) 299,000 Fatalities (33 percent of cases) 99,000 Survivors (33 percent sustain sequelae) 200,000 Distribution of sequelae Morbidity category D (12 percent of cases) 24,000 Morbidity category E (15 percent of cases) 30,000 Morbidity category F (6 percent of cases) 12,000 aAll cases assumed to occur in infants and children under 5 years of age. TABLE D-3.2 Morbidity and Mortality Associated with Nonmeningitic Hemophilus influenzae Type b Invasive Disease Cases Number of cases pneumonia, bacteremia, and epiglottitis (morbidity category C) 299,000 Age distribution of cases Under 5 years (70 percent) 209,000 5–14 years (10 percent) 30,000 15–59 years (15 percent) 45,000 60 years and over (5 percent) 15,000 Total fatalities (15 percent) 45,000 Age distribution of fatalities Under 5 years (70 percent) 32,000 5–14 years (10 percent) 5,000 15–59 years (15 percent) 7,000 60 years and over (5 percent) 2,000
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries 1985). To estimate the total burden of illness from H. influenzae type b it is assumed that the ratio of meningitis to nonmeningitic invasive disease is 50:50. Thus, the number of cases in the developing world is 299,000. (An obvious potential source of error in this estimate is the greater relative frequency of invasive lower respiratory tract disease in the developing world as compared to the United States.) The case fatality rate of these conditions (pneumonia, bacteremia, epiglottitis) is assumed to be about 15 percent. The age distribution of nonmeningitic invasive H. influenzae type b cases is assumed to be somewhat similar to the distribution assumed for the United States (i.e., under 5 years, 70 percent; 5–14 years, 10 percent; 15–59 years, 15 percent; 60 years and over, 5 percent [Institute of Medicine, 1985]). It is assumed that the occurrence of chronic sequelae arising from nonmeningitic invasive disease is negligible. Table D-3.2 shows the disease burden associated with nonmeningitic H. influenzae type b. Table D-3.3 shows the total disease burden resulting from H. influenzae type b meningitis (Table D-3.1) and other invasive disease (Table D-3.2). The estimated durations shown for category C illness under 5 years of age (12 days) is intermediate between that estimated for meningitis (14 days) and that estimated for other invasive disease (10 days). All episodes over 5 years of age are assumed due to nonmeningitic disease (duration about 10 days). PROBABLE VACCINE TARGET POPULATION The distribution of H. influenzae illness is described above. Up to 2 to 3 months of age, most infants exhibit declining maternal antibodies. In the developing world, most illness probably occurs between 4 and 12 months of age (Cadoz et al., 1983). Hence, the target population for active immunization probably will be all infants at about 2 to 3 months of age. Such a vaccine could readily be incorporated into the delivery schedules of the World Health Organization Expanded Program on Immunization (WHO-EPI). An earlier age of initial immunization may be practicable if a vaccine can be developed that induces immunity in younger infants. Vaccine Preventable Illness* The H. influenzae type b vaccine probably would be administered first at about 2 to 3 months of age when maternal antibody has * Vaccine preventable illness is defined as that portion of the disease burden that could be prevented by immunization of the entire target population (at the anticipated age of administration) with a hypothetical vaccine that is 100 percent effective (see Chapter 7).
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries TABLE D-3.3 Disease Burden: Hemophilus influenzae type b—Meningitis and Nonmeningitis Invasive Disease Under 5 Years 5–14 Years 15–59 Years 60 Years and Over Morbidity Category Description Number of Cases Duration Number of Cases Duration Number of Cases Duration Number of Cases Duration A Moderate localized pain and/or mild systemic reaction, or impairment requiring minor change in normal activities, and associated with some restriction of work activity B Moderate pain and/or moderate impairment requiring moderate change in normal activities, e.g., housebound or in bed, and associated with temporary loss of ability to work C Severe pain, severe short-term impairment, or hospitalization 508,000 12 30,000 10 45,000 10 15,000 10 D Mild chronic disability (not requiring hospitalization, institutionalization, or other major limitation of normal activity, and resulting in minor limitation of ability to work) 24,000 n.a. n.a. n.a. n.a. E Moderate to severe chronic disability (requiring hospitalization, special care, or other major limitation of normal activity, and seriously restricting ability to work) 30,000 n.a. n.a. n.a. n.a. F Total impairment 12,000 n.a. n.a. n.a. n.a. G Reproductive impairment resulting in infertility n.a. n.a. n.a. n.a. H Death 131,000 n.a. 5,000 n.a. 7,000 n.a. 2,000 n.a.
