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David Goldblatt

Publications and source records attributed to David Goldblatt.

At least 37 records · Page 2Linked to original sources
PubMed2004

Reduction of antibody response to an 11-valent pneumococcal vaccine coadministered with a vaccine containing acellular pertussis components.

In pneumococcal conjugate vaccines (PCVs), polysaccharide antigens are often conjugated to protein carriers related to other common vaccines. It is therefore important to test PCV interaction with other pediatric vaccines when administered simultaneously. We assessed the immune response to an 11-valent PCV conjugated to diphtheria and tetanus carriers (PncD/T11), administered concomitantly, but in separate sites, with a combined vaccine containing epitopes related antigenically to the carriers: polyribosylribitol phosphate-tetanus tox oid (PRP-T), diphtheria toxoid (DT), and tetanus toxoid (TT). In addition, these combinations contained inactivated poliovirus vaccine (IPV) and either whole-cell pertussis (wP) or acellular pertussis (aP) components. After coadministration of PncD/T11 with the combined vaccine containing wP (DTwP/IPV/PRP-T), the responses to all polysaccharides in the PncD/T11 were satisfactory. In contrast, when coadministered with an aP-containing combination (DTaP/IPV/PRP-T), the response to all seven pneumococcal conjugates to TT was significantly reduced after primary and booster immunization. The pneumococcal conjugates to DT were not significantly reduced after the primary series, but were somewhat reduced after booster. It is likely that some suppression of the tetanus-mediated response occurred even when the PncD/T11 was coadministered with wP, but this suppression was masked by the adjuvant effect of wP. By replacing wP with aP, this adjuvant effect was removed, unmasking the suppression of the tetanus-mediated response. With the increasing use of multiple aP-containing vaccines in infancy, novel approaches to adjuvants and carrier protein technology are likely to be required.

Antibodies, Bacterial↗
PubMed2003

Serological criteria for evaluation and licensure of new pneumococcal conjugate vaccine formulations for use in infants.

The World Health Organization (WHO) is undertaking a series of consultations on serological criteria for the evaluation and licensure of new formulations/combinations or different vaccination schedules of pneumococcal conjugate vaccines. The lack of a definitive serological correlate of protection and the multiplicity of antigens involved, especially since the clinical efficacy of most of the individual serotypes represented in the only licensed vaccine has not been established, are hindering the formulation of criteria for licensure of new formulations or combinations of the vaccine. This report analyses the various options with their relative merits and drawbacks and provides preliminary recommendations as guidance to regulatory agencies in evaluating these vaccines for the purposes of licensure. More detailed recommendations for production and control of pneumococcal conjugate vaccines, including criteria for evaluation for licensure, are currently being drafted.

Antibodies, Bacterial↗
PubMed2003

The nature of colitis in chronic granulomatous disease.

BACKGROUND: Patients with chronic granulomatous disease (CGD) may have gastrointestinal manifestations, commonly colitis. The etiology, prevalence, and inflammatory process of CGD colitis are unclear. OBJECTIVES: To characterize the inflammatory process of CGD colitis and to compare it with other inflammatory bowel disorders. METHODS: Colonic mucosal biopsies from 8 CGD patients were immunostained for eosinophils, neutrophils, macrophages, and adhesion molecules (ICAM; VCAM, E-selectin) and compared with normal and diseased controls (allergic colitis, ulcerative colitis, and melanosis coli). Cell types were counted and expressed as cell/mm2. RESULTS: The inflammatory infiltrate in CGD colitis differed from the normal controls by an increase in eosinophils (110; 48-176 [median and range] versus 14.5; 3-30; P < 0.005) and macrophages (291.5; 203-480 versus 38.5; 27-64; P < 0.005). There was a paucity of neutrophils compared to ulcerative colitis (10; 0-101 versus 315.5; 78-688; P < 0.005). Expression of HLA-DR was increased in the epithelium and vascular endothelium in CGD compared with normal controls. Patterns of expression of the adhesion molecules differed significantly in CGD from those in other inflammatory bowel diseases: intracellular adhesion molecule-1 was more strongly expressed in the lamina propria, vascular adhesion molecule-1 was more patchily expressed, and E-selectin was present only in the small vessels. CONCLUSIONS: The mechanism of inflammation and profile of inflammatory mediators in CGD colitis differs from that in other inflammatory bowel diseases.

Biopsy↗
PubMed2003

Multilaboratory evaluation of a viability assay for measurement of opsonophagocytic antibodies specific to the capsular polysaccharides of Streptococcus pneumoniae.

