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Biomedical subjects

K M Edwards

Publications and source records attributed to K M Edwards.

At least 37 records · Page 2Linked to original sources
PubMed2000

Effect of vitamin A therapy on serologic responses and viral load changes after influenza vaccination in children infected with the human immunodeficiency virus.

Vitamin A administered to children infected with the human immunodeficiency virus before influenza vaccination in a double-blind randomized study did not enhance vaccine serologic responses but did dampen the increase in the human immunodeficiency virus viral load 14 days after immunization (vitamin A, decrease of 0.13 +/- 0.09 log(10) copies/mL; placebo, increase of 0.14 +/- 0.08, P =.02).

Adolescent↗
PubMed2000

Acellular pertussis vaccines.

Although whole-cell pertussis vaccines have been highly effective in preventing whooping cough, their common and burdensome adverse reactions have spurred the development of safer alternatives. Seven acellular vaccines are licensed in one or more countries; four have been licensed thus far in the United States, and more may follow. Although the licensed acellular pertussis vaccines differ in their immunogenicity, adverse reactions, and efficacy, all are effective and, compared with whole-cell vaccine, are associated with markedly fewer and milder adverse reactions.

Antibodies, Bacterial↗
PubMed2000

Enhanced production of recombinant Mycobacterium tuberculosis antigens in Escherichia coli by replacement of low-usage codons.

A major obstacle to development of subunit vaccines and diagnostic reagents for tuberculosis is the inability to produce large quantities of these proteins. To test the hypothesis that poor expression of some mycobacterial genes in Escherichia coli is due, in part, to the presence of low-usage E. coli codons, we used site-directed mutagenesis to convert low-usage codons to high-usage codons for the same amino acid in the Mycobacterium tuberculosis genes for antigens 85A and 85B and superoxide dismutase. Replacement of five codons in the wild-type gene for antigen 85B increased recombinant protein production in E. coli 54-fold. The recombinant antigen elicited proliferation and gamma interferon production by lymphocytes from healthy tuberculin reactors and was recognized by monoclonal antibodies to native antigen 85, indicating that the recombinant antigen contained T-cell and B-cell epitopes. Northern blotting demonstrated only a 1.7- to 2.5-fold increase in antigen 85B mRNA, suggesting that the enhanced protein production was due primarily to enhanced efficiency of translation. Codon replacement in the genes encoding antigen 85A and superoxide dismutase yielded four- to sixfold increases in recombinant protein production, suggesting that this strategy may be generally applicable to overexpression of mycobacterial genes in E. coli.

Animals↗
PubMed2000

Characterization of bactericidal immune responses following vaccination with acellular pertussis vaccines in adults.

Sera from six adults, collected before and after acellular pertussis vaccination, and from a placebo control were examined for the ability to elicit two bactericidal immune defenses, (i) antibody-dependent complement-mediated bacterial lysis and (ii) opsonization and phagocytosis by human neutrophils. The samples were chosen based on low preimmunization titers and strong postimmunization responses to various combinations of vaccine antigens. All but two prevaccination samples demonstrated activity indicative of complement-mediated lysis. Preimmunization activity could have been due to prior infection or childhood immunization. Immunization did not result in improved bactericidal activity for any of the individuals, and in two cases immunization caused a statistically significant decrease in complement-mediated lysis. Similarly, opsonization with the postimmunization sera failed to enhance attachment or phagocytosis of bacteria by neutrophils, and one postimmunization sample with a strong response to filamentous hemagglutinin caused an inhibition of phagocytosis that was statistically significant compared to that observed for the no-serum control. In summary, booster immunization of adults with acellular pertussis vaccines was not found to increase bactericidal activity over preimmunization levels. Identifying ways to promote bactericidal immune responses might improve the efficacy of acellular pertussis vaccines.

Adenylyl Cyclases↗
PubMed2000

Safety and immunogenicity of six acellular pertussis vaccines and one whole-cell pertussis vaccine given as a fifth dose in four- to six-year-old children.

