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Biomedical subjects

B S Graham

Publications and source records attributed to B S Graham.

At least 73 records · Page 4Linked to original sources

Rhodococcus equi--an increasingly recognized opportunistic pathogen. Report of 12 cases and review of 65 cases in the literature.

Rhodococcus equi, a gram-positive, weakly acid-fast coccobacillus, initially isolated from horses, is becoming increasingly recognized as an important pathogen for immunosuppressed human hosts since the first human case was reported in 1967. A review of the English medical literature yielded 53 cases. During the last 11 years, the microbiology laboratories of the authors isolated the organism from 12 patients. Of the total 65 cases, 60 occurred in immunosuppressed patients with HIV infection, malignant neoplasms, or chronic immunosuppressive therapy. The lung is the most common primary site of infection. Typically, the lesion is densely infiltrated by histiocytes with multiple microabscesses. Intracellular gram-positive coccobacilli are easily demonstrated. R equi grows well on routine non-selective media at 35 degrees C. Previously, many cases may have been missed because the organism resembles oropharyngeal commensal diphtheroids. Clinical information with gram and Kinyoun strains on fresh isolates is helpful in recognizing the possibility of R equi infection.

Acquired Immunodeficiency Syndrome↗

Topical immunoprophylaxis of respiratory syncytial virus (RSV)-challenged mice with RSV-specific immune globulin.

The modulatory effects of passive antibody on viral replication, illness, and immunity were investigated in a murine model of respiratory syncytial virus (RSV) infection. Nasally administered RSV-specific immune globulin (RSVIG) given prophylactically in a large volume (100 microL) reduced illness and RSV replication in lung after primary challenge. However, passive antibody treatment diminished the host antibody response to primary RSV infection. This resulted in greater susceptibility to reinfection and an alteration in the composition of the immune response after rechallenge. RSV infection of lung during primary infection was necessary for complete protection of lung from RSV rechallenge. Nasal infection alone during primary infection was not sufficient to protect against RSV rechallenge of lung, suggesting that the immune responses in the murine system are compartmentalized. The influence of compartmentalized immunity and modulation of immune responses will be important considerations as new approaches for topical immunoprophylaxis of RSV are developed.

Administration, Intranasal↗

Interleukin-12 treatment during immunization elicits a T helper cell type 1-like immune response in mice challenged with respiratory syncytial virus and improves vaccine immunogenicity.

Adjuvant effects of exogenous interleukin (IL)-12 on induction of immune responses against respiratory syncytial virus (RSV) infection in mice were evaluated. Giving recombinant IL-12 at the time of immunization with a formalin-inactivated alum-precipitated RSV preparation resulted in significant reduction of virus replication in lungs 4 days after RSV challenge. Intraperitoneal or intramuscular IL-12 was effective when given at the time of immunization but not at the time of challenge. IL-12 treatment resulted in increased interferon-gamma mRNA in lungs, increased IgG2a RSV-specific antibody isotype utilization, and increased endogenous IL-12 p40 mRNA expression. IL-12 treatment did not significantly affect clinical outcome or cytotoxic T lymphocyte activity. These data demonstrate that IL-12 has potent adjuvant effects that may be due to induction of T helper cell type 1-like immune responses.

Adjuvants, Immunologic↗

Safety and pharmacokinetics of vitamin A therapy for infants with respiratory syncytial virus infections.

Infants with respiratory syncytial virus infection have low serum vitamin A levels. We treated 21 respiratory syncytial virus-infected children with 12,500 to 25,000 IU of oral vitamin A. Vitamin A levels were normalized at 6 h, and none of the children experienced vitamin A toxicity or exacerbation of respiratory illness. Vitamin A treatment of previously healthy respiratory syncytial virus-infected infants at these doses is safe and well tolerated.

Humans↗

Pathogenesis of respiratory syncytial virus vaccine-augmented pathology.