Opsonophagocytosis is a correlate of protection that measures the functional activity of vaccine-induced antibodies. A standardized opsonophagocytosis assay (OPA) should be used as part of the evaluation of current and future pneumococcal (Pnc) polysaccharide (Ps)-based vaccines. We enrolled five laboratories to evaluate a previously standardized viability OPA. Each laboratory was provided with a detailed OPA protocol, seven target Pnc strains (serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F), two quality control sera and 12 paired sera (blinded) from adult donors who received one dose of the 23-valent Pnc Ps vaccine. Laboratories sent their results to the Centers for Disease Control and Prevention for analysis. Sera were tested in duplicate (single run), and the results were averaged to yield a single OPA titer (> or = 50% killing) for each serum sample. The percentage of sera within one or two dilutions of the calculated median OPA titer was determined for each laboratory and for each serotype. In general, laboratories were capable of detecting OPA titers within one or two dilutions of the median for at least 75 and 88%, respectively, of the sera tested. The level of agreement with the median OPA titers varied depending on the participating laboratory (overall agreement = 0.8 [99% confidence interval = 0.75 to 0.85]). All OPA median titers reported for quality control sera were within one dilution of the expected titer. We conclude that this OPA can be done in multiple laboratories with a high degree of interlaboratory reproducibility.

Adult↗
PubMed2003

Immunogenicity of, and immunologic memory to, a reduced primary schedule of meningococcal C-tetanus toxoid conjugate vaccine in infants in the United kingdom.

It has been previously shown that one of the three meningococcal C conjugate (MCC) vaccines introduced in the United Kingdom proved highly immunogenic after the first dose of a three-dose schedule, with evidence of immune memory after dose 3. Thus, in infants a one- or two-dose schedule of this MCC vaccine, conjugated to tetanus toxoid (TT), may suffice. Healthy infants (n = 586) were randomized to receive either one (group 1), two (group 2), or three (group 3) doses of MCC-TT vaccine with a 10- micro g polysaccharide booster given at 13 to 14 months of age. Serum bactericidal antibody (SBA) levels were measured by utilizing rabbit complement (rSBA), meningococcal C-specific immunoglobulin G (IgG), and avidity indices (AIs). For groups 1, 2, and 3, the percentages of infants with an rSBA level of > or =8 against strain C11 were 98.4, 100, and 99.4%, respectively. Infants in group 1 with prevaccination rSBA titers of > or =8 had post-primary MCC rSBA geometric mean titers (GMTs) significantly lower than those infants with prevaccination rSBA titers of <8. One dose of MCC-TT vaccine given to infants at 2 months of age yielded significantly lower SBA GMTs and geometric mean AIs (GMAIs) than two or three doses but elicited a significantly greater response after boosting, as reflected by rSBA levels and GMAI. This study provides the first evidence that the number of doses of MCC-TT used in infant immunization schedules could be decreased.

Animals↗
PubMed2003

Diminished production of anti-inflammatory mediators during neutrophil apoptosis and macrophage phagocytosis in chronic granulomatous disease (CGD).

Genetic defects in the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme system result in chronic granulomatous disease (CGD). In addition to recurrent, life-threatening infections, patients with CGD frequently present with sterile inflammatory complications, suggesting that NADPH-oxidase deficiency predisposes to these responses in the absence of persistent microbial infection. The mechanisms involved in the aberrant, inflammatory process are unknown. In this study, we have shown that neutrophils isolated from CGD patients, which are more resistant to spontaneous apoptosis in vitro, also produce significantly less of the anti-inflammatory mediator cyclopentenone prostaglandin D(2) (PGD(2)). In addition, during phagocytosis of opsonized and nonopsonized apoptotic targets, CGD macrophages are severely compromised in their ability to produce PGD(2) and transforming growth factor-beta (TGF-beta). We suggest that delayed apoptosis of inflammatory cells, such as neutrophils and deficient production of the anti-inflammatory mediators PGD(2) and TGF-beta during macrophage clearance of apoptotic debris and invading pathogens, contributes to persistence of inflammation in CGD.

Adolescent↗
PubMed2002

Antibody persistence and immunological memory at age 4 years after meningococcal group C conjugate vaccination in children in the United kingdom.