OBJECTIVE: To evaluate the safety and immunogenicity of 6 different acellular pertussis vaccines combined with diphtheria and tetanus toxoids (DTaP) and with 1 licensed whole-cell pertussis vaccine (DTwP) as a fifth dose in children who had previously received the same DTaP, a different DTaP, or DTwP as primary and fourth-dose vaccinations. METHODS: Healthy 4- to 6-year-old children were enrolled at 5 National Institute of Allergy and Infectious Diseases Vaccine Treatment and Evaluation Units to receive a fifth dose of a DTaP or DTwP vaccine. All had been randomly assigned to receive 3 primary doses of DTaP or DTwP at 2, 4, and 6 months and a fourth-dose booster at 15 to 20 months of age as part of earlier National Institutes of Health multicenter acellular pertussis vaccine trials. Parents recorded the occurrence and magnitude of fever, irritability, and injection site redness, swelling, and pain for 3 days after vaccination. Sera obtained before and 1 month after the booster vaccination were analyzed by enzyme-linked immunosorbent assay for antibody to pertussis toxin, filamentous hemagglutinin, fimbriae, pertactin, and diphtheria and tetanus toxoid. Safety and/or immunogenicity data are reported for 317 children who received DTaP and 10 children who received DTwP. RESULTS: Fever and moderate or severe irritability were uncommon following the fifth dose of DTaP vaccine and were generally less frequent than following the fourth dose. However, for the DTaP vaccine groups, redness, swelling, and pain increased in prevalence compared with the fourth dose. The time course and frequency of reactions following DTaP vaccination were generally similar in children who received the same DTaP, a different DTaP, or DTwP for previous doses in the 5- dose series. No significant differences among the DTaP vaccines were detected in the occurrence of reactions, but the statistical power to detect differences was limited by sample size. Significant increases in antibodies directed against the included antigens were observed for all DTaP vaccines in paired pre- and post-fifth dose sera. Post-fifth dose antibody concentrations differed significantly among the DTaP vaccines. Some children in the study showed an antibody response to an antigen not reported to be in the DTaP vaccine. CONCLUSION: All the studied DTaP vaccines performed similarly with regard to reactions, whether given as a fifth sequential dose of the same vaccine, a mix of different DTaP vaccines in the 5-dose sequence, or after 3 DTwP and 1 DTaP vaccinations. Large injection site reactions occurred more frequently after the fifth dose of DTaP than after the previous 4 doses. A fifth dose of all DTaP vaccines induced an antibody response to those antigens contained in the vaccine. No DTaP was consistently most or least reactogenic or immunogenic.

Antibodies, Bacterial↗
PubMed2000

Extensive swelling after booster doses of acellular pertussis-tetanus-diphtheria vaccines.

BACKGROUND: Diphtheria and tetanus toxoid combined with acellular pertussis (DTaP) vaccines are less reactogenic than diphtheria and tetanus toxoid combined with whole cell pertussis (DTwP) vaccines. However, local reactions increase in rate and severity with each successive DTaP dose, and swelling of the entire injected limb has been reported after booster doses. METHODS: We reviewed reports of swelling of the entire thigh or upper arm after the fourth and fifth dose, respectively, of DTaP vaccines administered in the National Institutes of Health multicenter comparative DTaP studies. Relationships were explored among reports of severe swelling, rates of other reactions, quantity of vaccine contents, and prevaccination and postvaccination antibody levels to pertussis toxin, tetanus toxin, and diphtheria toxin. RESULTS: Entire thigh swelling was an unsolicited reaction reported in 20 (2%) of the 1015 children who received 4 consecutive doses of the same DTaP vaccine. The reaction was associated with 9 of the 12 DTaP vaccines evaluated. Although there were no reports of swelling of the entire upper arm in 121 children given a fifth dose of the same DTaP, 4 (2.7%) of 146 recipients of 5 doses of a mixed schedule of DTaP vaccines experienced such swelling. Rates of other reactions were higher in children with entire thigh swelling than in those without. Of the children with entire thigh swelling, 60% had local pain, and 60% had erythema. All swelling subsided spontaneously without sequelae. There was a significant linear association between the rates of entire thigh swelling after dose 4 and diphtheria toxoid content in the DTaP products. Lesser degrees of swelling (>50 mm but less than entire limb) correlated with pertussis toxoid content after dose 4 and aluminum content after dose 5. No relationship was established between levels of serum antibody to diphtheria, tetanus, or pertussis toxin and rates of swelling of the whole thigh. CONCLUSIONS: Booster doses of DTaP vaccines can cause entire limb swelling, which is usually associated with redness and pain. Our data suggest that this extensive swelling reaction may be more common with vaccines containing high diphtheria toxoid content.

