Candidate AIDS vaccines.
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AIDS Vaccines↗
Biomedical subjects
B S Graham
Publications and source records attributed to B S Graham.
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↗
Differences in the antibody response to human immunodeficiency virus-1 envelope glycoprotein (gp160) in infected laboratory workers and vaccinees.
Studies of the immune response to the human immunodeficiency virus (HIV) have been hampered by the antigenic diversity of the HIV envelope protein. In an effort to predict the efficacy of vaccination we have compared the systemic anti-envelope antibody response in seronegative volunteers immunized with recombinant gp160 (either in vaccinia or as soluble protein produced in baculovirus) derived from the HTLV-IIIB strain of HIV-1 and in two laboratory workers accidentally infected with the same strain. 11 of 14 vaccinees responded to immunization by producing anti-gp160 of similar titer and the same isotype as that seen in the laboratory workers. Four vaccinees also had antibody to the principal neutralizing domain (V3 loop) that was comparable in titer with that seen in the laboratory workers, but the fine specificity of anti-V3 antibody was qualitatively different in the two groups. Antibody that can block the interaction between CD4 and gp120 was present at comparable levels in three vaccines and the lab workers. Neutralizing antibody titers were markedly lower in the vaccinees than in the laboratory workers. In seven of the vaccinees, an immunodominant epitope was at amino acid 720-740. Analyses of monoclonal antibodies to this region indicate that they do not neutralize, bind to infected cells, nor function as immunotoxins. Although the anti-gp160 antibody response was of similar magnitude in both infected and vaccinated individuals, there were important qualitative differences.
AIDS Vaccines↗
Serum antibodies to HIV-1 in recombinant vaccinia virus recipients boosted with purified recombinant gp160. NIAID AIDS Vaccine Clinical Trials Network.
Serum antibody responses were studied in detail in four vaccinia-naive volunteers in a phase I trial evaluating primary vaccination with a recombinant vaccinia virus expressing the HIV-1 gp160 envelope glycoprotein (HIVAC-1e, Oncogen/Bristol-Myers Squibb), followed by booster immunization with baculovirus-derived rgp160 (VaxSyn, MicroGeneSys). Prior to boosting, low-titer Fc receptor (FcR)-mediated, antibody-dependent enhancing (ADE) activity was detected in two of four volunteers but no IgM, IgG, IgA, neutralizing activity, or complement-mediated ADE activity was detected. Two weeks after boosting, all four volunteers developed HIV-1-specific IgG with titers of 1:160 to 1:640 by immunofluorescence assay. IgG1 was present in sera from each individual, while IgG2 and IgG3 were present in sera from two individuals, and IgG4 was present in serum from one individual. IgM and IgA were undetectable in all sera. Only one volunteer had IgG to the heterologous HIV-1 isolates, RF, MN, and SF2, after boosting. Serum from this volunteer neutralized the vaccine strain, LAV/IIIB, but not the heterologous strains, RF, MN, and SF2. Antibodies from the remaining volunteers had no neutralizing activity. The neutralizing serum had a positive reaction in a peptide-based ELISA utilizing a peptide corresponding to the principal neutralizing domain of the third hypervariable region (i.e., V3 loop) of the envelope glycoprotein. Neutralizing activity was partially removed by adsorption to this peptide, suggesting that it contained a type-specific neutralizing vaccine epitope. A low titer (1:40 to 1:80) of complement-mediated ADE activity to HIV-1 IIIB was present in sera from three vaccinees after boosting. FcR-ADE activity for HIV-1 SF2 and SF-128A were present in sera from two of these three vaccinees. None of the volunteers developed antisyncytial antibodies. These results indicate that inoculation with recombinant vaccinia followed by rgp160 boosting is the most effective strategy to date for inducing serum antibodies to the envelope glycoproteins of HIV-1, but further study is needed to optimize the functionality and cross-reactivity of these responses.
AIDS Vaccines↗
Chronic fibrosing mediastinitis and superior vena caval obstruction from blastomycosis.
