Clinical development and regulatory points for consideration for second-generation live attenuated dengue vaccines.

Licensing and decisions on public health use of a vaccine rely on a robust clinical development program that permits a risk-benefit assessment of the product in the target population. Studies undertaken early in clinical development, as well as well-designed pivotal trials, allow for this robust characterization. In 2012, WHO published guidelines on the quality, safety and efficacy of live attenuated dengue tetravalent vaccines. Subsequently, efficacy and longer-term follow-up data have become available from two Phase 3 trials of a dengue vaccine, conducted in parallel, and the vaccine was licensed in December 2015. The findings and interpretation of the results from these trials released both before and after licensure have highlighted key complexities for tetravalent dengue vaccines, including concerns vaccination could increase the incidence of dengue disease in certain subpopulations. This report summarizes clinical and regulatory points for consideration that may guide vaccine developers on some aspects of trial design and facilitate regulatory review to enable broader public health recommendations for second-generation dengue vaccines

Effects of Pd on Catalysis by Au: CO Adsorption, CO Oxidation, and Cyclohexene Hydrogenation by Supported Au and Pd−Au Catalysts

Incorporating small amounts of Pd into supported Au catalysts has been shown to have beneficial effects on selective hydrogenation reactions, particularly 1,3-butadiene hydrogenation and the hydrogenation of nitroaromatics, especially p-chloronitrobenzene. Appropriate Pd incorporation enhances hydrogenation activity while maintaining the desirable high selectivity of supported Au catalysts. To better understand this phenomenon, a series of alumina- and titania-supported Au and dilute Pd–Au catalysts were prepared via urea deposition–precipitation. The catalysts were studied with infrared spectroscopy of CO adsorption, CO oxidation catalysis, and cyclohexene hydrogenation catalysis with the goal of understanding how Pd affects the catalytic properties of Au. CO adsorption experiments indicated a substantial amount of surface Pd when the catalyst was under CO. Adsorption experiments at various CO pressures were used to determine CO coverage; application of the Temkin adsorbate interaction model allowed for the determination of adsorption enthalpy metrics for CO adsorption on Au. These experiments showed that Pd induces an electronic effect on Au, affecting both the nascent adsorption enthalpy (ΔH0) and the change in enthalpy with increasing coverage. This electronic modification had little effect on CO oxidation catalysis. Michaelis–Menten kinetics parameters showed essentially the same oxygen reactivity on all the catalysts; the primary differences were in the number of active sites. The bimetallic catalysts were poor cyclohexene hydrogenation catalysts, indicating that there is relatively little exposed Pd when the catalyst is under hydrogen. The results, which are discussed in the context of the literature, indicate that a combination of surface composition and Pd-induced electronic effects on Au appear to increase hydrogen chemisorption and hydrogenation activity while largely maintaining the selectivities associated with catalysis by Au

The future of Japanese encephalitis vaccination: expert recommendations for achieving and maintaining optimal JE control

Vaccines against Japanese encephalitis (JE) have been available for decades. Currently, most JE-endemic countries have vaccination programs for their at-risk populations. Even so, JE remains the leading recognized cause of viral encephalitis in Asia. In 2018, the U.S. Centers for Disease Control and Prevention and PATH co-convened a group of independent experts to review JE prevention and control successes, identify remaining scientific and operational issues that need to be addressed, discuss opportunities to further strengthen JE vaccination programs, and identify strategies and solutions to ensure sustainability of JE control during the next decade. This paper summarizes the key discussion points and recommendations to sustain and expand JE control

Apolipoprotein E gene polymorphism modifies fasting total cholesterol concentrations in response to replacement of dietary saturated with monounsaturated fatty acids in adults at moderate cardiovascular disease risk

Consumption of ≤10% total energy from fat as saturated fatty acids (SFA) is recommended for cardiovascular disease risk reduction in the UK; however there is no clear guidance on the optimum replacement nutrient. Lipid-associated single-nucleotide polymorphisms (SNPs) have been shown to modify the lipid responses to dietary fat interventions. Hence, we performed a retrospective analysis in 120 participants from the Dietary Intervention and VAScular function (DIVAS) study to investigate whether lipoprotein lipase (LPL) and apolipoprotein E (APOE) SNPs modify the fasting lipid response to replacement of SFA with monounsaturated (MUFA) or n-6 polyunsaturated (PUFA) fatty acids. The DIVAS study was a randomized, single-blinded, parallel dietary intervention study performed in adults with a moderate cardiovascular risk who received one of three isoenergetic diets rich in SFA, MUFA or n-6 PUFA for 16 weeks. After the 16-week intervention, a significant diet-gene interaction was observed for changes in fasting total cholesterol (P = 0.001). For the APOE SNP rs1064725, only TT homozygotes showed a significant reduction in total cholesterol after the MUFA diet (n = 33; -0.71 ± 1.88 mmol/l) compared to the SFA (n = 38; 0.34 ± 0.55 mmol/l) or n-6 PUFA diets (n = 37; -0.08 ± 0.73 mmol/l) (P = 0.004). None of the interactions were statistically significant for the other SNPs. In summary, our findings have demonstrated a greater sensitivity of the APOE SNP rs1064725 to dietary fat composition, with a total cholesterol lowering effect observed following substitution of SFA with MUFA but not n-6 PUFA. Further large intervention studies incorporating prospective genotyping are required to confirm or refute our findings. The trial was registered at www.clinicaltrials.gov as NCT01478958