[Show abstract][Hide abstract]ABSTRACT: This paper examines how pneumococcal type 6B polysaccharide conjugated to tetanus toxoid (Pn6B-TT) compares to a 23 valent pneumococcal vaccine (pneumococcal polysaccharide (PPS)-23) with respect to immunogenicity and serum opsonic activity in patients with chronic obstructive pulmonary disease (COPD). Patients with COPD aged 55-75 yrs were vaccinated with Pn6B-TT (n=10) or with PPS-23 (n=9). Healthy young adults (HA) were vaccinated with Pn6B-TT as controls. Total antibodies to serotype 6B polysaccharide were measured by radioimmunoassay and immunoglobulin (Ig)G antibodies by enzyme-linked immunosorbent assay. Opsonic activity was measured by a phagocytosis assay using human neutrophils as effector cells. The patient groups were comparable by age, smoking history, lung function and use of steroids. COPD patients vaccinated with Pn6B-TT or PPS-23 showed an increase in IgG antibodies and a nonsignificant increase in opsonic activity. This was similar to the increase in IgG and opsonic activity seen in HA. There was a significant correlation between antibody levels and opsonic activity in COPD patients vaccinated both with Pn6B-TT and PPS-23. Pneumococcal antibodies have been shown to confer protection from infection. The results of the present study indicate that protective immunity can be expected in elderly chronic obstructive pulmonary disease patients vaccinated with conjugate vaccines.
Full-text · Article · Nov 2002 · European Respiratory Journal
[Show abstract][Hide abstract]ABSTRACT: Streptococcus pneumoniae is a major respiratory pathogen of infants, children, and the elderly. Polysaccharide vaccines have been useful in adult populations but do not elicit protective immunity in infants and young children. To enhance their immunogenicity, vaccines of pneumococcal polysaccharides conjugated to proteins are being developed. In this study antibody levels and opsonic activities were compared in sera of infants and adults injected with pneumococcal polysaccharide type 6B (Pn6B) conjugated to tetanus toxoid (TT) (Pn6B-TT). Healthy infants were injected with Pn6B-TT; group A was injected at 3, 4, and 6 months of age, and group B was injected at 7 and 9 months of age. A booster injection was given at 18 months. Adults were injected once. Antibodies were measured by enzyme-linked immunosorbent assay and radioimmunoassay, and their functional activities were measured by opsonophagocytosis of radiolabelled pneumococci. In adults, increases in immunoglobulin M (IgM), IgG, IgA, IgG1, and IgG2 to Pn6B were observed. Infants reached adult levels of IgG1 anti-Pn6B after the primary injections. After the booster injection the infant groups had total IgG- and IgM-Pn6B antibody levels similar to those of adults. After the booster injection, IgG1 was the dominant infant anti-Pn6B isotype and at a level higher than in vaccinated adults, but IgA and IgG2 antibodies remained at very low levels. Opsonic activity increased significantly after Pn6B-TT injections; the highest infant sera showed opsonic activity comparable to that of vaccinated adults. Overall, opsonic activity correlated best with total and IgG anti-Pn6B antibodies (r = 0.741, r = 0.653, respectively; n = 35) and was highest in sera with high levels of all Pn6B antibody isotypes. The results indicate the protective potential of a pneumococcal 6B polysaccharide protein conjugate vaccine for young infants.
Full-text · Article · Jul 1998 · Infection and Immunity
[Show abstract][Hide abstract]ABSTRACT: Hyposplenism as a complication of celiac sprue confers an increased risk of pneumococcal sepsis, but such patients do not routinely receive pneumococcal vaccine despite reports of overwhelming pneumococcal sepsis. Because antibody response in these patients has not been previously assessed, we measured pre- and postvaccination levels in 10 patients with documented sprue. All demonstrated appropriate acute antibody responses to a polyvalent pneumococcal vaccine. Vaccination of all patients with celiac sprue seems appropriate.
