Effect of vaccine dose on the safety and immunogenicity of a candidate TB vaccine, MVA85A, in BCG vaccinated UK adults

Purpose

A non-randomised, open-label, Phase I safety and immunogenicity dose-finding study to assess the safety and immunogenicity of the candidate TB vaccine Modified Vaccinia virus Ankara expressing Antigen 85A (MVA85A) from Mycobacterium tuberculosis (MTB) in healthy adult volunteers previously vaccinated with BCG.

Methods

Healthy BCG-vaccinated volunteers were vaccinated with either 1 × 10⁷ or 1 × 10⁸ PFU of MVA85A. All adverse events were documented and antigen specific T cell responses were measured using an ex vivo IFN-γ ELISPOT assay. Safety and immunogenicity were compared between the 2 dose groups and with a previous trial in which a dose of 5 × 10⁷ PFU MVA85A had been administered.

Results

There were no serious adverse events recorded following administration of either 1 × 10⁷ or 1 × 10⁸ PFU of MVA85A. Systemic adverse events were more frequently reported following administration of 1 × 10⁸ PFU of MVA85A when compared to either 5 × 10⁷ or 1 × 10⁷ PFU of MVA85A but were mild or moderate in severity and resolved completely within 7 days of immunisation. Antigen specific T cell responses as measured by the IFN-γ ELISPOT were significantly higher following immunisation in adults receiving 1 × 10⁸ PFU compared to the 5 × 10⁷ and 1 × 10⁷ doses. Additionally, a broader range of Ag85A epitopes are detected following 1 × 10⁸ PFU of MVA85A.

Conclusion

A higher dose of 1 × 10⁸ PFU of MVA85A is well-tolerated, increases the frequency of IFN-γ secreting T cells detected following immunisation and broadens the range of Ag85A epitopes detected.     

Anti-inflammatory activity of aqueous and ethanolic extracts of Zygophyllum gaetulum

Zygophylle or Zygophyllum gaetulum Emberger and. Maire is a Moroccan medicinal plant which has been used as an anti-inflammatory, antidiabetic, antispasmodic and antidiarrheic. The present study was carried out to study and compare the anti-inflammatory effect of ethanolic extract with aqueous extract of Z. gaetulum. Organic extract of Z. gaetulum was obtained in soxhlet apparatus. Aqueous extract was obtained by infusion. The Wistar albinos rats of either sex weighing 200-300 g aged 2-3 months were used for this experiment. The rats were housed under standard environmental conditions. The anti-inflammatory activity was estimated by measuring the oedema induced by carragenin according to the method of Winter and al. Ethanolic extract of Z. gaetulum reduced the increase of the paw volume with a percentage of inhibition of 46% (p<0.01), this percentage was 47.48% (p<0.01) with aqueous extract. The inhibition decrease in time, it arrived to 39% (p<0.01) at the sixth hour while the activity of aqueous extract decrease a lot. In conclusion, Z. gaetulum is an interesting plant which the aqueous and éthanolic extracts could be used scientifically in the treatment of inflammation.     

‘Open access’ generic method for continuous determination of major human CYP450 probe substrates/metabolites and its application in drug metabolism studies

1.?An ‘open access’ generic high-performance liquid chromatography method was developed for different combination sets each containing specific cytochrome P450 probe substrate and the corresponding metabolite. Method development, optimization and validation were carried out with the following combinations: phenacetin?+ paracetamol + internal standard (IS, celecoxib), bufuralol + hydroxybufuralol + IS, testosterone + 6β-hydroxytestosterone + IS, chlorzoxazone + 6-hydroxychlorzoxazone?+ IS, coumarin + 7-hydroxycoumarin + IS, tolbutamide + hydroxytolbutamide + IS, and diazepam?+ desmethyldiazepam + IS.

2.?The assay procedure involved a simple one-step liquid/liquid extraction followed by reverse phase chromatography (Inertsil ODS 3V column) employing a ternary gradient system and the eluate was monitored by a photodiode array/fluorescence detector. The standard curve for each compound, in the concentration range 0.1–10?μg?ml^?1, in various sets was linear (r²>0.99) and absolute recoveries of all analytes were >90%. The lower limit of quantification was 0.1?μg?ml^?1. The intraday precision and accuracy in the measurements of quality control were <15% relative standard deviation and <15% deviation from nominal values, respectively.

3.?Each combination set was tested with individual chemical inhibitors (furafylline, quinidine, ketoconazole, disulfiram, diethyldithiocarbamate, sulphaphenazole and tranylcypromine) and all analytes were well resolved. Overall, the assay is simple, uses conventional instrumentation and provides a scope to analyse all cytochrome P450 combination sets continuously. The application of the method in the cytochrome P450 liability screen of novel compounds is also presented.     

Prognostification of ALL by Cytogenetics

Cytogenetic abnormalities in chromosomal number and structure are common in pediatric ALL and some have prognostic significance. One interesting association between cytogenetic status and treatment response involves the metabolism of methotrexate. Hyperdiploid lymphoblasts accumulate increased amounts of MTX and MTX polyglutamates, and they have higher basal apoptotic rates compared with leukemic cells with lower ploidy and normal cells. These characteristics may contribute to the better outcomes observed for patients with hyperdiploid lymphoblasts. A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-precursor ALL. Some chromosomal abnormalities are associated with more favorable outcomes, such as high hyperdiploidy (51–65 chromosomes) and the ETV6–RUNX1 fusion. Others are associated with a poorer prognosis, including the Philadelphia chromosome [t(9;22)], rearrangements of the MLL gene (chromosome 11q23), and intrachromosomal amplification of the AML1 gene (iAMP21).