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Biomedical subjects

B Forrest

Publications and source records attributed to B Forrest.

11 recordsLinked to original sources
PubMed2001

A Phase I safety and immunogenicity trial of UBI microparticulate monovalent HIV-1 MN oral peptide immunogen with parenteral boost in HIV-1 seronegative human subjects.

Thirty-three HIV-seronegative adults were recruited into a Phase I safety and immunogenicity HIV-1 vaccine trial. The immunogens were as follows: a synthetic, monovalent, octameric HIV-1 MN V3 peptide in aluminum hydroxide (alum) adjuvant administered by intramuscular delivery; and a similar product encapsulated in biodegradable micro-spheres composed of co-polymers of lactic and glycolic acids, administered by the oral route. These were administered in three sequential oral doses, followed by a parenteral boost. No serious adverse experiences were observed. Oral administration of this vaccine, alone or in combination with parenteral boosting, resulted in no significant humoral, cellular, or mucosal immune responses.

AIDS Vaccines↗
PubMed1998

Induction of immunologic memory by conjugated vs plain meningococcal C polysaccharide vaccine in toddlers: a randomized controlled trial.

CONTEXT: Meningococcal polysaccharide vaccines are not used routinely in infants and toddlers, the groups at highest risk of invasive disease, because of poor immunologic responses to the Neisseria meningitidis serogroup C polysaccharide in these age groups. Meningococcal C conjugate vaccines offer the prospect of circumventing this problem. OBJECTIVE: To assess the immunogenicity and the induction of immunologic memory in toddlers by meningococcal C conjugate vaccine. DESIGN: A multicenter, randomized, observer-blinded controlled trial. SETTING: Urban and suburban family medicine or pediatric practices. PARTICIPANTS: Two hundred eleven healthy toddlers aged 15 to 23 months. INTERVENTION: Two injections at 2 months apart of meningococcal C conjugate (group 1, n = 69), plain meningococcal polysaccharide (group 2, n = 72), or hepatitis B virus vaccine (group 3, n = 70). All toddlers received a follow-up dose of plain meningococcal polysaccharide vaccine 12 months later. MAIN OUTCOME MEASURES: IgG meningococcal C anticapsular antibody concentrations determined by enzyme-linked immunosorbent assay and complement-mediated bactericidal antibody. RESULTS: In group 1, the magnitude of the IgG response to meningococcal C conjugate vaccine was more than 4-fold higher after dose 1 and more than 10-fold higher after dose 2 compared with meningococcal polysaccharide vaccine (group 2) (P<.001). Higher titers persisted in the meningococcal C conjugate group for at least 12 months (P<.001). Group 1, primed with meningococcal C conjugate, had 25-fold higher IgG responses to the meningococcal polysaccharide 1-year booster dose than the controls who had received hepatitis B virus vaccine initially and were given meningococcal polysaccharide vaccine 1 year later for the first time (P<.001). In contrast, group 2, primed with meningococcal polysaccharide, had a 2-fold lower response to the 1-year booster meningococcal polysaccharide dose than the hepatitis B virus control group (P = .006). Serum bactericidal responses paralleled the enzyme-linked immunosorbent assay responses. CONCLUSIONS: Immunization of toddlers with meningococcal C conjugate vaccine induces high titers of anticapsular and bactericidal antibody. Furthermore, this vaccine induces immunologic memory to meningococcal C polysaccharide. In contrast, meningococcal polysaccharide vaccine is less immunogenic than the conjugate vaccine and also induces a hyporesponsive state that persists for at least 12 months.

Antibodies, Bacterial↗
PubMed1998

Modified RNAs as potential drug targets.

Bleomycin (BLM) is a natural antibiotic that is effective in treatment of selected cancers. Although the exact therapeutic mechanism of bleomycin is not known, its target is thought to be a nucleic acid. Besides cleaving DNA, in vitro, Fe-bleomycin cleaves the anticodon of yeast tRNA(Phe) specifically. Using CD and fluorescence spectroscopy we have found that apo-bleomycin binds to synthetic RNA analogs of the anticodon of yeast tRNA(Phe) with an affinity similar to that previously reported for DNA. In order to understand BLM's selectivity, the role magnesium ions play in RNA recognition should be explained. Many RNA substrates for Fe-BLM, including yeast tRNA(Phe), are not cleaved by the drug when the Mg2+ concentration exceeds 1 mM. Competition experiments with anticodon analogs provide insight into the role of magnesium ions in RNA recognition by BLM. These simple modified RNAs may be useful as model systems for investigating BLM/RNA recognition and development of highly selective drugs toward RNA targets.