No preview · Article · Apr 1995 · Journal of Clinical Gastroenterology
[Show abstract][Hide abstract]ABSTRACT: To prevent serious pneumococcal infections, 23-valent pneumococcal polysaccharide vaccine is recommended for individuals over 24 months of age with chronic predisposing diseases and for healthy older adults. This nonrandomized controlled study in rural Alaska assessed the immunogenicity of revaccination in adults.
Twenty-six adults, 33 to 88 years of age, vaccinated a mean of 7.4 years before this study, were matched to 26 previously unvaccinated subjects by age, number of chronic diseases, sex, and ethnicity. One or more chronic diseases were validated in 62% of subjects (32 of 52). All received a first or second intramuscular dose of pneumococcal vaccine. Antibody levels were determined by radioimmunoassay for 12 pneumococcal capsular serotypes immediately before and 20 to 84 days after vaccination.
Six to 9 years after primary vaccination, over one third of serotype-specific antibody levels were below 500 ng of antibody nitrogen per milliliter, equal to the percentage in unvaccinated subjects of similar age. Antibody levels against all pneumococcal serotypes rose to similar levels after primary vaccination and revaccination, and 54% and 55%, respectively, of subjects who received primary vaccination and revaccination had at least a 1.4-fold increase in antibody levels. Only the antibody level for serotype 4 remained low. Neither gender nor age affected peak response. For those with chronic diseases, there was a trend toward fewer low antibody levels against three or more serotypes after revaccination (two subjects [13%]) than after primary vaccination (five subjects [31%]).
Following the initial immunization of high-risk and elderly patients with pneumococcal polysaccharide, pneumococcal antibody levels appear to wane with time. Primary vaccination and revaccination 6 or more years after a first dose of pneumococcal vaccine stimulate comparable mean antibody levels.
No preview · Article · Nov 1994 · Archives of Internal Medicine
[Show abstract][Hide abstract]ABSTRACT: Type 14 is one of the common types isolated from patients of all ages with infections caused by Streptococcus pneumoniae. Its capsular polysaccharide (Pn14) is composed of a neutrally charged tetrasaccharide repeat unit. Pn14 does not elicit protective levels of antibodies in infants and children and is a less than optimal immunogen of the 23-valent vaccine for adults. Pertussis toxin (PT) is both a virulence factor and protective antigen of Bordetella pertussis: it is not soluble at neutral pH and forms insoluble complexes with acidic polysaccharides. Both Pn14 and PT are potential components of vaccines for infants and children. Accordingly, a synthetic scheme was devised to prepare a conjugate of Pn14 and PT. An adipic acid hydrazide derivative of Pn14 was bound to PT at pH 3.9 by carbodiimide-mediated condensation. The conjugation procedure inactivated the PT as assayed by CHO cell and histamine-sensitizing activity. The Pn14-PT conjugate elicited antibodies in mice to Pn14 at levels estimated to be protective in humans and elicited neutralizing antibodies to PT. We plan to evaluate Pn14-PT clinically.
Preview · Article · Oct 1992 · Infection and Immunity
[Show abstract][Hide abstract]ABSTRACT: Concurrent injection of monophosphoryl lipid A (MPL) in saline or as an oil-in-water emulsion enhanced both the primary and secondary serum antibody responses to the capsular polysaccharide (CP) components of seven conjugates: the enhanced responses were Ag-specific. In contrast, MPL did not enhance the serum antibody response to five of the six unconjugated CP. MPL and trehalose dimycolate injected concurrently with the unconjugated Vi CP of Salmonella typhi (Vi) enhanced the serum antibody response to that Ag. MPL further enhanced the Vi antibody levels when injected with conjugates of this CP. The serum antibody responses to Pseudomonas aeruginosa exotoxin A, used as the carrier protein for the Staphylococcus aureus types 5 and 8 conjugates, were also enhanced by MPL. MPL in oil-in-water emulsion was generally more effective than when administered in saline.
