Adverse Events Associated with Childhood Vaccines Evidence Bearing on Causality (1994) / Chapter Skim
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9 Haemophilus Influenzae Type B Vaccines
9 Haemophilus Influenzae Type B Vaccines
Pages 236-273
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From page 236... ...
The mortality rate for children with meningitis was 3 to 6 percent, and 20 to 30 percent of survivors had permanent sequelae, including hearing loss, mental retardation, and seizure disorders (Cochi et al., 19851. Nearly 75 percent of cases of Hib disease occurred in children younger than 2 years of age, and the susceptibility of young children to infection with Hib correlated with their lack of antibody to the type b capsular polysaccharide, polyribosylribitol phosphate (PRP)
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From page 237... ...
Thus, in consideration of the side effects of Hib conjugate vaccines, it is plausible that variations in the type or frequency of adverse effects may occur because of differences in the polysaccharide or protein components of the vaccines. Routine immunization of infants with Hib conjugate vaccine in a multiple-dose schedule is now recommended in the United States (American Academy of Pediatrics, Committee on Infectious Diseases, l991b; Centers for Disease Control, 1991a)
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From page 238... ...
Following the widespread distribution and administration of Hib conjugate vaccines, few cases of vaccine failure (a case of Hib disease occurring more than 14 days after the second or third doses) have been reported (Black et al., 1992a; Holmes et al., 1991; Santosham et al., 1992)
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From page 239... ...
The risk of developing a Hib infection within the first 7 days following immunization with Hib vaccines is discussed later in this chapter. Rates of local reactions to Hib vaccines, such as pain, tenderness, swelling, and erythema at the site of injection, have varied from study to study, but the overall reaction rates to plain PRP vaccines are lower than those to conjugate vaccines.
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From page 240... ...
The conjugate vaccines also induce larger amounts of anti-PRP antibodies in vaccinees of all ages, and they induce an anti-PRP antibody response in many individuals who do not respond well to natural infection with Hib or to the plain PRP vaccine, including patients with Hib disease before the age of 2 years and those with splenectomy; sickle cell disease; malignancy; IgG2 deficiency; Navajo, Apache, and Alaskan natives; and allogeneic bone marrow recipients (Barre et al., 1992; Edwards et al., 1989; Feldman et al., 1990; Frank et al., 1988; Gigliotti et al., 1989, 1991; Granoff et al., 1989; Kafidi and Rotschafer, 1988; Kaplan et al., 1988; Marcinak et al., 1991; Rubin et al., 1989, 1992; Santosham et al., 1992; Siber et al., 1990; Steinhoff et al., 1991; Walter et al., 1990; Weinberg and Granoff, 1990; Weisman et al., 19871. It is evident that the different Hib vaccines produce not only different quantities of anti-PRP antibody but also that this antibody differs in such characteristics as IgG subclass, avidity, and affinity (Ambrosino et al., 1992;
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From page 241... ...
Good immune responses to the conjugate vaccines have been demonstrated as soon as 1 week after immunization in older children and adults (Daum et al., 1989; Marchant et al., 19891. Unlike plain PRP vaccines, PRP conjugate vaccines stimulate memory B cells capable of generating booster responses to immunization with either plain PRP or PRP conjugate vaccines and, thus, presumably, to the intact Hib organism (Weinberg et al., 1987~.
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From page 242... ...
There have been no cases of transverse myelitis reported in any case series or uncontrolled observational studies of Hib vaccines (Ahonkhai et al., 1990, 1991; Black et al., 1987; Claesson et al., 1991; Fritzell and Plotkin, 1992; Milstien et al., 1987; Parke et al., 1991; Popejoy et al., 1989; Rowe et al., 1990; Santosham et al., 1991a; Vadheim et al., 19901.
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From page 243... ...
The patient for whom sufficient documentation of transverse myelitis was provided also had received DPT, OPV, and MMR. No cases of transverse myelitis have been reported following administration of the other Hib vaccines, nor have any cases been reported in the literature.
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From page 244... ...
Case Reports, Case Series, and Uncontrolled Observational Studies A total of seven cases labeled GBS have been described following immunization with the three Hib conjugate vaccines that are currently licensed for use in the United States. The three cases following administration of the PRP-D vaccine noted above occurred during a period when approximately 6.2 million doses of PRP-D vaccine were distributed (D'Cruz et al., 1989~.
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From page 245... ...
The other three reports of GBS following the administration of Hib conjugate vaccines were detected by VAERS (submitted between November 1990 and July 1992~. Two of the three children developed an infection between the time of immunization and the onset of the necrologic symptoms.
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From page 246... ...
Seven cases labeled as GBS were reported to occur following immunization with three different Hib conjugate vaccines over a period when an estimated several million doses of Hib conjugate vaccines were distributed. Five of these cases fit the criteria for possible vaccine-related GBS discussed in Chapter 3.
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From page 247... ...
Thirty subjects were randomly assigned to receive two doses of either the PRP or the PRP-D vaccine. Because this was one of the first trials of Hib conjugate vaccine in human subjects, multiple hematologic, renal, and hepatic tests were performed after the administration of each dose.
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From page 248... ...
Case Reports, Case Series, and Uncontrolled Observational Studies Five cases of thrombocytopenia following immunization for Hib were reported through VAERS between November 1990 and July 1992, a period during which approximately 29.5 million doses of Hib vaccine were distributed in the United States (a rough estimate based on 1991 data provided by the Centers for Disease Control)
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From page 249... ...
Controlled Clinical Trials In several large prospective trials of PRP and Hib conjugate vaccine efficacy and safety (Black et al., 1987, l991b; Eskola et al., 1990a; Peltola et al., 1977; Santosham et al., l991b; Vadheim et al., 1990) , no subjects developed petechiae or purpura.
