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 long-term safety, public health impact, and cost-effectiveness of routine vaccination with a recombinant, live-attenuated dengue vaccine (Dengvaxia): a model comparison study

This is the final version of the article. Available from the publisher via the DOI in this record.Background: Large Phase III trials across Asia and Latin America have recently demonstrated the efficacy of a recombinant, live-attenuated dengue vaccine (Dengvaxia) over the first 25 mo following vaccination. Subsequent data collected in the longer-term follow-up phase, however, have raised concerns about a potential increase in hospitalization risk of subsequent dengue infections, in particular among young, dengue-naïve vaccinees. We here report predictions from eight independent modelling groups on the long-term safety, public health impact, and cost-effectiveness of routine vaccination with Dengvaxia in a range of transmission settings, as characterised by seroprevalence levels among 9-y-olds (SP9). These predictions were conducted for the World Health Organization to inform their recommendations on optimal use of this vaccine. Methods and Findings: The models adopted, with small variations, a parsimonious vaccine mode of action that was able to reproduce quantitative features of the observed trial data. The adopted mode of action assumed that vaccination, similarly to natural infection, induces transient, heterologous protection and, further, establishes a long-lasting immunogenic memory, which determines disease severity of subsequent infections. The default vaccination policy considered was routine vaccination of 9-y-old children in a three-dose schedule at 80% coverage. The outcomes examined were the impact of vaccination on infections, symptomatic dengue, hospitalised dengue, deaths, and cost-effectiveness over a 30-y postvaccination period. Case definitions were chosen in accordance with the Phase III trials. All models predicted that in settings with moderate to high dengue endemicity (SP9 ≥ 50%), the default vaccination policy would reduce the burden of dengue disease for the population by 6%–25% (all simulations: –3%–34%) and in high-transmission settings (SP9 ≥ 70%) by 13%–25% (all simulations: 10%– 34%). These endemicity levels are representative of the participating sites in both Phase III trials. In contrast, in settings with low transmission intensity (SP9 ≤ 30%), the models predicted that vaccination could lead to a substantial increase in hospitalisation because of dengue. Modelling reduced vaccine coverage or the addition of catch-up campaigns showed that the impact of vaccination scaled approximately linearly with the number of people vaccinated. In assessing the optimal age of vaccination, we found that targeting older children could increase the net benefit of vaccination in settings with moderate transmission intensity (SP9 = 50%). Overall, vaccination was predicted to be potentially cost-effective in most endemic settings if priced competitively. The results are based on the assumption that the vaccine acts similarly to natural infection. This assumption is consistent with the available trial results but cannot be directly validated in the absence of additional data. Furthermore, uncertainties remain regarding the level of protection provided against disease versus infection and the rate at which vaccine-induced protection declines. Conclusions: Dengvaxia has the potential to reduce the burden of dengue disease in areas of moderate to high dengue endemicity. However, the potential risks of vaccination in areas with limited exposure to dengue as well as the local costs and benefits of routine vaccination are important considerations for the inclusion of Dengvaxia into existing immunisation programmes. These results were important inputs into WHO global policy for use of this licensed dengue vaccinSF and MJ received funding from WHO and Gavi, the Vaccine Alliance, to conduct this work. LC is a paid employee at Sanofi Pasteur. GM and JK were funded by the University of Western Australia, with computing resources provided by the Pawsey Supercomputing Centre, which is funded by the Australian Government and the Government of Western Australia. MR is funded by a Royal Society University Research Fellowship. NF, ID and DJL received research funding from the UK Medical Research Council, the UK NIHR under the Health Protection Research Unit initiative, NIGMS under the MIDAS initiative, and the Bill and Melinda Gates Foundation. IRB and DATC were funded by MIDAS Center Grant NIH/NIGMS U54-GM088491 and the Bill and Melinda Gates Foundation. DATC was also supported by NIH/NIAID R01-AI114703. TJH, IL, and CABP were funded by a Dengue Vaccine Initiative Grant to IL, NIH/NIAID R37 AI32042. THJ, IL, and KK were funded by MIDAS Center Grant NIH/NIGMS 1135 U54 GM111274. All other authors have received no specific funding to conduct this work. The funders had no role in the study design, data analyses, decision to publish or preparation of the manuscript

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