No preview · Article · Nov 1991 · The Journal of Immunology
[Show abstract][Hide abstract]ABSTRACT: The immunomodulatory effects of low-level, chronic polychlorinated biphenyl PCB; (Aroclor 1254) exposure were investigated in female rhesus (Macaca mulatta) monkeys. Five groups of monkeys (initially 16 monkeys/group) were orally administered PCB at levels of 0, 5, 20, 40 or 80 micrograms/kg body wt/day. Tests for immunomodulation were initiated after 55 months of exposure to PCBs. Statistically significant observed immune changes included a dose-related decrease in the anamnestic (IgM and IgG) response to sheep red blood cells. Conversely, the antibody response to pneumococcus antigen did not differ significantly across the test groups. A statistically significant dose-related decrease in lymphoproliferation was noted with increasing doses of PCBs when phytohemagglutinin and Concanavalin A, but not when pokeweed mitogen, were used as mitogens. A trend toward reduced peak chemiluminescence (mV/min) was observed in zymosan-activated peripheral blood monocytes. The time to peak chemiluminescence of phorbol myristate acetate activation was statistically increased in a dose-response fashion. Flow cytometric analysis results of peripheral blood lymphocytes using the markers CD4, CD8, and CD20 were similar across the test groups. The mean percentage levels for the CD2 marker in the treated groups were statistically lower than the mean in the control, while absolute numbers for CD2 were similar across the test groups. Serum hydrocortisone levels did not differ among the test groups. Taken together these results indicate that low-level, chronic PCB exposure alters a number of rhesus monkey immune system components and that these effects may be due to altered T-cell and/or macrophage function. These data may be of use in extrapolating potential human health effects following chronic PCB exposure.
No preview · Article · Jun 1991 · Fundamental and Applied Toxicology
[Show abstract][Hide abstract]ABSTRACT: Conjugates of an uronic acid-containing capsular polysaccharide (CP), pneumococcous type 12F (Pn12F) bound to diphtheria toxoid (DT), were studied for safety and immunogenicity in adult volunteers. In mice, these conjugates, prepared with the same lot of DT and Pn12F-40234-006, a homogenous CP of high molecular weight, or Pn12-812408, a polydisperse CP with lower-molecular-weight material, were more immunogenic than the Pn12F alone and had T-cell dependent properties (A. Fattom, W. F. Vann, S.C. Szu, A. Sutton, X. Li, B. Bryla, G. Schiffman, J. B. Robbins, and R. Schneerson, Infect. Immun. 56:2292-2298, 1988). Adult volunteers, randomized into three groups, were injected either with one of these two conjugates or with Pnu-Imune, the 23 valent pneumococcus vaccine containing 25 micrograms of Pn12F as one of its components. Volunteers were injected two times, 4 weeks apart, with the Pn12F-DT conjugates and once with the Pnu-Imune. Side reactions following injection of the conjugates of Pnu-Imune were mild and short-lived. At 4 weeks and at 7 months after the first injection, higher levels of Pn12F antibodies were found in the volunteers injected with the conjugates than in the Pnu-Imune group (P less than 0.001). The conjugate prepared with the higher-molecular-weight Pn12F elicited higher levels of antibodies than the conjugate prepared with a lower-molecular-weight Pn12F preparation (P = 0.05). Both conjugates elicited about a 13-fold rise in DT antibodies.