Respiratory syncytial virus (RSV) is an important respiratory pathogen for which vaccine development has been thwarted by the legacy of vaccine-enhanced illness. A formalin-inactivated, alum-precipitated, whole virus vaccine did not protect children from infection and was associated with severe illness. Clues from clinical studies of RSV and vaccine-induced atypical measles illness suggest that an aberrant CD4+ lymphocyte response occurred in vaccinees. There is a growing body of evidence from murine models that show vaccine formulations can selectively activate different populations of CD4+ T helper lymphocytes that produce distinct cytokine expression patterns. The cytokine milieu in turn can influence the composition of the immune response and thereby impact the efficiency of virus clearance, type of pathology, and magnitude of illness. Major priorities of current vaccine development are to define the optimal combination of T lymphocyte subsets to safely clear RSV and to learn ways to modulate the composition of the immune response to vaccine antigens.

CD4-Positive T-Lymphocytes↗

Interpreting HIV serodiagnostic test results in the 1990s: social risks of HIV vaccine studies in uninfected volunteers. NIAID AIDS Vaccine Clinical Trials Group.

OBJECTIVE: To evaluate the influence of a human immunodeficiency virus (HIV) vaccine given to uninfected volunteers on the interpretation of serodiagnostic HIV test results. DESIGN: Retrospective cohort study. SETTING: 5 AIDS Vaccine Evaluation Units funded by the National Institute of Allergy and Infectious Diseases. PARTICIPANTS: The first 266 healthy adult volunteers (aged 18 to 60 years) who did not have HIV infection and whose history suggested that they were at low risk for acquiring HIV infection. MEASUREMENTS: HIV antibody was measured by enzyme-linked immunosorbent assay (ELISA) and Western blot test, the results of which were interpreted on the basis of four different published criteria. RESULTS: At some time during the first 12 months of the vaccine studies, 68% of volunteers were positive for HIV antibodies by ELISA. Depending on criteria used to interpret Western blot test results, 0% to 44% of volunteers had positive results that might have caused them to be incorrectly labeled as HIV infected. CONCLUSIONS: Significant social risks to volunteers participating in HIV vaccine studies were identified. Persons interpreting HIV serodiagnostic test results must consider that an HIV vaccine can cause a positive result in persons who are not infected.

AIDS Vaccines↗

Neutralizing antibodies to HIV-1 in seronegative volunteers immunized with recombinant gp120 from the MN strain of HIV-1. NIAID AIDS Vaccine Clinical Trials Network.

OBJECTIVE: To evaluate the safety and immunogenicity of the MN strain of recombinant gp120 (MN rgp120) as a vaccine prototype to prevent human immunodeficiency virus (HIV). DESIGN: Double-blind, randomized, placebo-controlled study with subjects vaccinated at 0, 4, 24, and 48 weeks and followed up through 64 weeks. SETTING: The AIDS Vaccine Evaluation Units in St Louis, Mo, Nashville, Tenn, and Rochester, NY, conducted the clinical study. Laboratory studies were conducted at Duke University, Raleigh, NC; data analysis was done by the Data Coordinating and Analysis Center at the EMMES Corporation, Potomac, Md. PARTICIPANTS: Fifty-seven persons seronegative for HIV, at low risk for acquiring HIV infection, and 18 to 60 years of age. INTERVENTIONS: The MN rgp120 vaccine was administered to 12 volunteers each in doses of 100 micrograms, 300 micrograms, or 600 micrograms, and 12 volunteers received a combination of 300 micrograms of MN rgp120 vaccine and 300 micrograms of vaccine from rgp120 of strain IIIB. Nine volunteers received alum adjuvant alone (control). MAIN OUTCOME MEASURES: Safety was assessed by monitoring lymphocyte subsets, serum creatinine, and liver enzymes. Immunogenicity was measured by enzyme-linked immunosorbent assay using the immunogen and synthetic peptide corresponding to the variable region 3 domain of gp120. Functional antibody assays included CD4 binding blocking; antibody-dependent, cell-mediated cytotoxicity; and neutralization of homologous and heterologous HIV strains. RESULTS: No severe adverse reactions occurred. In 33 of 48 volunteers, two doses of vaccine induced antibodies that neutralized the homologous strain HIV-1/MN. Three doses of vaccine induced antibodies that neutralized MN (in 46 of 48 volunteers), SF-2 (in 45 of 48 volunteers), or IIIB strains of HIV-1 (in 30 of 48 volunteers). CONCLUSION: The vaccines were safe and immunogenic. Multiple injections of vaccine broadened and increased the neutralizing antibody response.

