Candidate AIDS vaccines.
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AIDS Vaccines↗
Biomedical subjects
P F Wright
Publications and source records attributed to P F Wright.
Minimizing the risks associated with the prevention of poliomyelitis.
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Anti-Bacterial Agents↗
Diagnostic tests for poliovirus infection: a comparison of neutralization and immunofluorescence for the identification and typing of stool isolates.
Neutralization and indirect immunofluorescence were compared for the identification and serotyping of poliovirus. Indirect immunofluorescence was highly concordant with neutralization and offers a more rapid procedure for identification and characterization of poliovirus strains.
Feces↗
Global immunization--a medical perspective.
The global community is close to achieving universal childhood immunization against a group of important childhood diseases--measles, tuberculosis, diphtheria, pertussis, tetanus and polio. In addition, polio has been targeted for eradication by the year 2000 and neonatal tetanus for elimination by 1995. There are targeted reductions in mortality and cases of measles by the same year. This paper addresses the difficult issue of how optimally to integrate these public health initiatives into local health care practices and beliefs. At the workshop on Global Immunization and Culture I presented the perspective of a physician who has worked with the Expanded Programme on Immunization and has understanding at a global level of the logistics of vaccine delivery. This paper serves as a counterpoint to others at the workshop by raising the question of whether routine vaccine delivery and special eradication efforts can be best carried out with a uniform, technologically based approach rather than extensive adaptation of the program to local conditions and beliefs. The reliance on a largely technological approach to control of these childhood diseases which occur in all societies independent of social behavior is contrasted with efforts to control HIV infection in which social structure and practices predict the occurrence of disease.
Acquired Immunodeficiency Syndrome↗
A live attenuated bovine parainfluenza virus type 3 vaccine is safe, infectious, immunogenic, and phenotypically stable in infants and children.
The safety, infectivity, immunogenicity, transmissibility, and phenotypic stability of an intranasal bovine parainfluenza virus type 3 (BPIV-3) candidate vaccine was evaluated in a randomized, double-blind, placebo-controlled trial. Of human parainfluenza virus type 3 (HPIV-3)-seronegative children, 92% were infected, and 92% developed a serum hemagglutination-inhibiting (HAI) antibody response to BPIV-3 and 61% to HPIV-3. Geometric mean HAI titers were 1:40 to BPIV-3 and 1:16 to HPIV-3. In studies to evaluate vaccine transmissibility, none of 14 placebo recipients in close contact with 14 vaccinees shed BPIV-3. BPIV-3 isolates from seronegative vaccinees retained the attenuation phenotype when tested in rhesus monkeys. Although it is difficult to evaluate the safety and immunogenicity of such a vaccine in an open population of children who frequently become infected with HPIV-3, it appears that the live BPIV-3 vaccine is attenuated, infectious, immunogenic, poorly transmissible, and phenotypically stable and warrants further evaluation as a candidate vaccine in infants and children.
Animals↗
A live human parainfluenza type 3 virus vaccine is attenuated and immunogenic in healthy infants and children.
The safety, infectivity, immunogenicity, and phenotypic stability of the cold-passaged (cp) candidate vaccine cp-45, a cold-adapted (ca), temperature-sensitive (ts) mutant of the JS strain of human parainfluenza virus type 3 (HPIV-3), was evaluated in 114 children 6 months to 10 years old in a randomized, placebo-controlled, double-blind trial. The cp-45 vaccine was well tolerated when given intranasally to parainfluenza virus type 3 (PIV-3)-seropositive and -seronegative children. With 10(4) or 10(5) TCID50 of cp-45 vaccine, 86% of seronegative vaccines were infected, 83% of whom shed virus at a mean peak titer of 10(22) pfu/mL. Virus present in respiratory specimens retained the ts phenotype, and each of 86 PIV-3 isolates tested retained both the ca and ts phenotypes. One dose of 10(5) TCID50 of vaccine induced a serum hemagglutination-inhibiting antibody response in 81% of vaccinees; the geometric mean titer was 1:32. These studies indicate that the cp-45 HPIV-3 vaccine is satisfactorily attenuated, infectious, immunogenic, and phenotypically stable and merits further evaluation in infants and young children.
Antibodies, Viral↗
Seroresponse to trivalent oral poliovirus vaccine as a function of dosage interval.