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries declined. Because the immune response at this age is limited, no vaccine would be likely to reach full protective efficacy until after further doses had been administered. Meningitis incidence begins to rise rapidly after 4 months of age, peaks at 6 to 8 months, and declines to become relatively rare after 2 years of age (Cadoz et al., 1983). Only partial protection would be provided until 2 to 3 doses of vaccine had been administered to infants. About 20 percent of meningitic illness occurs before 6 months of age (Cadoz et al., 1983); hence, about 80 percent of meningitis is considered vaccine preventable and all other invasive disease—most of which occurs at an older age—should be preventable. Because the number of cases of meningitis is assumed to equal the number of cases of other invasive disease, about 90 percent of invasive illness caused by H. influenzae type b would be preventable with a vaccine that is 100 percent effective (after 2 to 3 doses) and that is delivered to the entire target population. SUITABILITY FOR VACCINE CONTROL Invasive disease caused by H. influenzae type b is well suited to control by active immunization because antibody appears to provide protection and because an opportunity to induce immunity exists between the decline of maternal antibodies (2 to 3 months) and the peak of illness (see above). Alternative Control Measures and Treatments Current treatment regimens are not satisfactory because chronic central nervous system sequelae often occur despite antibiotic therapy (Hill, 1983). Chemoprophylactic agents (e.g., rifampin [Band et al., 1984]) and passive immunization (with hyperimmune globulin) are possible post-exposure means of controlling secondary spread of disease; however, secondary disease probably represents a small proportion of the total disease burden, and these agents are not as practical as prevention in developing countries. Success in vaccine prevention of invasive disease, particularly meningitis, will depend on the development of a vaccine capable of inducing immunity in infants. Progress toward this goal is described below. PROSPECTS FOR VACCINE DEVELOPMENT Two major approaches have been taken toward development of an effective vaccine against invasive H. influenzae type b disease: (1) use of the purified type b capsular polysaccharide, and (2) preparation of polysaccharide-protein or oligosaccharide-protein conjugates. A third approach has been to use outer membrane protein vaccines. The first two approaches have been evaluated clinically; a major field
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries trial utilizing the purified capsular polysaccharide was carried out in 1974 in Finland (Peltola et al., 1977). The outer membrane protein vaccines have been examined only in animal models and are protective in these models (Hansen et al., 1982b; Shenep et al., 1983). The Finnish study involved use of an H. influenzae type b polysaccharide vaccine as a control in a group A meningococcal polysaccharide vaccine field trial. The Hemophilus vaccine was administered to approximately 49,000 children, 3 months to 5 years of age (Mäkelä et al., 1977; Peltola et al., 1977). There were no significant adverse reactions to the vaccine, but erythema and tenderness at the injection site were common. The vaccine currently licensed in the United States apparently produces such reactions less frequently (Broome, personal communication, 1985). The vaccine proved to be effective in preventing H. influenzae type b disease in children over about 18 months of age; but the vaccine was without protective effect in younger children (Peltola et al., 1984; Pincus et al., 1982). From these efficacy studies, it appears that a purified polysaccharide vaccine (which was licensed in the United States in April 1985) could prevent a substantial amount of invasive H. influenzae type b disease, but a conjugated vaccine (as envisaged in Table 5.1) probably would improve on this (especially in preventing meningitis) for the reasons discussed below. Antibody studies on children immunized with the polysaccharide vaccine show an age-related response: fewer than 10 percent of infants less than 6 months of age respond, about 40 percent between 6 and 12 months respond, and 80 percent or more respond after 24 months of age (Pincus et al., 1982). The success of the polysaccharide vaccine