AIDS Vaccines↗

Serum vitamin A levels in respiratory syncytial virus infection.

Respiratory syncytial virus causes worldwide epidemics of respiratory disease. Of 23 children infected with respiratory syncytial virus, 65% had low serum concentrations of vitamin A during acute illness; these low values were associated with more severe illness. Vitamin A supplementation may have a role in the management of infection with respiratory syncytial virus.

Case-Control Studies↗

Studies of high doses of a human immunodeficiency virus type 1 recombinant glycoprotein 160 candidate vaccine in HIV type 1-seronegative humans. The AIDS Vaccine Clinical Trials Network.

We examined the safety and immunogenicity of a baculovirus-derived recombinant HIV-1 envelope glycoprotein vaccine candidate, rgp160 (VaxSyn; MicroGeneSys, Meriden, CT), administered at doses of 160 or 640 micrograms to 56 healthy, HIV-1-seronegative adults, in a randomized, double-blind, placebo-controlled study. Immunizations were given intramuscularly at 0, 1, 6, and 12 months. Both doses were generally well tolerated, although self-limited local reactions were frequent. No other clinical or laboratory toxicities were noted, and no effects on CD4 or CD8 lymphocyte counts or percentages were noted. Serum antibody responses to HIV proteins were detected by Western blot (WB) in 19 of 20 and in 19 of 19 recipients of four doses of 160 and 640 micrograms, respectively. Western blot responses developed more rapidly in the 640-micrograms group. High rates of EIA antibody responses to HIV-1 lysate were also present in both groups, and developed more rapidly in the 640-micrograms group. Enzyme immunoassay antibody responses to the immunogen (rgp160) were also frequent, but were infrequent to V3 to gp41 peptides. Neutralizing antibodies against the homologous HIV-1 LAI isolate were seen in 3 of 20 subjects (GMT = 11) who received four doses of 160 micrograms, and in 10 of 19 subjects who received four doses of 640 micrograms (GMT = 32). Fusion inhibiting antibody was not detected. CD4 blocking activity was seen in 3 of 19 subjects who received four doses of 640 micrograms. Complement-mediated antibody-dependent enhancement was found in sera from 11 of 19 volunteers in the 640-micrograms group. Lymphocyte proliferative responses to the immunogen were detected in 4 of 4 subjects tested, but no cytotoxic T cell activity was noted in 11 subjects. Administration of the 640-micrograms dose of this rgp160 vaccine candidate relative to the lower doses was associated with increased immunogenicity, including higher rates of homologous neutralizing antibody responses, although at low titer.

AIDS Vaccines↗

Binding of human immunodeficiency virus type 1 to the C3b/C4b receptor CR1 (CD35) and red blood cells in the presence of envelope-specific antibodies and complement. National Institutes of Health AIDS Vaccine Clinical Trials Networks.

Immune complexes formed in vitro by incubating cell-free human immunodeficiency virus type 1 (HIV-1) with sera from infected or gp160-vaccinated persons, together with normal human serum as a source of complement, readily bound to K562 cells expressing recombinant human complement receptor type 1 (CR1). However, antibodies from seronegative persons had little or no effect. This effect was absent in the presence of heat-inactivated or C3-depleted normal human sera or when wild type K562 cells were used, confirming a requirement for complement and CR1. In additional experiments, complement alone targeted HIV-1 to CR1 on red blood cells, and envelope-specific antibodies increased this effect. These results demonstrate that envelope-specific antibodies promote HIV-1 immune complex formation with complement and that these complexes readily bind CR1 on cell surfaces.

Antigen-Antibody Complex↗

Determinants of antibody response after recombinant gp160 boosting in vaccinia-naive volunteers primed with gp160-recombinant vaccinia virus. The National Institute of Allergy and Infectious Diseases AIDS Vaccine Clinical Trials Network.

