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Biomedical subjects

D M Granoff

Publications and source records attributed to D M Granoff.

At least 73 records · Page 4Linked to original sources
PubMed1990

Bactericidal and opsonic activity of IgG1 and IgG2 anticapsular antibodies to Haemophilus influenzae type b.

Complement-mediated bactericidal and opsonic activity of IgG1 and IgG2 antibodies to Haemophilus influenzae type b polysaccharide (polyribosyl ribitol phosphate [PRP]) were investigated. The antibody sources were IgG1 or IgG2 subclass polyclonal antibody fractions prepared by immunoabsorption of sera from adults immunized with PRP or PRP-diphtheria toxoid conjugate vaccine or clonally purified anti-PRP antibodies from eight adults immunized with PRP vaccine. In bactericidal assays using an inoculum of 3 x 10(3) colony-forming units (cfu)/ml, twofold lower concentrations of IgG1 compared with IgG2 antibody were required for 50% killing. With approximately 10(6) cfu/ml, IgG1 antibody killed 3 logs more of bacteria than were killed by comparable concentrations of IgG2 antibody. The IgG1 antibody also required lower concentrations of complement than did the IgG2 antibody for comparable bacteriolytic activity. Clonally purified IgG1 and IgG2 anti-PRP antibodies from most individuals showed similar relative differences in bactericidal activity. IgG1 anti-PRP antibody was also more efficient than IgG2 anti-PRP antibody in enhancing the uptake of radiolabeled type b H. influenzae by human polymorphonuclear leukocytes in the presence of complement and in protecting infant rats from developing bacteremia. However, the differences in opsonic or protective activity of the two subclasses were smaller than the differences in bactericidal activity. Thus, IgG1 anti-PRP antibody is functionally more effective than IgG2 antibody, but it is likely that both subclasses can confer protection against disease.

Animals↗
PubMed1990

A major crossreactive idiotype associated with human antibodies to the Haemophilus influenzae b polysaccharide. Expression in relation to age and immunoglobulin G subclass.

Using idiotypic analysis, we examined the variable (V) region diversity of human antibodies specific for the capsular polysaccharide of Haemophilus influenzae b (Hib PS). A goat anti-idiotypic serum (anti-Id) was prepared against anti-Hib PS antibodies isolated from the serum of an adult immunized with Hib PS. The anti-Id bound donor anti-Hib PS antibodies and inhibited Hib PS binding of donor anti-Hib PS. In contrast, the anti-Id did not bind donor or pooled Ig depleted of Hib PS antibodies, nor did it inhibit antigen binding of human antibodies to pneumococcal PS's, meningococcal A PS or diphtheria toxoid. Crossreactive idiotype (CRI), as measured by anti-Id inhibition of Hib PS binding, was found in 74 of 98 subjects (76%) vaccinated with Hib PS at 1.7-57 yr of age. 60 of these 74 subjects had greater than 50% of their serum Hib PS-binding activity inhibited by anti-Id. No correlation was found between age and CRI expression. In subjects showing both IgG1 and IgG2 antibody responses, CRI was most frequently detected in both subclasses (71% of subjects). CRI was limited to either IgG1 or IgG2 in 19% of subjects, a finding suggestive of independent B cell lineages. 13 of 15 infants less than 17 mo of age, who responded to Hib PS-outer membrane protein conjugate vaccine, had greater than 50% of their serum anti-Hib PS antibody activity inhibited by anti-Id. The ability of native Hib PS and Hib PS oligomer to partially inhibit (60 and 35%, respectively) the binding between anti-Id and heterologous anti-Hib PS, indicated that some CRI determinants are in or near the combining site. In summary, our findings demonstrate a highly penetrant and frequently predominant CRI, which is expressed in both infants and adults. The results underscore the limited V region diversity of anti-Hib PS antibodies and indicate that CRI predominance is manifest early in ontogeny and is induced by both TI and TD forms of the Hib PS antigen.

Adolescent↗
PubMed1990

Clinical and immunologic characteristics of healthy children with subnormal serum concentrations of IgG2.