Full-text · Article · Aug 1990 · Infection and Immunity
[Show abstract][Hide abstract]ABSTRACT: We measured IgG-class antibodies to 12 pneumococcal antigens pre- and post-immunization with polyvalent pneumococcal vaccine in 31 children who had experienced chronic chest symptoms. The purpose of the study was to determine the relation of IgG subclasses, especially IgG2, to the subjects' antibody responses to bacterial polysaccharide antigens, to see if measuring IgG subclasses would predict these responses. Twenty-nine children (90%) had low or low-normal levels of one or more IgG subclasses, including 20 out of 31 (65%) with low or low-normal levels of IgG2. Children studied had a relatively poor increase in levels of antibody to 10 of the 12 pneumococcal vaccine antigens investigated. Both pre- and post-immunization antibody levels were related to pre-immune serum concentrations of IgG2. Pre-immunization antibody levels were strongly related to post-immunization levels; when post-immunization antibody levels were adjusted for pre-immunization levels by partial correlation, the correlation between anticapsular antibody level post-immunization and IgG2 was no longer significant. Thus, in children with chronic chest symptoms, levels of antibody measured at a random interval after natural exposure to these bacterial polysaccharide antigens are related to levels of IgG2 subclass, but antibody increases after vaccination appear to be affected more by other factors.
[Show abstract][Hide abstract]ABSTRACT: This study examined the effect of mixed bacterial vaccine (MBV), a biological response modifier prepared from Streptococcus pyogenes and Serratia marcescens, on the immune system of mice and on the regression of a transplantable mouse tumor sarcoma 37. The study examined MBV's biological properties and analyzed its chemical composition. The chemical composition varied with the growth media. A typical centrifuged, dialyzed supernate of the serum-containing preparation was found to consist mainly of protein and minimal amounts of carbohydrate and endotoxin, while MBV made with synthetic medium contained similar amounts of all three. MBV was nontoxic for mice, which gained weight following the injection of 0.5-1.0 ml of MBV. MBV caused regression of 20-100% of well-established mouse tumors without appreciable toxicity. MBV also had a striking effect on the immune response of mice to sheep red blood cells. When administered simultaneously with antigen injection, MBV increased the number of antibody-secreting splenocytes measured by the plaque-forming assay threefold. Serum antibody levels also increased two- to threefold. MBV did not enhance the immune response to pneumococcal polysaccharide type III, a B-cell-dependent response. However, the in vivo administration of MBV increased the in vitro response to MBV and the B-cell mitogen lipopolysaccharide. MBV compares favorably with other biological response modifiers because of its enhancing effect on the immune response and its oncolytic properties at nontoxic levels.
No preview · Article · May 1990 · Journal of biological response modifiers
[Show abstract][Hide abstract]ABSTRACT: Pneumococcus vaccine, injected alone or mixed with diphtheria-tetanus toxoid-pertussis, did not elicit significant concentrations of pneumococcus type 6 antibodies in 2- to 5-year-old sickle cell anemia patients (n = 22). Reinjection 5 months later failed to elicit a booster response to pneumococcus type 6. We then injected conjugates of pneumococcus type 6B and of Haemophilus influenzae type b (Hib), each bound to tetanus toxoid (TT), alternatively at monthly intervals into sickle cell anemia patients of the same age group (n = 25); most received 3 injections of each vaccine. Pneumococcus vaccine was administered to 19 patients and Hib to 1 at approximately 1 year of age. Blood samples were taken before each and approximately 6 months after the last injection. Infrequent and minimal local reactions and only 6 episodes of fever (3%) occurred after injection of the conjugates. Pneumococcus type 6B-TT elicited a rise in the geometric mean concentration of pneumococcus type 6 antibodies (Ab) from 104 ng of antibody nitrogen (AbN)/ml in preimmunization sera to 385 ng of AbN/ml after the first injection (P less than 0.01). There were further increases after the 2 subsequent injections; 6 months after the third injection, the mean concentration was 940 ng of AbN/ml and 15 of 16 (94%) had greater than 300 ng of AbN/ml. Hib-TT elicited a 160-fold increase of Hib antibodies to a geometric mean concentration of 39.0 micrograms of Ab/ml after the first injection. These levels rose approximately 2-fold following 2 additional injections to 71.7 micrograms/ml and declined to 10.7 micrograms/ml at the 6-month sampling.