is thus limited by its poor immunogenicity in the age groups at greatest risk. For this reason, several alternative approaches have been investigated (Hill, 1983). They include: (1) mixing the polysaccharide with pertussis organisms (Williams et al., 1982); (2) covalently coupling the polysaccharide to a protein carrier (Schneerson et al., 1980); (3) covalently coupling oligosaccharides derived from the type b polysaccharide to a protein carrier (Anderson, 1983); and (4) use of outer membrane protein vaccines (Shenep et al., 1983). The first alternative, mixture of the polysaccharide with Bordetella pertussis cells as an adjuvant, has been evaluated as single and multiple injections in infants and young children (Williams et al., 1982). In some studies the combination appeared to be more immunogenic than the type b polysaccharide alone, but these vaccines were significantly more reactogenic than the pure polysaccharide. The polysaccharide-protein conjugate vaccines hold considerable promise as candidate vaccines. These vaccines are based on observations that coupling of polysaccharide antigens to protein carriers can alter the immune response to the polysaccharide (Schneerson et al., 1980). The polysaccharide is converted from a T-cell independent antigen to one that can recruit T-helper cells. Clinical trials have demonstrated that a conjugate vaccine, prepared using high-molecular-weight polysaccharide attached to diphtheria is clearly superior to the polysaccharide alone in children under 3 years of age. It induces antibody levels above those considered to be protective in 100 percent
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries of children over 9 months of age (Lepow et al., 1985) and 90 percent of infants (Eskola et al., 1985). These results have been confirmed in clinical studies conducted with the PRP-D vaccine in over 2,000 children between 2 and 24 months of age (Gordon, personal communication, 1985). The National Institutes of Health-National Institute of Allergy and Infectious Diseases initiated an efficacy study with this vaccine in Alaska in 1984. This vaccine may be available for use in pediatric immunization programs within the next 1 to 2 years. Successful immunization of infants with conjugates appears likely to require at least two doses. The other approach to conjugate vaccines is to couple small oligosaccharides, derived from the type b polysaccharide, to diphtheria toxoid (Anderson, 1983). These vaccines also are immunogenic in young children. Neither conjugate vaccine appears to be reactogenic in children (King et al., 1981); however, additional studies are required to determine their overall acceptability. Preliminary studies suggest that concurrent use of the polysaccharide-protein conjugate vaccine with the DTP vaccine has been shown to enhance the immune response to the free toxoid (Zahradnik and Gordon, 1984). In conclusion, the purified type b polysaccharide has been demonstrated to be effective in children over 18 months of age, but not useful in children under 18 months of age. The polysaccharide-protein and oligosaccharide-protein conjugate vaccines are clearly more immunogenic than the polysaccharide alone in younger children. Predictions on the further development of a vaccine for H. influenzae type b appear in Chapter 5. REFERENCES Anderson, P. 1983. Antibody responses to Haemophilus influenzae type b and diphtheria toxin induced by conjugates of oligosaccharides of the type b capsule with the nontoxin protein CRM 197. Infect. Immun. 39(1):233–238. Anderson, P., D.H.Smith, D.L.Ingram, J.Wilkins, P.F.Wherle, and V.M.Howie. 1977. Antibody of polyribophosphate of Haemophilus influenzae type b in infants and children: Effect of immunization with polyribophosphate. J. Infect. Dis. 136(suppl.):S57–S62. Band, J.D., D.W.Fraser, G.Ajello, and Hemophilus influenzae Disease Study Group. 1984. Prevention of Hemophilus influenzae type b disease. JAMA 251(18):2381–2386. Broome, C.V. 1985. Personal communication, Centers for Disease Control, Atlanta, Ga. Cadoz, M., F.Denis, and I.Diop Mar. 1981. An epidemiological study of purulent meningitis cases admitted to hospitals in Dakar, 1970–1979 (in French). Bull. Organ. Mond. Santé 59(4)575–584. Cadoz, M., M.Prince-David, I.Diop Mar, and F.Denis. 1983. Haemophilus influenzae meningitis in Africa: Epidemiology and prognostic (901 cases) (in French). Path. Biol. 31(2):128–133.
