Safety, immunogenicity and dose ranging of a new Vi-CRM₁₉₇ conjugate vaccine against typhoid fever: randomized clinical testing in healthy adults

Background

Typhoid fever causes more than 21 million cases of disease and 200,000 deaths yearly worldwide, with more than 90% of the disease burden being reported from Asia. Epidemiological data show high disease incidence in young children and suggest that immunization programs should target children below two years of age: this is not possible with available vaccines. The Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM₁₉₇) for infant vaccination concomitantly with EPI vaccines, either starting at 6 weeks with DTP or at 9 months with measles vaccine. We report the results from a Phase 1 and a Phase 2 dose ranging trial with Vi-CRM₁₉₇ in European adults.

Methodology

Following randomized blinded comparison of single vaccination with either Vi-CRM₁₉₇ or licensed polysaccharide vaccines (both containing 25·0 µg of Vi antigen), a randomised observer blinded dose ranging trial was performed in the same center to compare three concentrations of Vi-CRM₁₉₇ (1·25 µg, 5·0 µg and 12·5 µg of Vi antigen) with the polysaccharide vaccine.

Principal Findings

All vaccines were well tolerated. Compared to the polysaccharide vaccine, Vi-CRM₁₉₇ induced a higher incidence of mild to moderate short lasting local pain. All Vi-CRM₁₉₇ formulations induced higher Vi antibody levels compared to licensed control, with clear dose response relationship.

Conclusions

Vi-CRM₁₉₇ did not elicit safety concerns, was highly immunogenic and is therefore suitable for further clinical testing in endemic populations of South Asia.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01123941","term_id":"NCT01123941"}}NCT01123941 {"type":"clinical-trial","attrs":{"text":"NCT01193907","term_id":"NCT01193907"}}NCT01193907     

First hominoid from the Late Miocene of the Irrawaddy Formation (Myanmar)

For over a century, a Neogene fossil mammal fauna has been known in the Irrawaddy Formation in central Myanmar. Unfortunately, the lack of accurately located fossiliferous sites and the absence of hominoid fossils have impeded paleontological studies. Here we describe the first hominoid found in Myanmar together with a Hipparion (s.l.) associated mammal fauna from Irrawaddy Formation deposits dated between 10.4 and 8.8 Ma by biochronology and magnetostratigraphy. This hominoid documents a new species of Khoratpithecus, increasing thereby the Miocene diversity of southern Asian hominoids. The composition of the associated fauna as well as stable isotope data on Hipparion (s.l.) indicate that it inhabited an evergreen forest in a C3-plant environment. Our results enlighten that late Miocene hominoids were more regionally diversified than other large mammals, pointing towards regionally-bounded evolution of the representatives of this group in Southeast Asia. The Irrawaddy Formation, with its extensive outcrops and long temporal range, has a great potential for improving our knowledge of hominoid evolution in Asia.     

Die Geschwindigkeit des Transpirationsstromes

Ohne Zusammenfassung     

Selective Insulin Resistance in Adipocytes

Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin.     

The imprinted gene DIO3 is a candidate gene for litter size in pigs

Genomic imprinting is an important epigenetic phenomenon, which on the phenotypic level can be detected by the difference between the two heterozygote classes of a gene. Imprinted genes are important in both the development of the placenta and the embryo, and we hypothesized that imprinted genes might be involved in female fertility traits. We therefore performed an association study for imprinted genes related to female fertility traits in two commercial pig populations. For this purpose, 309 SNPs in fifteen evolutionary conserved imprinted regions were genotyped on 689 and 1050 pigs from the two pig populations. A single SNP association study was used to detect additive, dominant and imprinting effects related to four reproduction traits; total number of piglets born, the number of piglets born alive, the total weight of the piglets born and the total weight of the piglets born alive. Several SNPs showed significant (q-value < 0.10) additive and dominant effects and one SNP showed a significant imprinting effect. The SNP with a significant imprinting effect is closely linked to DIO3, a gene involved in thyroid metabolism. The imprinting effect of this SNP explained approximately 1.6% of the phenotypic variance, which corresponded to approximately 15.5% of the additive genetic variance. In the other population, the imprinting effect of this QTL was not significant (q-value > 0.10), but had a similar effect as in the first population. The results of this study indicate a possible association between the imprinted gene DIO3 and female fertility traits in pigs.     

Carbendazim as an alternative plant growth regulator in tissue culture systems

Summary Carbendazim is the fungitoxic ingredient of different fungicides. In our experiments it was used as a supplement to stage II (multiplication) media for the micropropagation ofCordyline terminalis andPrunus avium. The product can be autoclaved without any loss of activity and there is no degradation of the product over a normal culture period of 32 days. WithC. terminalis andP. avium no phytotoxic effect was revealed up to 160μg/ml. ForC. terminalis shoot height was reduced and the number of shoots smaller than 15 mm increased significantly. Presented in the Session-in-Depth Novel Plant Growth Regulators at the 1992 World Congress on Cell and Tissue Culture, Washington, DC, June 20–25, 1992.     

The effects of cholesterol inclusion on the molecular organisation of bimolecular lipid membranes

Dielectric measurements on planar egg phosphatidylcholine bilayers formed from n-hexadecane solutions indicate that these bilayers contain very low equilibrium concentrations of alkane. In 100 mM KCl the capacitance of the hydrophobic region was found to be 7.0 ±0.2 mF/m². The addition of cholesterol (at 2:1 mole ratio) was found to affect only marginally the capacitance of the hydrophobic region of such bilayers. Precise measurements of the frequency dependence of the bilayer impedance at very low frequencies now allow the resolution of several electrically distinct substructural regions within the bilayer. Examination of the effects of cholesterol inclusion upon the electrical parameters of these substructural regions indicate that cholesterol spans the acetyl region (i.e. the region containing the glycerol bridge of the phosphatidylcholine molecules in the bilayer) with the hydroxyl group of the cholesterol molecules located inbetween the phosphate group and the glycerol oxygens of the phosphatidylcholine molecules. The capacitance of the hydrophobic region of both phosphatidylcholine and phosphatidylcholine/cholesterol bilayers formed from n-hexadecane solutions was found to decrease slightly as the external KCl concentration was decreased.