Antibody persistence and immunological priming for 2 formulations of a meningococcal group C (menC) conjugate (MCC) vaccine (containing 2 or 10 microg of menC polysaccharide) administered at 2, 3, and 4 months of age was investigated by boosting vaccine recipients at age 13-16 months or 4 years with 10 microg of unconjugated menC polysaccharide. At age 4 years, geometric mean titers (GMTs) and concentrations of menC-specific immunoglobulin G and serum bactericidal antibody (SBA) had decreased to prevaccination levels. Geometric mean avidity indices increased after the primary vaccination until age 13-16 months and then remained constant until age 4 years. One month after boosting at age 4 years, menC immunoglobulin G and SBA levels increased significantly. The postbooster SBA GMT for the 2-microg vaccination (2181.2; 95% confidence interval [CI], 975.9-4875.1) was 2-fold higher than that for the 10-microg vaccination (931.6; 95% CI, 338.0-2568.1). This is the first demonstration of immunological memory at 4 years of age in children receiving MCC vaccine on the United Kingdom's 2/3/4-month immunization schedule.

Antibodies, Bacterial↗
PubMed2002

Avidity maturation following vaccination with a meningococcal recombinant hexavalent PorA OMV vaccine in UK infants.

To date, there are no data assessing the utility of avidity indices as a surrogate marker for the induction of immunological memory following meningococcal serogroup B outer membrane vesicle (OMV) vaccination. We studied infants who had been immunized with three doses of a recombinant hexavalent PorA OMV vaccine at ages 2-4 months, together with a fourth dose at age 12-18 months. A control group had received a single dose of the same vaccine at age 12-18 months. As previously reported, serum bactericidal antibody (SBA) titres increased after each of the first three doses, with a significant increase observed from 6 months post third dose to 1 month post fourth dose. The geometric mean avidity indices (GMAI), against strain H44/76 OMVs, increased from 1 month post first dose to 1 month post third dose. Significant increases in GMAI were observed at 6 months post third dose and again following the fourth dose. At 32-42 months of age, though the SBA titres had returned to post first dose levels, the GMAI remained elevated. No increase in avidity was observed in the control group. Antibody avidity indices are useful laboratory markers for the priming of immunological memory following vaccination with meningococcal serogroup B OMV vaccines.

Antibodies, Bacterial↗
PubMed2002

Natural and vaccine-induced immunity and immunologic memory to Neisseria meningitidis serogroup C in young adults.

The immune response to polysaccharides and conjugate vaccines in adults is poorly understood. This study assessed meningococcal serogroup C responses after AC polysaccharide (MACP) and C conjugate (MCC) vaccine administration in young adults and explored immune memory by measuring antibody avidity. The geometric mean avidity indices (GMAIs) measured 1 month after MACP vaccination were relatively high and failed to increase significantly in the 6 months before and after a second dose of MACP/MCC. Although the GMAI of naive adults increased immediately following MCC vaccination to 215.7 (95% confidence interval, 181.0-257.1), a level similar to that seen after MACP vaccination, no further maturation in the subsequent 6 months was seen. Antibody induced by polysaccharide antigens in adults is already of relatively high avidity (compared with that in infants and toddlers) and fails to mature further, probably because both MACP and MCC predominantly stimulate memory B cells.

Adult↗
PubMed2002

Prenatal diagnosis in two families with autosomal, p47(phox)-deficient chronic granulomatous disease due to a novel point mutation in NCF1.

OBJECTIVE: Prenatal diagnosis was required in two unrelated families with chronic granulomatous disease (CGD) patients who lacked expression of p47(phox) protein; thus a search for mutations in NCF1 was undertaken. METHODS: Gene scanning was applied to establish the relative number of coding and pseudo-NCF1 genes. PCRs specific for coding NCF1 cDNA and coding NCF1 exon-7 genomic DNA were devised. RESULTS: The normal 1:2 ratio of coding and pseudo-NCF1 genes was found in the patients. Sequencing of the RT-PCR product specific for mRNA from the coding NCF1 genes revealed a novel homozygous G579A mutation in both patients, changing the TGG codon for Trp193 into the TAG stop codon. This mutation was confirmed in genomic DNA. The parents of both patients were found to be heterozygotes for this mutation. In the chorionic villus DNA of the first family a heterozygous G579A mutation was found. Postpartum, functional NADPH oxidase tests were normal. In the second family, this mutation was present in homozygous form in the chorionic villus DNA. Following termination of the pregnancy, the diagnosis of p47(phox)-deficient CGD was confirmed on DNA extracted from fetal blood. CONCLUSION: This is the first report of prenatal diagnosis in p47(phox)-deficient CGD.

Adolescent↗
PubMed2002

Safety and immunogenicity of pneumococcal conjugate vaccine in combination with diphtheria, tetanus toxoid, pertussis and Haemophilus influenzae type b conjugate vaccine.