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From page 250... ...
The annual incidence of Hib has decreased dramatically with the introduction of Hib vaccines. History of Suspected Association In conducting vaccine efficacy trials for Hib vaccines, investigators expected to observe a number of vaccine "failures" (i.e., none of the Hib vaccines was likely to be 100 percent effective in the prevention of disease, particularly after administration of a single dose to young infants)
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From page 251... ...
Evidence for Association Biologic Plausibility PRP vaccine contained only purified capsular polysaccharide, so the early-onset cases of Hib infection could not have been caused by infectious material in the vaccine itself. Several investigators postulated that the apparent increased susceptibility to infection in the immediate postimmunization period might be related to a transient decrease in preexisting antibody caused by the formation of complexes of antigen with antibody or by transient suppression of antibody synthesis (Merchant et al., 1989; Sood and Daum, 19901.
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From page 252... ...
The conjugate vaccines varied in their ability to reverse passive immunity in rats, a phenomenon that may be related to variations in the binding of anti-capsular antibody to the different vaccine antigens (Sood and Daum, 1990~. The demonstration of detectable antigenuria in many children for as long as 7 days following immunization with PRP vaccine (Spinola et al., 1986)
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From page 253... ...
demonstrated that PRP vaccine induces high antibody responses within 6 to 9 days after vaccination when given to 12-month-old infants who were previously vaccinated with Hib conjugate vaccine beginning at 2 months of age. Proof that transient suppression of preexisting antibody may be associated with increased susceptibility to Hib disease can come only from epidemiologic studies of recently immunized versus unimmunized populations.
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From page 254... ...
Among children immunized at 18-71 months of age, no cases of Hib disease were observed within the 7-day interval following immunization. Among 37,393 children immunized with Hib vaccine, 2 developed bacteremic Hib infection (20 and 21 months after receiving vaccine, respectively)
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From page 256... ...
Uncontrolled Observational Studies, Controlled Observational Studies, and Controlled Clinical Trials (Hib conjugate vaccines) Studies that bear on the risk of early Hib disease in recipients of the more recently developed Hib conjugate vaccines (first dose only)
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From page 257... ...
and the small immunogenicity studies did not include control groups, metaanalysis could not be used to estimate the relative risk of early Hib disease following receipt of the conjugate vaccines. Nonetheless, a pooled relative risk can be estimated from the ratio of the total number of observed cases among vaccine recipients in all of the studies combined (i.e., ignoring the control groups of Black et al.
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259 oo .
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From page 260... ...
However, the immunologic data showing rapid development of high antibody levels in previously immunized children given PRP vaccine at 12 months of age suggest that these children, like unimmunized children receiving Hib conjugate vaccine, would not be at increased risk of Hib disease in the early postvaccination interval. Conclusion The evidence favors acceptance of a causal relation between unconjugated PRP vaccine and early-onset Hib disease in children over 18 months of age who receive their first Hib immunization with unconjugated PRP vaccine.
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From page 261... ...
The evidence favors rejection of a causal relation between immunization with Hib conjugate vaccines and early-onset Hib disease. The evidence is inadequate to accept or reject a causal relation between PRP vaccine and early-onset disease in individuals who previously received one or more doses of Hib conjugate vaccine.
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From page 262... ...
Controlled Observational Studies and Controlled Clinical Trials None of the controlled studies identified by the committee contained reports of anaphylaxis in association with the administration of any Hib vaccine. Causality Argument There is biologic plausibility that Hib vaccines, like all foreign proteins, could cause anaphylaxis.
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From page 263... ...
The risk would appear to be extraordinarily low. The evidence favors rejection of a causal relation between conjugated Hib vaccines and death from early-onset Hib disease.
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From page 264... ...
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.
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From page 265... ...
Serum opsonic activity after immunization of adults with Haemophilus influenzae type lo-diphtheria toxoid conjugate vaccine. Infection and Immunity 1985;48:183-189.
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From page 266... ...
Food and Drug Administration approval of use of a new Haemophilus b conjugate vaccine and a combined diphtheria-tetanus-pertussis and Haemophilus b conjugate vaccine for infants and children. Morbidity and Mortality Weekly Report 1993;42:296-298.
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From page 267... ...
The clinical and immunologic response of Chilean infants to Haemophilus influenzae type b polysaccharide-tetanus protein conjugate vaccine coadministered in the same syringe with diphtheria-tetanus toxoids-pertussis vaccine at two, four and six months of age. Pediatric Infectious Disease Journal 1991; 10:764-771.
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From page 268... ...
Induction of immunologic memory in infants primed with Haemophilus influenzae type b conjugate vaccines. Journal of Infectious Diseases, In press.
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From page 269... ...
Safety and immunogenicity of Haemophilus influenzae type b polysaccharide-diphtheria toxoid conjugate vaccine in adults. Journal of Infectious Diseases 1984b; 150:402-406.
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From page 270... ...
Depression of anticapsular antibody after immunization with Haemophilus influenzas type b polysaccharide-diphtheria conjugate vaccine. Pediatric Infectious Disease Journal 1989;8:508-511.
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From page 271... ...
Safety and immunogenicity of a Haemophilus influence type b conjugate vaccine in a high risk American Indian population. Pediatric Infectious Disease Journal l991a;10:113-117.
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From page 272... ...
Functional characterization of human IgG, IgM, and IgA antibody directed to the capsule of Haemophilus influenzae type b. Journal of Infectious Diseases 1986;153:8-16.
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From page 273... ...
Weinberg GA, Granoff DM. Immunogenicity of Haemophilus influenzae type polysaccharideprotein conjugate vaccines in children with conditions associated with impaired antibody responses to type b polysaccharide vaccine.
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