(ABSTRACT TRUNCATED AT 250 WORDS)
No preview · Article · Apr 1990 · The Pediatric Infectious Disease Journal
[Show abstract][Hide abstract]ABSTRACT: A scheme for the synthesis and purification of conjugates, composed of the type 12F capsular polysaccharide of Streptococcus pneumoniae (Pn12F) and diphtheria toxoid, is described. The scheme is a modification of that described previously for the Vi capsular polysaccharide of Salmonella typhi, a linear homopolymer of N-acetylgalactoseaminouronic acid (S. C. Szu, A. L. Stone, J. D. Robbins, R. Schneerson, and J. B. Robbins, J. Exp. Med. 166:1510-1524, 1986). Pn12F is a branched-chain copolymer composed of a hexasaccharide repeating unit containing an aminouronic acid, N-acetylmannoseaminouronic acid (K. Leontein, B. Lindberg, and J. Lonngren, Can. J. Chem. 59:2081-2085, 1981). Sulfhydryl groups were introduced into Pn12F by forming an amide bond between cystamine and carboxyl groups of N-acetylmannoseaminouronic acid in the presence of a carbodiimide. The disulfide moiety of cystamine was reduced to form the cysteamine derivative of Pn12F which was, in turn, covalently bound to diphtheria toxoid by using the heterobifunctional linker N-succinimidyl-3-(2-pyridylthio)propionate. Unbound, high-molecular-weight Pn12F was removed from the conjugate by hydrophobic interaction chromatography through octyl Sepharose by using n-octyl-beta-D-glucopyranoside as the eluent. In young outbred mice, Pn12F did not elicit detectable serum antibodies. Pn12F-diphtheria toxoid, in contrast, elicited antibodies after two injections and had T-cell-dependent properties as evidenced by a response to priming and by its ability to elicit booster responses. This scheme seems applicable to the synthesis of conjugates with other capsular polysaccharides containing aminouronic acids. Clinical evaluation of Pn12F-diphtheria toxoid conjugates in healthy and in immunocompromised hosts is planned.
Full-text · Article · Oct 1988 · Infection and Immunity
[Show abstract][Hide abstract]ABSTRACT: The role of the spleen in antibody production and in susceptibility to pneumococcal infections remains poorly understood. Recently we showed that in A/J mice high antibody responses to polysaccharide antigens depend upon dosage, antigenic structure, interval between immunization and assay and the presence of the spleen. To investigate the possibility of alternative patterns of response, intact and splenectomized (Sx) C57BR/cdj mice were assayed for antibody responses to two structurally different pneumococcal polysaccharides, type 3 (SIII) and type 14 (SXIV). After 50 or 100 ng of SIII, intact C57BR/cdj mice produced uniformly low antibody responses that were further suppressed by splenectomy, but after 1,000 ng of SIII, C57BR/cdj mice, regardless of whether they were intact or Sx, produced antibody responses as high as those of intact A/J mice. Following SXIV, a spleen-dependent antigen, C57BR/cdj mice produced consistently lower antibody responses than A/J mice. Antibody responses to 500 or 5,000 ng of SXIV were totally obliterated in Sx C57BR/cdj mice; but unlike A/J mice, responses to 10,000 ng were similar regardless of whether C57BR/cdj mice were intact or Sx. The inability of intact C57BR/cdj mice to produce elevated responses to SIII or SXIV suggests that C57BR/cdj mice may lack the subset of spleen cells necessary for a vigorous response to these antigens. The data suggest that these mice could provide useful animal models for studying host variability in antibody responses to pneumococcal polysaccharides.