Antibodies, Bacterial↗
PubMed1999

The human cytotoxic T cell granule serine protease granzyme H has chymotrypsin-like (chymase) activity and is taken up into cytoplasmic vesicles reminiscent of granzyme B-containing endosomes.

Serine proteases (granzymes) contained within the cytoplasmic granules of cytotoxic T cells and natural killer cells play a variety of roles including the induction of target cell apoptosis, breakdown of extracellular matrix proteins and induction of cytokine secretion by bystander leukocytes. Different granzymes display proteolytic specificities that mimic the activities of trypsin or chymotrypsin, or may cleave substrates at acidic ("Asp-ase") or at long unbranched amino acids such as Met ("Met-ase"). Here, we report that recombinant granzyme H has chymotrypsin-like (chymase) activity, the first report of a human granzyme with this proteolytic specificity. Recombinant 32-kDa granzyme H expressed in the baculovirus vector pBacPAK8 was secreted from Sf21 cells and recovered by Ni-affinity chromatography, using a poly-His tag encoded at the predicted carboxyl terminus of full-length granzyme H cDNA. The granzyme H efficiently cleaved Suc-Phe-Leu-Phe-SBzl (v = 185 nM/s at [S] = 0.217 mM) and also hydrolyzed Boc-Ala-Ala-X-SBzl (X = Phe, Tyr, Met, Nle, or Nva) with slower rates but had little tryptase or Asp-ase activity. Enzymatic activity was inhibited completely by 0.1 mM 3,4-dichloroisocoumarin and 84% by 1.0 mM phenylmethylsulfonyl fluoride. Fluoresceinated granzyme H was internalized in a temperature-dependent manner by Jurkat cells into endosome-like vesicles, suggesting that it can bind to cell surface receptors similar to those that bind granzyme B. This suggests a hitherto unsuspected intracellular function for granzyme H.

Amino Acid Sequence↗
PubMed1999

Early childhood mortality from community-acquired infections.

In this study, the authors identified maternal and child characteristics that were independent predictors of death from infectious diseases acquired in the community and determined if these factors could be used to identify groups of children with excess risk of mortality from infection. A historical cohort study was conducted of children less than 5 years of age between 1985 and 1994 (the study period), who were born in Tennessee, and had complete information on their birth certificates. The primary outcome was death from infection identified from death certificates and confirmed through medical record review. Among the 1,014,976 children less than 5 years of age, who contributed 3,351,568 child-years of follow-up, there were 247 deaths from infections (7.4 deaths from infections per 100,000 child-years). Respiratory infections accounted for approximately one half of the deaths. Children having three or more older siblings or birth weight of less than 1,500 g had a 3-fold and 10-fold increased risk of death from infection, respectively, while children with both characteristics had a nearly 20-fold increased risk that persisted beyond the first year of life. Interventions should be focused on prevention of these infections in vulnerable children. At-risk children should be targeted for careful follow-up and early hospitalization when signs of infection develop.

Child, Preschool↗
PubMed1999

Periodic fever syndrome in children.

OBJECTIVES: To describe the presentation, clinical course, therapeutic response, and long-term follow-up of patients with a syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA). STUDY DESIGN: Patients with PFAPA (n = 94) referred over a 10-year period completed a registry form and provided medical records. Follow-up telephone calls were made in late 1997 to determine the persistence of episodes and sequelae. RESULTS: PFAPA episodes lasted 4.8 days (95% confidence interval 4.5 to 5.1) and recurred every 28 days (confidence interval 26 to 30), with a maximal temperature of 40.5 degrees C (confidence interval 40. 4 degrees to 40.6 degrees ). Of the 83 children available for follow-up, 34 no longer had episodes. In the remainder the episodes did not differ in character but recurred less frequently over time. The affected children had no long-term sequelae. Glucocorticoids were highly effective in controlling symptoms. Tonsillectomy and cimetidine treatment were associated with remission in a small number of patients. CONCLUSIONS: PFAPA is a not uncommon cause of periodic fever in children. In some children the syndrome resolves, whereas symptoms in others persist. Long-term sequelae do not develop. The syndrome is easily diagnosed when regularly recurring episodes of fever are associated with aphthous stomatitis, pharyngitis, or cervical adenitis.

Age of Onset↗
PubMed1999

Acellular pertussis vaccines in adults.

The pathogenesis of pertussis, and the epidemiology and clinical manifestations of pertussis after childhood are reviewed as a background for a discussion of recent clinical trials of acellular pertussis vaccines in adults, and the vaccines' potential for routine use in adolescents and adults.