Chronic fibrosing mediastinitis is most commonly a complication of granulomatous disease caused by histoplasmosis. We report a case of Blastomyces dermatitidis causing superior vena caval obstruction from fibrosing mediastinitis.
Aged↗
Clinical trials of AIDS vaccines in seronegative volunteers: vectors and combinations.
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AIDS Vaccines↗
Acute pubic osteomyelitis in athletes.
Three cases of pubic osteomyelitis in athletes are reported. The clinical presentation in each case was acute groin, hip, or perineal pain; fever; chills; inability to bear weight; and pubic symphysis tenderness. Since radiographic changes in the pubic bone can be delayed, a high index of suspicion is required by the clinician. Although Staphylococcus aureus is the dominant pathogen in pubic osteomyelitis, it is recommended that the diagnosis be established by culture of blood or pubic bone aspirate so that specific therapy can be instituted quickly.
Acute Disease↗
Vaccination of vaccinia-naive adults with human immunodeficiency virus type 1 gp160 recombinant vaccinia virus in a blinded, controlled, randomized clinical trial. The AIDS Vaccine Clinical Trials Network.
The safety and immunogenicity of a human immunodeficiency virus type 1 (HIV-1) gp160 recombinant vaccinia virus (HIVAC-1e) vaccine was evaluated in vaccinia-naive, healthy adults at low risk for acquiring HIV-1 infection. Volunteers (n = 36) were randomized to receive HIVAC-1e or control vaccinia virus at two dosages by bifurcated needle puncture at 0 and 2 months; 12 HIVAC-1e and 6 control vaccinia virus recipients received either 10(6) or 10(7) pfu/mL at each inoculation. There was no significant difference in lesion size, level of viral replication, or systemic symptoms after vaccination with HIVAC-1e or control vaccinia virus. Of 22 HIVAC-1e recipients with lesion formation, 16 developed low-titer gp160-specific antibody responses detectable by Western blot. The peak response occurred between days 70 and 120 and was still detectable at day 365 in 9 of 18 vaccinees. gp160-specific lymphoproliferative responses were detected in 5 of 10 vaccinees. Vaccination with HIVAC-1e was safe in vaccinia-naive, healthy adults and could induce both humoral and cell-mediated gp160-specific immune responses.
AIDS Vaccines↗
Perinatal transmission of human immunodeficiency virus-1 infection and maternal immunization strategies for prevention.
OBJECTIVES: To review the current understanding of the epidemiologic and pathogenetic features of human immunodeficiency virus-1 (HIV-1) infection in pregnancy and perinatal HIV infection, and to explore immunization strategies for preventing maternal-infant transmission of HIV. DATA SOURCES: MEDLINE data base and reference lists of articles were used to identify relevant papers. Reports from conferences were noted if the data had not yet been published. METHODS OF STUDY SELECTION: We reviewed all English-language papers pertaining to maternal or fetal infection with HIV, immunology of HIV infection, immunization of pregnant women, or immunization against HIV. DATA EXTRACTION AND SYNTHESIS: Human immunodeficiency virus infection of women is increasing, and vertical transmission of HIV to children is a growing problem. There is evidence for intrauterine, intrapartum, and immediate postpartum transmission, but it is thought that the majority of transmissions occur peripartum by a minor subset of the maternal HIV-1 strains. Diagnostic advances include measurement of HIV-specific immunoglobulin A (IgA) and improved systems for polymerase chain reaction and virus isolation from potentially infected infants. Clinical and immunologic correlates of transmission remain uncertain. CONCLUSIONS: The epidemiology of transmission must be determined in more diverse populations. The timing and pathogenesis of HIV transmission from infected mother to fetus require better description, and improved diagnostic tools are needed. Immunologic and mechanical determinants that prevent transmission in the majority of cases need to be identified more precisely. Clinical trials to evaluate active immunization of HIV-infected pregnant women with candidate AIDS vaccines will potentially help answer many of these questions.
Acquired Immunodeficiency Syndrome↗
The safety and immunogenicity of a human immunodeficiency virus type 1 (HIV-1) recombinant gp160 candidate vaccine in humans. NIAID AIDS Vaccine Clinical Trials Network.