Seroresponses to trivalent oral poliovirus vaccine are not uniform throughout the world. Definition of the variables that determine successful immunization is vital to ensure global polio eradication. One such variable may be dosage interval. To investigate this effect 108 infants were enrolled in a clinical trial and randomly assigned to receive three doses of trivalent oral poliovirus vaccine (standard United States formulation) at 2, 3 and 4 or 2, 4 and 6 months of age. After three doses of vaccine given before 6 months of age, immunity was virtually complete for each of the three poliovirus types in both groups. After two doses the seroresponse rate to each type was less with the shorter dose interval. However the difference was not significant (P = 0.15) in the sample size studied. Such responses differ markedly from those seen in developing countries, where four or more doses of vaccine may fail to provide complete protection. Differences other than dosage interval must contribute to those failures.
Antibodies, Viral↗
A randomized controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease.
A double-blind, randomized controlled trial over 5 years compared the safety, immunogenicity, and efficacy of cold-adapted and inactivated influenza A vaccines in 5210 normal subjects. Both vaccines were well tolerated. Inactivated vaccine significantly increased hemagglutination inhibition antibody titers. Significant titer rises were also noted after cold-adapted vaccine but of lesser magnitude than with inactivated vaccine. The efficacy of inactivated vaccine in preventing culture-positive influenza was 76% (95% confidence interval [CI], 58%-87%) for H1N1 disease and 74% (95% CI, 52%-86%) for H3N2; for cold-adapted vaccine, 85% (95% CI, 70%-92%) and 58% (95% CI, 29%-75%), respectively. The efficacy of inactivated vaccine in preventing a four-fold rise in antibody titer over the influenza season was 69% (95% CI, 61%-76%) for H1N1 and 73% (95% CI, 65%-79%) for H3N2; for cold-adapted vaccine, 54% (95% CI, 44%-62%) and 32% (95% CI, 17%-44%), respectively. Cold-adapted and inactivated influenza vaccines are safe and effective for preventing influenza A disease.
Administration, Intranasal↗
Sustained transmission of mumps in a highly vaccinated population: assessment of primary vaccine failure and waning vaccine-induced immunity.
From January to July 1991, an outbreak of mumps occurred in Maury County, Tennessee. At the primarily affected high school, where 98% of students and all but 1 student with mumps had been vaccinated before the outbreak, 68 mumps cases occurred among 1116 students (attack rate, 6.1%). Students vaccinated before 1988 (the first year mumps vaccination was required for school attendance in Tennessee) may have been at greater risk of mumps than those vaccinated later (65[6.1%] of 1001 vs. 2[2.2%] of 89; risk ratio, 2.9; 95% confidence interval, 0.7-11.6). Of 13 persons with confirmed mumps who underwent serologic testing, 3 lacked IgM antibody in well-timed acute- and convalescent-phase serum specimens. Vaccine failure accounted for a sustained mumps outbreak in a highly vaccinated population. Most mumps cases were attributable to primary vaccine failure. It is possible that waning vaccine-induced immunity also played a role.
Adolescent↗
Comparison of live attenuated and inactivated influenza vaccines in cystic fibrosis patients and their families: results of a 3-year study.
Forty-one cystic fibrosis (CF) patients and 89 family members were immunized in a double-blind randomized 3-year trial with either intranasal live cold-adapted (ca) influenza A vaccine or the recommended intramuscular trivalent inactivated (triv) influenza vaccine. Local, respiratory, and systemic symptoms after vaccine were infrequent and did not differ between vaccine groups. CF patients did not differ from family members in immune response to either vaccine. Although antibody responses tended to be higher after triv vaccine, > or = 85% of subjects had mean hemagglutination inhibition antibody titers > or = 1:32 to influenza H1N1 and H3N2 after the first dose of either vaccine. Infection with influenza H3N2 viruses circulating during this study occurred with comparable low frequency in CF patients after ca (14 infections/100 subject-years of observation) or triv vaccine (10 infections/100 subject-years of observation). Influenza A ca vaccines appear to be safe, immunogenic alternatives to influenza A inactivated vaccines for CF patients and their families.
Adolescent↗
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↗
Tetravalent rhesus rotavirus vaccine in young infants.