To understand the relevance of subnormal serum concentrations of IgG2, we measured IgG2 in serum of 575 healthy children and identified 11 with concentrations greater than 2 SD less than the mean for age. The levels of IgG2 present were similar to those found in symptomatic children with IgG2 subclass deficiency associated with antibody deficiency. The 11 children ranged in age from 1 to 14 y (mean = 5.7). Detailed clinical information was available on 10 of the 11 children and each was matched for age with two controls. The median number of visits/y to the doctor for infectious illnesses was identical for the two groups (1.0). Nine of the children with subnormal IgG2 were followed for 1 to 5 y (mean = 2.3). All nine children had normal serum concentrations of IgA, IgG1, IgG3, and IgG4 but seven had persistently subnormal or low-normal serum IgG2 concentrations. One of these seven children also had a subnormal serum concentration of IgG, and one had subnormal IgM. Antibody responses to Haemophilus b polysaccharide vaccine were normal in five of six who were immunized. In vitro secretion of Ig by mitogen-stimulated peripheral blood mononuclear cells was measured in six of seven children with persistently subnormal or low-normal IgG2; five showed decreased secretion of IgG2, and two of the five also had subnormal secretion of IgG1 and IgG3. An important implication of this study is that the subnormal concentrations of serum IgG2 found in infection-prone children are not a sufficient explanation for their increased susceptibility to infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Variability in the functional activity of vaccine-induced antibody to Haemophilus influenzae type b.

Sera from 3 of 30 adults vaccinated with Haemophilus influenzae type b polysaccharide vaccine (Hib PS) had poor complement-mediated bacterial activity despite the presence of anti-Hib PS antibody concentrations of 8.6 to 20.5 micrograms/mL. These "nonkiller" antibodies killed less than 0.4 log cfu/mL compared to greater than 3 logs with all but one of the other sera. To investigate the basis of this poor functional activity, we characterized in detail the IgG antibodies to Hib PS present in two of the nonkiller sera, and compared the results with two of the "killer" sera. The latter were selected based on comparable levels of total antibody to Hib PS. No consistent differences were found between the relative proportions of IgG or IgA antibody to total anti-Hib PS antibody, or the respective ratios of IgG1 to IgG2 antibody in the nonkiller and killer sera. IgG fractions, and IgG affinity purified antibody to Hib PS were prepared. When tested at 2 micrograms/mL of antibody, the IgG fractions from the two nonkiller sera had much lower bactericidal activity than the corresponding fractions from the killer sera (3 logs less killing), and the former also had lower complement-mediated opsonic activity (20 and 13% uptake by human PMN compared to 62 and 93%). These data show the striking variability in the functional activity of vaccine-induced antibody to Hib PS. Antibody functional activity is likely to be affected by a number of factors but one important variable appears to be avidity since the IgG anti-Hib PS antibody from the two nonkiller sera had 2- to 5-fold lower avidity than the IgG antibody from the two killer sera.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Antimicrobial susceptibility patterns of Haemophilus isolates from children in eleven developing nations. BOSTID Haemophilus Susceptibility Study Group.

The antimicrobial susceptibilities of 426 isolates of Haemophilus species, which were collected as part of a worldwide study of the etiology of acute respiratory disease in children in selected developing countries, were determined. Eleven antibiotics were tested using the recently described Haemophilus Test Medium. There was a low prevalence of antibiotic resistance; 6% of strains were resistant to ampicillin, and 1.6% were resistant to chloramphenicol. Strains resistant to both ampicillin and chloramphenicol were recovered only from Thailand. Susceptibility to penicillin G was also determined; the minimum inhibitory concentrations for penicillin and ampicillin were concordant within one 2-fold dilution in 97% of the isolates. Thus, Haemophilus isolates were as susceptible to penicillin G as they were to ampicillin, and penicillin resistance was infrequent overall. These data provide support for the current protocols for the management of acute respiratory infections in children in developing countries, in which penicillin G is a first-line agent.

Anti-Bacterial Agents↗
PubMed1989

Decline in serum antibody to the capsule of Haemophilus influenzae type b in the immediate postimmunization period.

STUDY OBJECTIVE: To determine what change, if any, occurs in the serum anticapsular antibody concentration immediately after immunization with either Haemophilus influenzae type b capsular polysaccharide vaccine (PRP) or a vaccine consisting of the capsular polysaccharide conjugated to diphtheria toxoid (PRP-D). SETTING AND PATIENTS: Children: a convenience sample of 32 healthy 2-year-old children from diverse locales. Adults: a convenience sample of 16 healthy adults chosen from employees at the Washington University and Tulane University schools of medicine. INTERVENTIONS: PRP or PRP-D vaccine administered to the adults and serum obtained daily for 5 days. PRP vaccine was administered to the children, and serum was sampled 2 or 3 days or 4 or 5 days after immunization, or both. MEASUREMENTS AND MAIN RESULTS: Decline in serum antibody in all seven (100%) adult recipients of PRP. The nadir occurred on days 1 to 3, and the decrease average 26.0% of the preimmunization concentration. Eight (89%) of nine PRP-D recipients had a similar decline that averaged 25.9%. Of 29 children, 20 (69%) had a decline that averaged 14.7%. The magnitude of anticapsular antibody present before immunization was correlated with the magnitude of the observed decrease. CONCLUSIONS: A decrease in serum anticapsular antibody occurs in most children and adults immunized with PRP (adults and children) or PRP-D (adults). Such a decrease might transiently increase the risk of invasive disease if it occurred during a period of asymptomatic colonization with H. influenzae type b.