Priming with a live recombinant vector followed by subunit boosting is a promising strategy for human immunodeficiency virus (HIV) immunization. Twenty-nine vaccinia-naive volunteers were primed with gp160-recombinant vaccinia virus (HIVAC-1e) and boosted with recombinant (r) gp160 to define factors associated with the magnitude and specificity of antibody response after booster immunization. A longer interval between inoculation and boost, two inoculations of HIVAC-1e with lesion formation occurring after the first, and Western blot-detectable antibody to gp160 after inoculation were significantly associated with higher neutralizing antibody titers and fusion-inhibiting activity after boosting. HIVAC-1e-primed vaccinees were more likely to have antibody to V3- and CD4-binding regions of gp120 and less likely to have antibody to constant regions 2 and 3 than vaccinees immunized with rgp160 alone. Priming volunteers with HIVAC-1e was a key determinant of the epitope specificity and magnitude of functional antibody responses induced by rgp160 boosting.

AIDS Vaccines↗

HIV-1 recombinant gp160 vaccine given in accelerated dose schedules. NIAID AIDS Vaccine Clinical Trials Network.

The purpose of this randomized, double-blind study was to test the safety and immunogenicity of an HIV-1LAI recombinant gp160 (rgp160) vaccine in healthy, uninfected volunteers using accelerated dosing schedules. Thirty volunteers were randomly assigned to receive 50-micrograms doses of rgp160 in one of two immunization schedules. Group 1 received rgp160 at times 0, 1, 2 and 5 months; and group 2 received rgp160 at times 0, 1, 2, 3 and 4 months. The vaccine was safe and stimulated high levels of HIV-1 envelope-specific binding antibody and T cell memory. There was a trend (P < 0.10) suggesting neutralizing antibodies were better induced by the regimen incorporating a rest period before the final immunization in group 1 volunteers. Both accelerated immunization schedules induced immune responses at levels similar to or better than those achieved by four rgp160 vaccine injections given over 12-18 months in other studies.

AIDS Vaccines↗

Anti-IL-4 treatment at immunization modulates cytokine expression, reduces illness, and increases cytotoxic T lymphocyte activity in mice challenged with respiratory syncytial virus.

Upon respiratory syncytial virus (RSV) challenge, mice previously immunized intramuscularly with inactivated whole virus express a Th2-like pattern of cytokine mRNA, while mice immunized with live virus intranasally express a Th1-like pattern. In this study, we evaluated the effects of anti-IL-4 treatment on the induction of immune responses after immunization. Mice treated with anti-IL-4 at the time of immunization with inactivated RSV had reduced clinical illness after live virus challenge, as measured by weight loss, illness score, and virus replication. This was associated with an augmented CD8+ cytotoxic T lymphocyte (CTL) activity, increased expression of IFN-gamma mRNA relative to IL-4 mRNA, and a higher titer of RSV-specific IgG2a in the anti-IL-4 treated mice before challenge. Anti-IL-4 administration at the time of challenge had no effects on illness, immunoglobulin isotype, or cytokine patterns. These results suggest that inhibition of IL-4 action at immunization can shift the selective activation of lymphocytes to a more Th1-like response. This cytokine milieu is associated with augmented CTL activity, which may be the factor responsible for rapid viral clearance and reduced illness at the time of remote RSV challenge.

Animals↗

Extrapulmonary thoracic disease caused by Blastomyces dermatitidis.

A case of blastomycosis is reported involving the mediastinum and compromising the plexus brachialis. The pathology, pathophysiology, and treatment of this patient and of a previously reported patient are discussed and compared with the characteristics of extrapulmonary thoracic disease caused by histoplasmosis. Because of the favorable response of these patients to prolonged antifungal therapy, blastomycosis should be considered in the differential diagnosis of invasive extrapulmonary thoracic disease.

Adult↗

Priming immunization determines T helper cytokine mRNA expression patterns in lungs of mice challenged with respiratory syncytial virus.