[Show abstract][Hide abstract]ABSTRACT: Twenty patients with malignant melanoma were treated with cyclophosphamide (100, 300 or 500 mg/m2 i.v.) in pilot studies to determine whether such treatment affected suppressor-cell activity. Delayed hypersensitivity to dinitrochlorobenzene and other recall antigens, the serological response to primary immunization with pneumococcal or influenza virus antigens, and the serological response to melanoma antigens were found to be normal and were not changed by cyclophosphamide (Cy) treatment. In vitro assays for production of antibodies against sheep red blood cell (SRBC) antigens, reactivity in the mixed lymphocyte culture reaction, and induction of suppressor cells by Concanavalin-A (Con-A) yielded abnormal results as a consequence of increased suppressor-cell activity in eleven, three, and nine patients, but no concordance was seen between results with the three assays prior to treatment. After treatment with Cy, the results of these tests became normal in seven, three, and seven of the patients with previously abnormal results, independent of the dose given. Examining all patients as a group, a statistically significant effect was seen after treatment with Cy on days 14 and 21 in the assay for the production of antibodies against SRBC, and days 7, 14, 21, 28, and 35 in the assay for Con-A-induced suppressor cells. The decrease in suppressor-cell activity was largely restricted to patients who showed increased suppressor-cell activity prior to treatment with Cy. Our results suggest that increased suppressor-cell activity in patients with malignant melanoma does not affect immune reactions generally but is selective, and that the anti-suppressor-cell effect of Cy is restricted to reactions with increased suppressor-cell activity to start. Based on these results, attempts at increasing the immune response to melanoma antigen vaccines administered between 7 and 35 days after treatment with Cy seem justified.
No preview · Article · Sep 1987 · Journal of biological response modifiers
[Show abstract][Hide abstract]ABSTRACT: Antibody responses to two structurally different pneumococcal polysaccharides, type 3 (SIII) and type 14 (SXIV), were examined in intact and splenectomized (Sx) A/J mice to determine whether the role of the spleen in immune responses to these antigens varies with respect to the dosage, the antigenic structure, or the interval between immunization and assay. Antibody responses to SIII and SXIV, measured over a 4-week period by radioimmunoassay, differed in antigenic load requirements, kinetics, and extent of dependence upon the spleen. Intact mice given 50 or 100 ng of SIII produced peak antibody responses on day 5, which tapered off by days 14 and 21. Intact mice given SXIV required doses 100 times greater than those of SIII to stimulate high levels of antibody response; antibody responses increased on day 5 and remained elevated through day 28. In Sx mice given 50 or 100 ng of SIII, the peak antibody response on day 5 was obliterated, but extrasplenic sources produced low levels of antibody which peaked by day 14. In Sx mice given SXIV, all anti-SXIV responses were abrogated regardless of the dose or day of assay. Differences between the anti-SIII and anti-SXIV responses in dependence upon the spleen were probably due to structural differences between the two antigens and to the localization of each to different sites in the reticuloendothelial system. These results attest to the importance of the spleen in antibacterial resistance. They show that, even in the presence of extrasplenic antibody synthesis, the spleen is required for early antibody production, the timing of which is critical for the effective clearance of bacteria.
Preview · Article · Jul 1987 · Infection and Immunity
[Show abstract][Hide abstract]ABSTRACT: The immune response of 271 elderly persons to the new 23-valent pneumococcal vaccine was studied prospectively. Sera were obtained prevaccination, at 1 month post- and 12 months postvaccination. They were analyzed by radioimmunoassay for the presence of antibody Types 1, 3, 6A, 7F, 8, and 9N. The results showed differences in antibody levels by sex of the individual (p less than .01 pre and p = .04 at 1 month post), with women having lower antibody levels than men. Women responded better to vaccination than men (p = .05), but they also lost their acquired antibodies faster (p less than .01). No age effect and no effect of level of functioning were observed within this group of elderly individuals. Participants who died had high initial levels and responded well. Major differences between the six types were noticed. Type 6A exhibited the described pattern most clearly, whereas Type 3 often behaved in an opposite pattern from the other five types. We conclude that sex differences persist even among elderly adults, that high levels of antibodies are not necessarily an indicator of good health, and that much unexplained variation between antibody types exist.
No preview · Article · Jun 1987 · Journal of Gerontology