A case-control study of risk factors for Haemophilus influenzae type B disease in Navajo children.
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To understand the potential risk factors and protective factors for invasive Haemophilus influenzae type b (Hib) disease, we conducted a case-control study among Navajo children less than two years of age resident on the Navajo Nation. We analyzed household interview data for 60 cases that occurred between August 1988 and February 1991, and for 116 controls matched by age, gender, and geographic location. The Hib vaccine recipients were excluded from the analyses. Conditional logistic regression models were fit to examine many variables relating to social and environmental conditions. Risk factors determined to be important were never breast fed (odds ratio [OR] = 3.55, 95% confidence interval [CI] = 1.52, 8.26), shared care with more than one child less than two years of age (OR = 2.32, 95% CI = 0.91, 5.96); wood heating (OR = 2.14, 95% CI = 0.91, 5.05); rodents in the home (OR = 8.18, 95% CI = 0.83, 80.7); and any livestock near the home (OR = 2.18, 95% CI = 0.94, 5.04). (+info)
Efficacy of Haemophilus influenzae type b conjugate vaccines and persistence of disease in disadvantaged populations. The Haemophilus Influenzae Study Group.
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OBJECTIVES: The purpose of this study was to evaluate the effectiveness of Haemophilus influenzae type b (Hib) conjugate vaccines among children aged 2 to 18 months and to determine risk factors for invasive Hib disease during a period of declining incidence (1991-1994). METHODS: A prospective population-based case-control study was conducted in a multistate US population of 15.5 million. A laboratory-based active surveillance system was used for case detection. RESULTS: In a multivariate analysis, having a single-parent mother (odds ratio [OR] = 4.3, 95% confidence interval [CI] = 1.2, 14.8) and household crowding (OR = 3.5, 95% CI = 1.03, 11.7) were risk factors for Hib disease independent of vaccination status. After adjustment for these risk factors, the protective efficacy of 2 or more Hib vaccine doses was 86% (95% CI = 16%, 98%). Among undervaccinated subjects, living with a smoker (P = .02) and several indicators of lower socioeconomic status were risk factors for Hib disease. CONCLUSIONS: Hib disease still occurs at low levels in the United States, predominantly in socioeconomically disadvantaged populations. Low immunization coverage may facilitate continuing transmission of Hib. Special efforts to achieve complete and timely immunization in disadvantaged populations are needed. (+info)
Structural requirements of the major protective antibody to Haemophilus influenzae type b.
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Protective antibodies to the important childhood pathogen Haemophilus influenzae type b (Hib) are directed against the capsular polysaccharide (HibCP). Most of the antibody is encoded by a well-defined set of ("canonical") immunoglobulin genes, including the Vkappa A2 gene, and expresses an idiotypic marker (HibId-1). In comparison to noncanonical antibodies, the canonical antibody is generally of higher avidity, shows higher levels of in vitro bactericidal activity, and is more protective in infant rats. Using site-directed mutagenesis, we here characterize canonical HibCP antibodies expressed as antigen-binding fragments (Fabs) in Escherichia coli, define amino acids involved in antigen binding and idiotype expression, and propose a three-dimensional structure for the variable domains. We found that canonical Fabs, unlike a noncanonical Fab, bound effectively to HibCP in the absence of somatic mutations. Nevertheless, pronounced mutation-based affinity maturation was demonstrated in vivo. An almost perfect correlation was found between unmutated gene segments that mediated binding in vitro and those encoding canonical HibCP antibodies in vivo. Thus, the Vkappa A2a gene could be replaced by the A2c gene but not by the highly homologous sister gene, A18b, corresponding to the demonstrated usage of A2c but not of A18b in vivo. Similarly, only Jkappa1 and Jkappa3, which predominate in the response in vivo, were able to facilitate binding in vitro. These findings suggest that the restricted immunoglobulin gene usage in HibCP antibodies reflects strict structural demands ensuring relatively high affinity prior to somatic mutations-requirements met by only a limited spectrum of immunoglobulin gene combinations. (+info)
Neutralization of macrophage inflammatory protein 2 (MIP-2) and MIP-1alpha attenuates neutrophil recruitment in the central nervous system during experimental bacterial meningitis.
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Chemokines are low-molecular-weight chemotactic cytokines that have been shown to play a central role in the perivascular transmigration and accumulation of specific subsets of leukocytes at sites of tissue damage. Using in situ hybridization (ISH), we investigated the mRNA induction of macrophage inflammatory protein 2 (MIP-2), MIP-1alpha, monocyte chemoattractant protein 1 (MCP-1), and RANTES. Challenge of infant rats' brains with Haemophilus influenzae type b intraperitoneally resulted in the time-dependent expression of MIP-2, MIP-1alpha, MCP-1, and RANTES, which was maximal 24 to 48 h postinoculation. Immunohistochemistry showed significant increases in neutrophils and macrophages infiltrating the meninges, the ventricular system, and the periventricular area. The kinetics of MIP-2, MIP-1alpha, MCP-1, and RANTES mRNA expression paralleled those of the recruitment of inflammatory cells and disease severity. Administration of anti-MIP-2 or anti-MIP-1alpha antibodies (Abs) resulted in significant reduction of neutrophils. Administration of anti-MCP-1 Abs significantly decreased macrophage infiltration. Combined studies of ISH and immunohistochemistry showed that MIP-2- and MIP-1alpha-positive cells were neutrophils and macrophages. MCP-1-positive cells were neutrophils, macrophages, and astrocytes. Expression of RANTES was localized predominantly to resident astrocytes and microglia. The present study indicates that blocking of MIP-2 or MIP-1alpha bioactivity in vivo results in decreased neutrophil influx. These data are also the first demonstration that the C-C chemokine MIP-1alpha is involved in neutrophil recruitment in vivo. (+info)
Antibody response to accelerated Hib immunisation in preterm infants receiving dexamethasone for chronic lung disease.