A study of a tetravalent live oral rhesus rotavirus vaccine was conducted in 26 healthy infants 6-22 weeks of age to evaluate safety, viral shedding, and immunogenicity in a double-blind, placebo-controlled fashion. The tetravalent rhesus rotavirus vaccine (RRV-TV) contained equal amounts of RRV (serotype 3) and the VP7 reassortants DxRRV (serotype 1), DS1xRRV (serotype 2), and ST3xRRV (serotype 4). RRV-TV was highly infectious; 16 of 18 recipients shed virus. However, the recovered virus was almost exclusively the parent rhesus strain, RRV. Humoral immune responses were largely limited to the RRV strain. The most consistent response, seen in 14 of 18 vaccines, was an ELISA IgM response to purified RRV. Mucosal antibody responses were not seen. The limited immune response may be a function of age, presence of maternal antibody, timing of the convalescent specimens, or the polyvalent nature of the vaccine.
Administration, Oral↗
Histoplasmosis during childhood.
To define the clinical presentation of histoplasmosis among hospitalized children, we reviewed the charts of patients treated for histoplasmosis at Vanderbilt University Children's Hospital during the years 1968 through 1988. Thirty-five patients with histoplasmosis diagnosed by culture, pathologic examination, or serologic testing were identified, including 29 patients (83%) with pulmonary/mediastinal infection, 5 (14%) with disseminated disease, and 1 (3%) with primary cutaneous histoplasmosis. The most common symptoms included fever, present in 26 patients (74%), and cough, present in 20 (57%). Of 26 patients with fever, 18 (69%) had fever of > 2 weeks' duration and 7 (27%) had temperatures > or = 40.5 degrees C (> or = 105 degrees F). Abnormal physical findings were few, but 19 patients (54%) had wheezing. Chest radiographs were obtained in all cases except one; 31 (91%) showed abnormalities, including adenopathy in 25 cases (74%) and infiltrates in 19 (56%). Histoplasmin skin tests were positive for 22 (96%) of the 23 patients tested. No cases of classic disseminated histoplasmosis of infancy were identified. Histoplasmosis should be considered in the differential diagnosis when children living in endemic areas are evaluated for persistent fever, cough, and/or wheezing, particularly if adenopathy is seen on the chest radiograph.
Adult↗
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↗
Is aspirin a prodrug for antioxidant and cytokine-modulating oxymetabolites?
Aspirin and salicylate are transformed by stimulated human polymorphonuclear leucocytes (PMN), likely to be found at inflammatory sites, into both 2,3- and 2,5-dihydroxybenzoates (DHB). These DHB inhibit both the production of hydrogen peroxide by stimulated human PMN and prostaglandin (PG) E2 by activated rat macrophages. In contrast, DHB stimulated production of interleukin (IL)-1 and tumour necrosis factor (TNF) but inhibited IL-6 production by rat macrophages. These effects were probably a consequence of PGE2 inhibition. Gentisate (2,5-DHB) and homogentisate (a tyrosine metabolite) inhibited the lymphoproliferative action of IL-1. Some related phenols, e.g. 5-aminosalicylate, inhibited H2O2 production but had little effect on PGE2 production. These findings suggest that the local synthesis of DHB may contribute to the overall anti-inflammatory activity of salicylate, which (unlike aspirin) has little direct effect on PG production.
Animals↗
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↗
Comparative trial of large-particle aerosol and nose drop administration of live attenuated influenza vaccines.
Healthy adult subjects (n = 198) were randomized to receive bivalent cold-adapted (ca) influenza A vaccine containing 10(7.4) TCID50 each of A/Kawasaki/9/86 (H1N1) and A/Los Angeles/2/87 (H3N2) by either nose drops (ND) or large-particle aerosol (LPA). All subjects had received monovalent inactivated influenza B vaccine intramuscularly in the previous year. Ninety percent of LPA recipients and 82% of ND recipients preferred intranasal administration to their previous experience with intramuscular vaccine. Twenty-six (27%) of 98 LPA recipients and 47 (49%) of 97 ND recipients reported swallowing vaccine (P = .008). Fever was observed uncommonly (< or = 5%), and incidence of respiratory symptoms was comparable between groups. Fourfold or greater hemagglutination antibody response to at least one of the influenza A vaccine viruses was significantly more frequent after LPA (64%) than ND vaccination (43%; P = .005). LPA administration of ca influenza to the nasopharynx was well tolerated, safe, and more immunogenic than ND delivery.
Administration, Intranasal↗
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↗