Adult↗
PubMed1989

Immunogenicity of Haemophilus influenzae type b polysaccharide-outer membrane protein conjugate vaccine in patients who acquired Haemophilus disease despite previous vaccination with type b polysaccharide vaccine.

To investigate the basis of the immune defect in children who acquire invasive Haemophilus disease despite previous vaccination with Haemophilus influenzae type b (Hib) polysaccharide vaccine, we determined the ability of vaccine failure patients with low levels of serum anticapsular antibody (less than 1 microgram/ml) to respond to reimmunization. Thirty-four patients, ranging in age from 27 to 61 months, were vaccinated with either Hib polysaccharide (n = 20) or Hib polysaccharide-outer membrane protein conjugate vaccine (n = 14). All but three of the children had normal serum concentrations of immunoglobulins, including IgG2. The geometric mean serum anticapsular antibody concentration of the group given polysaccharide vaccine increased from 0.27 microgram/ml before vaccination to 0.65 microgram/ml 1 month later (p less than 0.05), but the magnitude of the response was nearly 10-fold less than that of 31 age-matched control children given polysaccharide vaccine (6.3 micrograms/ml, p less than 0.001). In contrast, all 14 patients with vaccine failure who were given conjugate vaccine showed increases of fivefold or more in serum anticapsular antibody (geometric means 0.35 and 12.8 micrograms/ml, respectively; p less than 0.001). All patients with vaccine failure who did not respond to polysaccharide vaccine were subsequently given conjugate vaccine, and all had high antibody responses. Most patients tested showed increases in complement-mediated serum bactericidal activity. These data suggest that immunization with conjugate vaccine confers protection against Hib disease to children who, because of genetic or other reasons, cannot respond to the unconjugated form of the polysaccharide vaccine.

Age Factors↗
PubMed1989

Host and bacterial factors associated with Haemophilus influenzae type b disease in Minnesota children vaccinated with type b polysaccharide vaccine.

Host and bacterial factors were evaluated among 86 Minnesota children with Haemophilus influenzae type b disease detected by active surveillance after introduction of type b polysaccharide vaccine in the state. Children were 2-6 y of age. Thirty-three (38%) had been vaccinated. There was no significant difference between the frequency of low serum concentrations of IgM, IgA, IgG, or IgG2 in the vaccinated and nonvaccinated subjects (13% vs. 8%, P = .5). The presence of the Gm immunoglobulin allotype phenotype (1,3,17;23;5,13,21), previously associated with a lower relative risk of vaccine failure in children from other states, was associated with a fourfold decrease in the relative risk of vaccine failure in Minnesota (P less than .07). Haemophilus isolates from 58 of the children were available for clonal characterization by multilocus electrophoresis and outer membrane protein subtyping. There were no significant differences between the clone distribution of the strains causing disease in vaccinated and nonvaccinated patients, and nearly all disease-producing clones in Minnesota also are known to cause disease in other areas of the country. Thus, vaccine failure in Minnesota is infrequently associated with hypogammaglobulinemia or with infection by unusual clones of a H. influenzae type b. Also, the Gm phenotype associated with protection against vaccine failure in other areas of the USA appears to be protective in Minnesota.

Antibodies, Bacterial↗
PubMed1989

Excretion of Haemophilus influenzae type b polysaccharide antigen in urine of healthy nasopharyngeal carriers.