Defining the mechanism for the vaccine-enhanced illness associated with respiratory syncytial virus (RSV) is critical for advancing RSV vaccine development. Previous studies in which infants were vaccinated with formalin-inactivated alum-precipitated whole virus did not protect from RSV infection, and those infected had a high incidence of severe illness. In contrast, previous clinical trials evaluating live attenuated RSV showed no associated vaccine-enhanced illness. We have used a mouse model to explore the immunopathogenesis of RSV infection. In this study cytokine mRNA expression was examined using 32P-labeled oligonucleotide probes in Northern blot analyses of polyA RNA extracted from lungs of mice primed with various vaccine preparations then challenged nasally with live RSV. We have shown that upon challenge, priming of mice with inactivated virus or subunit F glycoprotein induced a pattern of cytokine mRNA expression suggesting a dominant Th2-like lymphocyte response (relative increase in IL-4 mRNA expression). In contrast, challenge of mice primed with live RSV by parenteral or mucosal routes induced a Th1-like pattern of cytokine mRNA expression (relative decrease in IL-4 mRNA expression compared to IFN-gamma mRNA expression). Thus, the formulation and route of delivery of vaccine products can influence the pattern of cytokine expression in lung upon RSV challenge.

Animals↗

Adult immunization with acellular pertussis vaccine.

OBJECTIVE: To evaluate the safety and immunogenicity in adults of several different concentrations of an acellular pertussis vaccine. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Medical center immunization clinic. PARTICIPANTS: One hundred eighteen healthy adult volunteers. INTERVENTIONS: Participants received standard adult tetanus-diphtheria vaccine alone or combined with full-strength, half-strength, or quarter-strength concentrations of a currently licensed acellular pertussis vaccine used for booster doses in young children. Full-strength vaccine contained 40 micrograms of pertussis proteins, consisting of 86% filamentous hemagglutinin, 8% pertussis toxin, 4% 69-kd outer-membrane protein, and 2% agglutinogens. MAIN OUTCOME MEASURES: Local and systemic reactions were assessed for 14 days after vaccination. Serum samples for antibody assay were obtained before, 1 month after, and 1 year after immunization. RESULTS: Adverse reactions were few and minor and did not differ in frequency or severity among the four study groups. The groups receiving acellular pertussis vaccine showed strong antibody responses to pertussis antigens, which did not significantly differ by concentration of vaccine. After 1 year, levels of antibody to pertussis had declined by approximately 50% but remained substantially higher than preimmunization levels. The four groups did not differ in antibody responses to tetanus or diphtheria toxoids. CONCLUSIONS: Routine reimmunization of adults with a vaccine containing acellular pertussis antigens in addition to diphtheria and tetanus toxoids can substantially enhance pertussis antibody levels without an increase in adverse reactions or diminution in response to the diphtheria and tetanus components. Such a program might materially reduce respiratory illness among both adults and children.

Adult↗

Augmentation of human immunodeficiency virus type 1 neutralizing antibody by priming with gp160 recombinant vaccinia and boosting with rgp160 in vaccinia-naive adults. The NIAID AIDS Vaccine Clinical Trials Network.

Twelve vaccinia-naive volunteers were inoculated with recombinant vaccinia virus expressing the human immunodeficiency virus type 1 (HIV-1) strain IIIB (HIV-1IIIB) envelope glycoprotein gp160 and subsequently immunized with 640 micrograms of recombinant (r) gp160 protein produced in baculovirus. After booster immunization with rgp160, the sera of all vaccinees showed strong antibody responses detected by Western blot and ELISA; 8 had neutralizing activity and 5 had fusion inhibition activity against the homologous strain; 5 blocked binding of CD4 cells to gp120. Cross-reactive neutralization of HIV-1MN was detected in 3 of 8 sera that neutralized HIV-1IIIB. The combination of live recombinant vaccinia followed by subunit booster immunization was more immunogenic than either product alone and represents a promising approach for HIV-1 immunoprophylaxis. Further definition of recombinant vaccinia safety and augmentation of immune responses to geographically prevalent HIV-1 strains will be necessary before expanding clinical trials to high-risk groups.

AIDS Vaccines↗