Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: A vaccine for enterovirus 71 (EV71) is needed to address the high burden of disease associated with infection. We assessed the efficacy, safety, immunogenicity, antibody persistence, and immunological correlates of an inactivated alum-adjuvant EV71 vaccine. METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 trial. Healthy children aged 6-35 months from four centres in China were randomly assigned (1:1) to receive vaccine or alum-adjuvant placebo at day 0 and 28, according to a randomisation list (block size 30) generated by an independent statistician. Investigators and participants and their guardians were masked to the assignment. Primary endpoints were EV71-associated hand, foot, and mouth disease (HFMD) and EV71-associated disease during the surveillance period from day 56 to month 14, analysed in the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01508247. FINDINGS: 10,245 participants were enrolled and assigned: 5120 to vaccine versus 5125 to placebo. 4907 (with three cases of EV71-associated HFMD and eight cases of EV71-associated disease) versus 4939 (with 30 cases of EV71-associated HFMD and 41 cases of EV71-associated disease) were included in the primary efficacy analysis. Vaccine efficacy was 90·0% (95% CI 67·1-96·9) against EV71-associated HFMD (p=0·0001) and 80·4% (95% CI 58·2-90·8) against EV71-associated disease (p<0·0001). Serious adverse events were reported by 62 of 5117 (1·2%) participants in the vaccine group versus 75 of 5123 (1·5%) in the placebo group (p=0·27). Adverse events occurred in 3644 (71·2%) versus 3603 (70·3%; p=0·33). INTERPRETATION: EV71 vaccine provides high efficacy, satisfactory safety, and sustained immunogenicity. FUNDING: China's 12-5 National Major Infectious Disease Program, Beijing Vigoo Biological.

Synthesis and drug resistant reversal activities of taxane-like multi-drug resistant reversal agents / 药学学报

<p><b>AIM</b>To design and synthesize a series of new taxoids with a 5-O-sidechain, and to test the multi-drug resistant reversal activity of these compound on KB/V200 cells which is 180 times more resistant to vincristine.</p><p><b>METHODS</b>Using Sinenxan A as a common synthetic starting material, three different types of 5-O-sidechain molecules were synthesized through different route. For type I compounds, 14-acetoxy of Sinenxan A was selectively removed by hydrolysis, xanthation and reduction with tributyltin; A C-10-oxo group was introduced by PCC oxidation; 5-O-acetyl group was selectively removed by potassium tert-butoxide and finally the side chain was introduced by acylating with the corresponding acid. For type II compounds, 5-O-sidechain was introduced to the 5-deacetyl Sinenxan A which was obtained by selective hydrolysis with tBuOK. For type III compounds, 9-acetoxy group was introduced, then 5-OH was left free by thorough hydrolysis and reacetylation. Acylation at 5-position, the final product was obtained. Structure of the compounds have been confirmed by FABMS and 2DNMR. The activity of the compounds in vitro was tested on KB/V200 resistant cell line using MTT method.</p><p><b>RESULTS</b>Nine compounds showed resistant reversal activity and enhancing the cytotoxicity of vicristine against KB/V200 cells. Compounds I2, I3, I4 restored the sensitivity of KB/V200 towards vicristine to a level of IC50 at 1 x 10(-8) mol.L-1 which is better than the positive control Verapamil.</p><p><b>CONCLUSION</b>The drug resistant reversal activity of taxane derivatives can be affected by substitution at different positions and the length of side chains of Sinenxan A. It is worthy to be further studied.</p>