OBJECTIVE: To evaluate the safety and immunogenicity of a human immunodeficiency virus type 1 (HIV-1) recombinant envelope glycoprotein (rgp 160) candidate vaccine in humans. SUBJECTS: Healthy adults (72) who were seronegative for HIV-1 were randomly assigned to one of four groups. INTERVENTIONS: The subjects were randomly assigned to receive 40 or 80 micrograms of rgp 160, 10 micrograms of hepatitis B vaccine, or placebo in three doses (on days 0, 30, and 180), with an elective, nonblinded administration of a fourth dose on day 540. MEASUREMENTS AND MAIN RESULTS: Neither clinical nor laboratory toxicity was encountered during a follow-up period exceeding 21 months. No effect of immunization was noted on lymphocyte counts, mitogenic responses, or delayed-type hypersensitivity. Serum antibody responses to HIV envelope proteins detected by Western blot were seen in 30 of 33 subjects (91%; 95% CI, 71% to 97%) receiving either 40- or 80-micrograms doses of rgp160 and were most commonly of weakly reactive intensity. Responses were first noted by Western blot after the second dose. They markedly increased in frequency after the third dose and declined over the next 12 to 18 months. The administration of a fourth dose resulted in homologous neutralizing activity in sera from 5 to 24 subjects (21%; CI, 7% to 37%) as well as in complement-mediated antibody-dependent enhancement in sera from 6 of 24 subjects (25%; CI, 10% to 42%). Antibody responses were detected by enzyme-linked immunosorbent assay (ELISA) less frequently than by Western blot, and these responses persisted for a shorter time. CONCLUSIONS: The administration of rgp160 was well tolerated and safe, resulted in a high rate of antibody response by Western blot after the administration of the third and fourth doses, and generated serum neutralizing activity and complement-mediated antibody-dependent enhancement in some subjects after the fourth dose.
Adult↗
Reinfection of mice with respiratory syncytial virus.
A BALB/c model of respiratory syncytial virus infection has been developed in which high-titered replication occurs in lung, immunological infiltrates in lung can be detected histologically, and illness can be consistently reproduced. The immunodeterminants of RSV reinfection in this system were investigated by rechallenging mice with RSV early (less than 2 months after primary infection) and late (16 to 21 months after primary infection) and correlating illness and titer of RSV isolated from lungs and noses with RSV-specific serological responses and lung histology. After early rechallenge, RSV was cleared within 24 hours from both nose and lung. After late rechallenge, RSV was isolated at 72 hours from nose in 21/24 mice, but from lung in only 5/24 mice. Isolation of RSV from lung after rechallenge was associated with low RSV-specific antibody titers measured by ELISA and plaque-reduction neutralization. The presence of lymphocyte aggregates around the bronchovascular bundles was associated with inability to isolate RSV from lung and lack of illness. The basophilic lymphocytes were small and uniform in size with dense nuclei and a small amount of cytoplasm. These studies demonstrate that nasal and pulmonary reinfection with RSV is possible in mice after late rechallenge. The studies also indicate the potential importance of RSV-specific antibody in protecting lung from reinfection.
Animals↗
Clinical implications of resilient denture lining material research. Part II: Gelation and flow properties of tissue conditioners.
The clinical effectiveness of tissue conditioners and functional impression materials is influenced by their gelation and flow properties. Laboratory tests were previously conducted that simulated the conditions of clinical use to the extent possible on six commercial intraoral-gelling resilient denture liners. The liners were found to vary significantly in their gelation times and to flow throughout the 7-day study. Their initial flow after mixing was influenced most by the time of loading. While extrapolations to the clinical environment require caution, the results of this study imply that the dentist should (1) adapt clinical techniques to the gelation times of particular materials, (2) reduce the initial flow of some materials by delaying denture placement on the supporting mucosa, and (3) expect the materials to be effective tissue conditioners for at least 7 days.
Acrylic Resins↗
In vivo fungal presence and growth on two resilient denture liners.