Adult↗
PubMed1999

Anti-viral strategies of cytotoxic T lymphocytes are manifested through a variety of granule-bound pathways of apoptosis induction.

Cytotoxic T cells and natural killer cells together constitute a major defence against virus infection, through their ability to induce apoptotic death in infected cells. These cytolytic lymphocytes kill their targets through two principal mechanisms, and one of these, granule exocytosis, is essential for an effective in vivo immune response against many viruses. In recent years, the authors and other investigators have identified several distinct mechanisms that can induce death in a targeted cell. In the present article, it is postulated that the reason for this redundancy of lethal mechanisms is to deal with the array of anti-apoptotic molecules elaborated by viruses to extend the life of infected cells. The fate of such a cell therefore reflects the balance of pro-apoptotic (immune) and anti-apoptotic (viral) strategies that have developed over eons of evolutionary time.

Animals↗
PubMed1999

A randomized clinical trial of acellular pertussis vaccines in healthy adults: dose-response comparisons of 5 vaccines and implications for booster immunization.

The safety and immunogenicity of 5 acellular pertussis vaccines (ACVs) were compared in a multicenter, randomized, double-blind trial. A total of 481 healthy adults were given a single intramuscular booster dose of ACV or placebo. Three different dose levels were tested for 4 ACVs: full strength (the dose level proposed for infant immunization), one-third strength, and one-tenth strength. For 1 multicomponent vaccine, only the pertussis toxoid dose level varied. Minor injection site reactions were common and similar in frequency among vaccinated groups. Late-onset injection site reactions were seen in all ACV groups. Dose-related increases in mean antibody titers against vaccine antigens were seen after immunization with all ACVs. Antibody responses against antigens not known to be present in the vaccines were detected after immunization with 4/5 ACVs. Antibody levels fell significantly during the year after immunization. These data support evaluation of ACVs for broader use among adolescents and adults.

Adolescent↗
PubMed1999

Immunity to cross-reactive serotypes induced by pneumococcal conjugate vaccines in infants.

Infants were immunized with 1 of the 3 experimental pneumococcal conjugate vaccines that contain 6B and 19F but not 6A or 19A serotypes. Their sera were studied for the capacity to opsonize Streptococcus pneumoniae 6A, 6B, 19A, and 19F serotypes and the level of IgG antibody to the 4 serotypes. Significant increases were observed in the number of infants with detectable opsonophagocytic titers with 3 conjugate vaccines for 6B (vaccine) serotype but with only 2 vaccines for 6A (cross-reactive) serotype. Significant increases were observed with 2 conjugate vaccines for 19F serotype but with only 1 vaccine for 19A serotype. Thus, some conjugate vaccines may elicit cross-protection better than others. In addition, correlations between opsonophagocytic titers and IgG antibody levels by ELISA were high for 6B and 19F serotypes but low for 6A and 19A serotypes. Thus, ELISA may be an inadequate surrogate assay of vaccine response for cross-reactive serotypes.

Adult↗
PubMed1999

Incidence of pertussis infection in healthcare workers.

OBJECTIVE: To determine the incidence of pertussis infection in two groups of healthcare workers. DESIGN: Retrospective cohort study. SETTING: 660-bed, urban, tertiary-care university hospital. PARTICIPANTS: 106 resident physicians and 39 emergency department employees. INTERVENTIONS: Antibodies to pertussis toxin and filamentous hemagglutinin were determined in fresh serum specimens and in stored sera collected 1 to 3 years previously. A 50% rise in both the pertussis toxin and filamentous hemagglutinin from the initial to the follow-up specimen was considered diagnostic of a pertussis infection. RESULTS: Two of 106 residents had serological evidence of a pertussis infection during 151.3 subject-observation years, for an annual incidence rate of 1.3% (95% confidence interval [CI95], 0%-3.5%). Three of 39 emergency department employees had serological evidence of a pertussis infection during 81.2 subject-observation years, for an annual incidence of 3.6% (CI95, 0%-9.6%). Of these 5 subjects, 2 had symptomatic disease. CONCLUSION: We found both symptomatic and asymptomatic pertussis infections in two cohorts of healthcare workers. Although the incidence rates were somewhat lower than found in other studies, they nonetheless were higher than for almost all other diseases for which we vaccinate healthcare workers. Our results would support the use of acellular pertussis vaccine in healthcare workers.

Adult↗