BACKGROUND: Pneumococcal polysaccharide/protein conjugate vaccines (PnCV) are immunogenic and effective in infancy. However, an addition to the nine currently recommended vaccine injections during the first year of life of African children may be a deterrent to participation in a PnCV program. Thus we have evaluated the safety and immunogenicity of a 9-valent PnCV (Wyeth Lederle Pediatrics and Vaccines) mixed with diphtheria, tetanus toxoid, cell pertussis and type b (TETRAMUNE). METHODS: Healthy Gambian infants were randomized at the age of 2 months to receive three doses 1 month apart of either (1) placebo reconstituted in TETRAMUNE in the right thigh (control) or (2) PnCV in the left thigh and TETRAMUNE in the right thigh (separate) or (3) PnCV reconstituted in TETRAMUNE as a single injection in the right thigh (combined). The vaccines were given together with routine Expanded Program on Immunization vaccines. Adverse reactions were recorded after vaccination, and antibody concentrations were measured by enzyme-linked immunosorbent assays. RESULTS: Local induration and tenderness were observed more commonly at the site of injection of TETRAMUNE than at the site of injection with PnCV after each dose of vaccination. Swelling at the site of injection was encountered more frequently at the site of administration of TETRAMUNE than at the site of administration PnCV ( P< 0.00001 for Doses 1 and 2 and P< 0.0009 for Dose 3). Swelling at the site of administration of TETRAMUNE mixed with PnCV was comparable with that observed for TETRAMUNE alone. Although most mothers reported that the babies "felt hot" 24 h after each injection, febrile reactions (temperature, >or=38 degrees C) were infrequent and resolved with antipyretics. Geometric mean titer for anti-polyribosylribitol phosphate antibody was 11.6 microg/ml [95% confidence limits (95% CI), 9.2, 14.6] in the control group and comparable with 13.3 microg/ml (95% CI 11.0, 16.0) in the combined group and significantly higher at 17.9 microg/ml (95% CI 14.7, 21.9; P= 0.01) in the separate group. Geometric mean concentrations of serotype-specific pneumococcal antibodies were higher in the combined group than the separate group for all nine serotypes. Antibody responses to diphtheria and pertussis antigens were similar in all groups. Anti-tetanus toxoid antibody concentrations were lowest in the combined group (6.66 IU/ml, 95% CI 5.77, 7.68 in the control group; 5.15 IU/ml, 95% CI 4.39, 6.03 in the combined group; P= 0.02). However, all vaccinees achieved protective antibody values. CONCLUSION: The combination of TETRAMUNE and PnCV is safe and immunogenic.

Bacterial Capsules↗
PubMed2002

Effect of vaccination with carrier protein on response to meningococcal C conjugate vaccines and value of different immunoassays as predictors of protection.

In order to plan for the wide-scale introduction of meningococcal C conjugate (MCC) vaccine for United Kingdom children up to 18 years old, phase II trials were undertaken to investigate whether there was any interaction between MCC vaccines conjugated to tetanus toxoid (TT) or a derivative of diphtheria toxin (CRM(197)) and diphtheria-tetanus vaccines given for boosting at school entry or leaving. Children (n = 1,766) received a diphtheria-tetanus booster either 1 month before, 1 month after, or concurrently with one of three MCC vaccines conjugated to CRM(197) or TT. All of the MCC vaccines induced high antibody responses to the serogroup C polysaccharide that were indicative of protection. The immune response to the MCC-TT vaccine was reduced as a result of prior immunization with a tetanus-containing vaccine, but antibody levels were still well above the lower threshold for protection. Prior or simultaneous administration of a diphtheria-containing vaccine did not affect the response to MCC-CRM(197) vaccines. The immune responses to the carrier proteins were similar to those induced by a comparable dose of diphtheria or tetanus vaccine. The results also demonstrate that, for these conjugate vaccines in these age groups, both standard enzyme-linked immunosorbent assays and those that measure high-avidity antibodies to meningococcal C polysaccharide correlated equally well with assays that measure serum bactericidal antibodies, the established serological correlate of protection for MCC vaccines.

Adolescent↗
PubMed2002

Current treatment options for chronic granulomatous disease.

Chronic granulomatous disease is a rare inherited disorder of phagocytic cells which results in a susceptibility to infections of catalase-positive bacteria and fungi (especially Aspergillus species), as well as granuloma formation. The mainstay of therapy is antibacterial and antifungal prophylaxis. Trimethoprim sulfamethoxazole is the drug of choice for the prevention of bacterial infection, while itraconazole is most widely used for the prevention of fungal infection. Immunomodulatory agents, such as IFN-phi, have a role in the prevention and treatment of intractable infection. New antifungal agents provide the promise of improved cure rates for invasive Aspergillus, while bone marrow transplants and gene therapy may offer the promise of complete cure.

Adjuvants, Immunologic↗