To determine whether two intraoral-setting resilient denture liners supported the in vivo presence or growth of oral commensal fungi, the liners were randomly placed in the mandibular complete dentures of 14 patients. Cytologic smears were made from the liner surfaces at 1 hour and 1, 2, 7, 14 and 30 days after intraoral placement. Yeast forms were observed in six patient trials of material A and in two trials of material B. Hyphae were observed in only one patient trial of material A and in two trials of material B. When yeast forms and hyphae findings were combined and were considered as indicative of fungal presence or growth, the prevalence up to 30 days was seven for material A and four for material B. Statistical analysis revealed no significant difference in the prevalence of fungal presence or growth between the two resilient denture liners tested.
Acrylic Resins↗
Gel strength and rate of gelation of soft polymers.
A rheometer was used to characterize the gelation rate of six commercial short- to medium-term (chairside intra-oral gelation) denture soft-lining materials. Shear puncture force was measured from one to 60 days for six short- to medium-term materials as well as for three heat-cured (polymerizable) materials. The observed increase in puncture force with age of the specimen was considered to be a function of increased polymer chain entanglement and/or loss of plasticizer. Reduction in puncture force with age occurred for some materials as a result of hydration of the polymer gel. Rheometer setting time (gelation rate) and puncture force values for the intra-oral gelation materials were influenced by the quantity of ethyl alcohol present in the mixing liquid. In general, the higher the level of ethyl alcohol, the shorter the gelation time and the stronger the gel. The characterization of the properties may help develop improved prosthodontic treatment procedures, and allow better management of soft-tissue recovery following trauma.
Denture Liners↗
Respiratory syncytial virus infection in anti-mu-treated mice.
BALB/c mice were depleted of B cells by anti-mu treatment to investigate the pathogenesis of respiratory syncytial virus (RSV) infection in the absence of antibody. Termination of RSV replication after primary infection occurred with the same kinetics in anti-mu-treated mice as in phosphate-buffered saline (PBS)-treated controls. Yet, when rechallenged, anti-mu-treated mice were more permissive to RSV replication than PBS-treated controls. Anti-mu-treated mice also experienced greater illness than PBS-treated controls during both primary infection and rechallenge. Passive transfer of RSV-specific immune serum to anti-mu-treated mice before rechallenge reconstituted complete protection from RSV replication and diminished illness. Thus, RSV-specific antibody is not required to terminate RSV replication in primary infection, but without antibody, only partial immunity against rechallenge is induced. While it is unknown whether the mechanism is a direct effect on RSV titer or modulation of the illness-causing cellular immune response, the presence of RSV-specific antibody reduces illness in both primary RSV infection and rechallenge of mice.
Animals↗
Role of T lymphocyte subsets in the pathogenesis of primary infection and rechallenge with respiratory syncytial virus in mice.
The role of CD4+ and CD8+ T lymphocytes in terminating respiratory syncytial virus (RSV) replication, causing disease, and protecting from reinfection was investigated using a BALB/c mouse model in which CD4+ or CD8+ lymphocytes or both were depleted by injections of Mab directed against the respective mouse lymphocyte determinants. Kinetics of RSV replication, illness, and pathology were assessed after primary infection and rechallenge. Both CD4+ and CD8+ lymphocyte subsets were involved in terminating RSV replication after primary infection. When both T lymphocyte subsets were depleted RSV replication was markedly prolonged, yet no illness was evident, suggesting that host immune response rather than viral cytocidal effect was the primary determinant of disease in mice. Both CD4+ and CD8+ lymphocytes contributed to illness, although CD8+ lymphocytes appeared to play the dominant role in this particular system. Analysis of histological responses suggested that CD4+ lymphocytes were required for the appearance of peribronchovascular lymphocytic aggregates seen in normal mice after rechallenge, and that the presence of alveolar lymphocytes was correlated with illness. It is postulated that antibody is an illness-sparing mechanism for protecting mice from RSV infection, and that T lymphocytes are an important determinant of illness. Further delineation of RSV-induced immunopathogenesis in primary infection and reinfection will provide important information for the development of vaccine strategies.
Animals↗