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Cochi, S.L. 1983. Personal communication. Centers for Disease Control, Atlanta, Ga. Egan, W.M., F.-P.Tsui, and G.Zon. 1982. Structural studies of the Haemophilus influenzae capsular polysaccharides. Pp. 185–196 in Haemophilus influenzae, S.H.Sell and P.P.Wright, eds. New York: Elsevier Science. Eskola, J., H.Peltola, P.H.Mäkelä, H.Käyhty, V.Karanko, J.Samuelson, and L.K.Gordon. 1985. Antibody levels achieved in infants by course of Haemophilus influenzae type b polysaccharide/ diphtheria toxoid conjugate vaccine. Lancet I:1184–1186. Fothergill, L.D., and J.Wright. 1933. Influenzal meningitis; relation of age incidence to the bactericidal power of blood against the causal organism. J. Immunol. 24:273–284. Gordon, L.K. 1985. Personal communication, Connaught Research Institute, Ontario, Canada. Griffiss, J.M. 1985. Personal communication, School of Medicine, University of California, San Francisco. Hansen, E.J., C.F.Frisch, K.H.Johnston. 1982a. Cell envelope proteins of Haemophilus influenzae type b: Potential vaccination candidates. Pp. 197–206 in Haemophilus influenzae, S.H.Sell and P.F.Wright, eds. New York: Elsevier Science. Hansen, E.J., S.M.Robertson, P.A.Gulig, C.F.Frisch, E.J.Haanes. 1982b. Immunoprotection of rats against Haemophilus influenzae type b disease mediated by monoclonal antibody against a Haemophilus outer-membrane protein. Lancet I (8268):366–368. Hill, J.C. 1983. Summary of a workshop on Haemophilus influenzaetype b vaccines. J. Infect. Dis. 148:167–175. Institute of Medicine. 1985. New Vaccine Development: Establishing Priorities, Volume I. Diseases of Importance in the United States. Washington, D.C.: National Academy Press. King, S.D., A.Ramlal, H.Wynter, K.Moodie, D.Castle, J.S.C.Kuo, L. Barnes, and C.L.Williams. 1981. Safety and immunogenicity of a new Haemophilus influenzae type b vaccine in infants under one year of age. Lancet II (8249):705–709. Lepow, M.L., J.S.Samuelson, and L.K.Gordon. 1985. Safety and immunogenicity of Haemophilus influenzae type b-polysaccharide diphtheria toxoid conjugate vaccine in infants 9 to 15 months of age. J. Pediatrics 106:185–189. Loeb, M.R., and D.H.Smith. 1980. Outer membrane protein composition in disease isolates of Haemophilus influenzae: Pathogenic and epidemiological implication. Infect. Immun. 30(3):709–717. Mäkelä, P.H., J.Peltola, H.Käyhty, H.Jousimies, O.Pettay, E. Ruoslahti, A.Sivonen, and O.-V.Renkonen. 1977. Polysaccharide vaccine of group A Neisseria meningtitidis and Haemophilus influenzae type b: Field trial in Finland. J.Infect. Dis. 136(Suppl.):S43–50. Myerowitz, R.L., and C.W.Norden. 1977. Immunology of the infant rat experimental model of Haemophilus influenzae type b meningitis. Infect. Immun. 16 (1):218–225.
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New Vaccine Development: Establishing Priorities, Volume II, Diseases of Importance in Developing Countries Norden, C.W. 1982. Haemophilus influenzae type b. pp. 259–273 in Bacterial Infections of Humans, A.S.Evans and H.A.Feldman, eds. New York: Plenum. Peltola, H., H.Käyhty, A.Sivonen, and P.H.Mäkelä. 1977. Haemophilus influenzae 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. Pediatrics 60:730–737. Peltola, H., H.Käyhty, M.Virtanen, and H.Mäkelä. 1984. Prevention of Hemophilus influenzae type b bacteremic infections with the capsular polysaccharide vaccine. N.Engl. J.Med. 310(24):1561–1566. Pincus, D.J., D.Morrison, C.Andrews, E.Lawrence, S.H.Sell, and P.F.Wright. 1982. Age-related response to two Haemophilus influenzae type b vaccines. J.Pediatr. 100:197–201. Schneerson, R., O.Barrera, A.Sutton, and J.B.Robbins. 1980. Preparation, characterization, and immungenicity of Haemophilus influenzae type b polysaccharide-protein conjugates. J. Exp. Med. 152:361–376. Shenep, J.L., R.S.Munson, Jr., S.J.Barenkamp, and D.M.Granoff. 1983. Further studies of the role of noncapsular antibody in protection against experimental Haemophilus influenzae type b bacteremia. Infect. Immun. 42(1):257–263. Solotorovsky, M., and M.Lynn. 1978. Haemophilus influenzae: Immunology and immunoprotection. CRC Crit. Rev. Microbiol. 6(1):1–32. Williams, C.L., L.Barnes, and J.S.C.Kuo. 1982. Clinical studies of an Haemophilus influenzae type b PRP vaccine with a Bordetella pertussis adjuvant in infants. Pp. 285–295 in Haemophilus influenzae, S.H.Sell and P.F.Wright, eds. New York: Elsevier Science.
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