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AIM: To study the effect of dexamethasone on the routine immunisation of preterm infants with chronic lung disease. METHODS: Serum samples were obtained before and after immunisation from an unselected cohort of 59 preterm infants. Haemophilus influenzae antibodies were measured using an ELISA method and differences in the geometric mean values between the two groups of babies analysed. RESULTS: Sixteen infants received no dexamethasone. Before and after immunisation antibody titres for those receiving no dexamethasone were 0.16 and 4.63 mcg IgG/ml. Corresponding values for those receiving dexamethasone were 0.10 and 0.51 mcg IgG/ml, respectively. CONCLUSION: Dexamethasone used in the treatment of chronic lung disease seems to significantly affect the antibody response of preterm infants to immunisation against Haemophilus influenzae. (+info)
Effect of multiple mutations in the hemoglobin- and hemoglobin-haptoglobin-binding proteins, HgpA, HgpB, and HgpC, of Haemophilus influenzae type b.
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Haemophilus influenzae requires heme for growth and can utilize hemoglobin and hemoglobin-haptoglobin as heme sources. We previously identified two hemoglobin- and hemoglobin-haptoglobin-binding proteins, HgpA and HgpB, in H. influenzae HI689. Insertional mutation of hgpA and hgpB, either singly or together, did not abrogate the ability to utilize or bind either hemoglobin or the hemoglobin-haptoglobin complex. A hemoglobin affinity purification method was used to isolate a protein of approximately 120 kDa from the hgpA hgpB double mutant. We have cloned and sequenced the gene encoding this third hemoglobin/hemoglobin-haptoglobin binding protein and designate it hgpC. Insertional mutation of hgpC did not affect the ability of the strain to utilize either hemoglobin or hemoglobin-haptoglobin. An hgpA hgpB hgpC triple mutant constructed by insertional mutagenesis showed a reduced ability to use the hemoglobin-haptoglobin complex but was unaltered in the ability to use hemoglobin. A second class of mutants was constructed in which the entire structural gene of each of the three proteins was deleted. The hgpA hgpB hgpC complete-deletion triple mutant was unable to utilize the hemoglobin-haptoglobin complex and showed a reduced ability to use hemoglobin. We have identified three hemoglobin/hemoglobin-haptoglobin-binding proteins in Haemophilus influenzae. Any one of the three proteins is sufficient to support growth with hemoglobin-haptoglobin as the heme source, and expression of at least one of the three is essential for hemoglobin-haptoglobin utilization. Although the three proteins play a role in hemoglobin utilization, an additional hemoglobin acquisition mechanism(s) exists. (+info)
The induction of immunologic memory after vaccination with Haemophilus influenzae type b conjugate and acellular pertussis-containing diphtheria, tetanus, and pertussis vaccine combination.
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The significance of reduced antibody responses to the Haemophilus influenzae type b (Hib) component of acellular pertussis-containing combination vaccines (DTaP-Hib) is unclear. A DTaP-Hib vaccine evaluated in infants vaccinated at ages 2, 3, and 4 months showed reduced anti-Hib polysaccharide IgG (geometric mean concentration [GMC], 1.23 microgram/mL; 57%, >1.0 microgram/mL). Polyribitolribosyl phosphate (PRP) and Hib conjugate (PRP-T) vaccine given as a booster during the second year of life was evaluated for the presence of immunological memory. After boosting, most children achieved anti-PRP IgG >1.0 microgram/mL, although the GMC was higher with PRP-T (88.5 microgram/mL) than with PRP vaccine (7.86 microgram/mL, P<.001). The GMC of the PRP group was higher than anticipated for naive PRP recipients of the same age. PRP-specific IgG avidity was significantly higher after boosting than after priming, providing further evidence for the generation of memory. Despite reduced immunogenicity, DTaP-Hib combination vaccines appear to prime for immunologic memory. (+info)
The pathogenic role of fimbriae of Haemophilus influenzae type b in murine bacteraemia and meningitis.
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Complement activation and development of murine bacteraemia and meningitis following intranasal instillation of cell-bound fimbriated or non-fimbriated organisms were compared to clarify the role of fimbriae in the pathogenesis of illnesses caused by Haemophilus influenza type b (Hib). In-vitro resistance of non-fimbriate bacteria to the bactericidal effects of normal human serum was at least 400 times greater than that of fimbriate bacteria. The amount of C3 bound to fimbriate Hib was more than that to non-fimbriate Hib. When mice were infected with fimbriate bacteria, 11.5% died. When mice were infected with non-fimbriate bacteria, the mean number of viable organisms gradually increased or was constant up to day 7; 38.5% of these mice died. These in-vivo results were coincident with the in-vitro data. However, the content of polyribosyl ribitol phosphate (PRP) in fimbriate organisms was the same as in non-fimbriate organisms. These results indicate that fimbriate Hib may be less likely to produce bacteraemia and meningitis, correlating with the greater susceptibility to complement-mediated bacteriolysis and the lower mortality seen with this type of organism, although fimbriae increase adherence to epithelial cells (mucosal surface). (+info)