We measured concentrations of Haemophilus influenzae type b (Hib) polysaccharide antigen by ELISA in urine samples from 81 healthy North American children with positive or negative throat cultures for Hib, to investigate the possibility that asymptomatic carriers may have antigenuria. For comparison, we determined the concentrations of Hib polysaccharide antigen in urine samples from 56 patients with proven Haemophilus disease, including 13 children with lower respiratory infections who resided in developing countries. Among the healthy children, antigen was detected in the urine of seven of 19 (37%) carriers of Hib compared with one of 62 (2%) children with negative throat cultures (p less than 0.001). Among the patients with invasive Haemophilus infections, 93% had antigen detected. Although there was overlap in the concentrations of antigen in the positive urines from the asymptomatic carriers and those of the ill patients, the concentrations of the ill patients were higher than those of the carriers. The respective geometric means of the positive patients were: American patients with meningitis, 42.5 ng/mL (range 1.7-9800 ng/mL); American patients with infections not involving the CNS, 5.8 ng/mL (range: 1.0-96 ng/mL); patients from developing countries with lower respiratory infections, 29.6 ng/mL (range: 0.9-5290), and American asymptomatic carriers, 1.9 ng/mL (range: 0.6-16.7 ng/mL). Thus, antigenuria is present in a high proportion of healthy children with positive throat cultures for Hib, and the antigen concentrations of the carriers overlap those of ill patients. These results suggest that either mucosal colonization itself is sufficient to produce antigen-uria, or asymptomatic carriers may be experiencing asymptomatic invasive Hib infection.

Antigens, Bacterial↗
PubMed1988

Lack of efficacy of Haemophilus b polysaccharide vaccine in Minnesota.

We evaluated the efficacy of Haemophilus b polysaccharide vaccine in children in Minnesota using a case-control study. The vaccine became available in Minnesota in August 1985. During the subsequent 28 months, 88 cases of invasive H influenzae type b disease were identified in children 24 to 71 months of age, the group targeted for vaccination. Of the 88 cases, 36 (41%) occurred in vaccinated children. Fifty-eight (33%) of 176 controls were vaccinated during a similar period. The vaccine's protective efficacy for children with any history of vaccination was -58% (95% confidence interval = -204% to 18%). The vaccine's protective efficacy for children who were most likely to be protected by vaccination was -55% (95% confidence interval = -238% to 29%). Our results indicate that vaccination with Haemophilus b polysaccharide vaccine had no effect in preventing H influenzae type b disease in Minnesota children.

Bacterial Capsules↗
PubMed1988

Genes associated with the G2m(23) immunoglobulin allotype regulate the IgG subclass responses to Haemophilus influenzae type b polysaccharide vaccine.

We determined whether genes associated with the G2m(23) allotype, a genetic marker on IgG2 molecules, influence the subclass composition of the antibody response to Haemophilus influenzae type b polysaccharide vaccine. After immunizing 70 white adults, the geometric means (GMs) of the total, IgG, IgG1, and IgG2 antibody concentrations increased approximately 10-fold over preimmunization concentrations. There was no significant difference in the GMs of the total, IgG, or IgG1 antibody concentrations in postimmunization sera from subjects positive versus those negative for G2m(23). Adults positive for G2m(23) had a GM IgG2 concentration more than threefold higher than that of negative subjects (P less than .001). The antibody responses of 61 Amish adults immunized with type b polysaccharide vaccine were also analyzed. Those adults positive for G2m(23) had a higher GM serum IgG2 response to capsule than did those who were negative (P less than .01). These data indicate that genes associated with the G2m(23) locus regulate the IgG subclass composition of the antibody response to H. influenzae type b polysaccharide vaccine.

Adolescent↗
PubMed1988

IgG subclass response to immunization with Haemophilus influenzae type b polysaccharide-outer membrane protein conjugate vaccine.

We immunized 117 children with either Haemophilus influenzae type b polysaccharide vaccine or type b polysaccharide coupled to an outer membrane protein of group B Neisseria meningitidis (conjugate vaccine), and measured the IgG, IgG1, and IgG2 subclass composition of antibody to type b polysaccharide in postimmunization sera by ELISA. The IgG responses of 51 children, 24-83 months of age, immunized for the first time with the conventional type b vaccine consisted of both IgG1 and IgG2 antibody (respective geometric means of 2.24 and 0.77 micrograms/ml). In contrast, the IgG responses of 28 infants, 2-17 months of age, immunized with conjugate vaccine were predominantly or exclusively IgG1 (genometric mean IgG1 and IgG2 antibody concentrations of 1.92 and 0.19 micrograms/ml). A total of 38 children was primed with conjugate vaccine between 2 and 17 months of age and boosted approximately 1 yr later. The 28 children boosted with type b polysaccharide vaccine showed memory antibody responses consisting of both IgG1 and IgG2 (respective geometric means of 12.7 and 4.8 micrograms/ml); the 10 children boosted with conjugate vaccine showed a similar pattern of IgG subclass responses (respective geometric means of 20.8 and 5.1 micrograms/ml, p greater than 0.4 compared to the respective geometric mean IgG1 and IgG2 values of the group boosted with polysaccharide). Thus, in children 24-83 months of age, immunization with conventional type b polysaccharide vaccine generally elicits both IgG1 and IgG2 responses, with a slight predominance of IgG1.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