Antibiotics, Antineoplastic↗
PubMed1994

Aminoacyl-tRNA synthetase and U54 methyltransferase recognize conformations of the yeast tRNA(Phe) anticodon and T stem/loop domain.

The enzyme-catalyzed posttranscriptional modification of tRNA and the contributions of modified nucleosides to tRNA structure and function can be investigated with chemically synthesized domains of the tRNA molecule. Heptadecamer RNAs with and without modified nucleosides and DNAs designed as analogs to the anticodon and T stem/loop domains of yeast tRNA(Phe) were produced by automated chemical synthesis. The unmodified T stem/loop domain of yeast tRNA(Phe) was a substrate for the E coli m5U54-tRNA methyltransferase activity, RUMT. Surprisingly, the DNA analog of the T stem/loop domain composed of d(A,U,G,C) was also a substrate. In addition, the DNA analog inhibited the methylation of unfractionated, undermodified E coli tRNA lacking the U54 methylation. RNA anticodon domains and DNA analogs differentially and specifically affected aminoacylation of the wild type yeast tRNA(Phe). Three differentially modified tRNA(Phe) anticodon domains with psi 39 alone, m1G37 and m5C40, or psi 39 with m1G37 and m5C40,stimulated phenylalanyl-tRNA synthetase (FRS) activity. However, one anticodon domain, with m5C40 as the only modified nucleoside and a closed loop conformation, inhibited FRS activity. Modified and unmodified DNA analogs of the anticodon, tDNA(PheAC), inhibited FRS activity. Analysis of the enzyme activity in the presence of the DNA analog characterized the DNA/enzyme interaction as either partial or allosteric inhibition. The disparity of action between the DNA and RNA hairpins provides new insight into the potential allosteric relationship of anticodon binding and open loop conformational requirements for active site function of FRS and other aaRSs. The comparison of the stimulatory and inhibitory properties of variously modified RNA domains and DNA analogs demonstrates that conformation, in addition to primary sequence, is important for tRNA-protein interaction. The enzyme recognition of various DNA analogs as substrate and/or inhibitors of activity demonstrates that conformational determinants are not restricted to ribose and the standard A-form RNA structure.

Amino Acyl-tRNA Synthetases↗
PubMed1990

Safety, immunogenicity, and efficacy against cholera challenge in humans of a typhoid-cholera hybrid vaccine derived from Salmonella typhi Ty21a.

A live oral vaccine consisting of attenuated Salmonella typhi Ty21a expressing Vibrio cholerae O1 Inaba lipopolysaccharide (LPS) O antigen was constructed and tested in volunteers for safety, immunogenicity, and efficacy. Fourteen adults ingested three doses of 10(10) viable organisms with buffer. One month later, 8 vaccinees and 13 unimmunized controls were challenged with 10(6) pathogenic V. cholerae O1 E1 T or Inaba organisms. No significant adverse reactions to vaccination were observed. All volunteers had significant rises in serum immunoglobulin G (IgG) antibody to S. typhi LPS. Only 2 (14%) of 14 had significant rises in serum IgA or IgG antibody to Inaba LPS, and 5 (36%) of 14 had fourfold rises in vibriocidal antibody. In the challenge study, diarrhea occurred in 13 of 13 controls and 6 of 8 vaccinees (vaccine efficacy, 25%; P = 0.13). The vaccine significantly reduced the severity of the clinical illness (P less than 0.05) and caused decreased excretion of challenge vibrios (P less than 0.05). Although the typhoid-cholera hybrid vaccine did not provide significant protection overall against experimental cholera, this study demonstrates the importance of antibody to V. cholerae O antigen in ameliorating clinical illness and illustrates the use of an S. typhi carrier vaccine strain expressing a foreign antigen.

Antibodies, Bacterial↗
PubMed1988

A galE via (Vi antigen-negative) mutant of Salmonella typhi Ty2 retains virulence in humans.

We have recently described the construction of a galE derivative of Salmonella typhi Ty2 (Ty2H1) which had a 0.4-kilobase deletion in the galE gene and was sensitive to galactose-induced lysis when cultured with greater than or equal to 0.06 mM galactose (D. M. Hone, R. Morona, S. Attridge, and J. Hackett, J. Infect. Dis. 156:167-174, 1987). We now report the selection of a rifampin-resistant, via derivative of Ty2H1, EX462. Compared with the Ty2 parent strain, EX462 was serum sensitive and highly attenuated in the mouse mucin virulence assay. When four human volunteers ingested 7 X 10(8) viable EX462, two became ill and developed a typhoidlike disease with fever and bacteremia. Blood isolates from these individuals were indistinguishable from the vaccine strain by a variety of criteria. We concluded that, even in a via background, the galE mutation was not attenuating for S. typhi in humans.

Animals↗