Immunogenicity and safety of three consecutive production lots of the non replicating smallpox vaccine MVA: A randomised, double blind, placebo controlled phase III trial

<div><p>Background</p><p>Modified Vaccinia Ankara (MVA) is a live, viral vaccine under advanced development as a non-replicating smallpox vaccine. A randomised, double-blind, placebo-controlled phase III clinical trial was conducted to demonstrate the humoral immunogenic equivalence of three consecutively manufactured MVA production lots, and to confirm the safety and tolerability of MVA focusing on cardiac readouts.</p><p>Methods</p><p>The trial was conducted at 34 sites in the US. Vaccinia-naïve adults aged 18-40 years were randomly allocated to one of four groups using a 1:1:1:1 randomization scheme. Subjects received either two MVA injections from three consecutive lots (Groups 1-3), or two placebo injections (Group 4), four weeks apart. Everyone except personnel involved in vaccine handling and administration was blinded to treatment. Safety assessment focused on cardiac monitoring throughout the trial. Vaccinia-specific antibody titers were measured using a Plaque Reduction Neutralization Test (PRNT) and an Enzyme-Linked Immunosorbent Assay (ELISA). The primary immunogenicity endpoint was Geometric Mean Titers (GMTs) after two MVA vaccinations measured by PRNT at trial visit 4. This trial is registered with ClinicalTrials.gov, number NCT01144637.</p><p>Results</p><p>Between March 2013 and May 2014, 4005 subjects were enrolled and received at least one injection of MVA (n = 3003) or placebo (n = 1002). The three MVA lots induced equivalent antibody titers two weeks after the second vaccination, with seroconversion rates of 99·8% (PRNT) and 99·7% (ELISA). Overall, 180 (6·0%) subjects receiving MVA and 29 (2·9%) subjects in the placebo group reported at least one unsolicited Adverse Event (AE) that was considered trial-related. Vaccination was well tolerated without significant safety concerns, particularly regarding cardiac assessment.</p><p>Conclusions</p><p>The neutralizing and total antibody titers induced by each of the three lots were equivalent. No significant safety concerns emerged in this healthy trial population, especially regarding cardiac safety, thus confirming the excellent safety and tolerability profile of MVA.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01144637" target="_blank">NCT01144637</a></p></div

Asymmetric dynamical ocean responses in warming icehouse and cooling greenhouse climates

Warm periods in Earth's history tend to cool more slowly than cool periods warm. Carbon cycle feedbacks play a major role in these dynamics, from the slower rate of recovery of ocean carbon export production, to the slower re- establishment of geosphere carbon reservoirs, relative to rates of loss. Here we explore one- differences in how the global ocean takes up and gives up heat and carbon in forced rapid warming and cooling climate scenarios. We force an intermediate- complexity earth system model using two atmospheric CO2 scenarios. A ramp-up (1% per year increase in atmospheric CO2 for 150 years) starts from an average global CO2 concentration of 285 ppm to represent warming of an icehouse climate. A ramp- down (1% per year decrease in atmospheric CO2 for 150 years) starts from an average global CO2 concentration of 1257 ppm to represent cooling of a greenhouse climate. Atmospheric CO2 is then held constant in each simulation and the model is integrated an additional 350 years. The ramp-down simulation shows a weaker response of surface air temperature to changes in radiative forcing relative to the ramp-up scenario. This weaker response is due to a relatively large and fast release of heat from the ocean to the atmosphere. This asymmetry in heat exchange in cooling and warming scenarios exists mainly because of differences in the response of the ocean circulation to forcing. In the ramp-up, increasing stratification and weakening of meridional overturning circulation slows ocean carbon and heat uptake. In the ramp-down, cooling accelerates meridional overturning and deepens vertical mixing, accelerating the release of carbon and heat stored at depth. Though idealized, our experiments offer insight into differences in ocean dynamics in icehouse and greenhouse climate transitions

A web-based collaborative translation management system for public health workers

Copyright is held by the author/owner(s)

The introduction of the Cancer Research UK Stratified Medicine Programme 2 (CRUK SMP2) in North East England; lessons learned and experience gained

Introduction: The CRUK SMP2 programme was set-up to evaluate the feasibility of performing large scale molecular analysis within the NHS on the (often small) diagnostic biopsies obtained in NSCLC. The results are used to allocate patients to an appropriate molecular therapy within the “umbrella” MATRIX trial. Newcastle opened SMP2 on 01/10/2014. Here we report our first year’s experience. Methods: NSCLC patients with PS 0–2 were consented onto the CRUK SMP2. Matched residual diagnostic tissue and blood were sent to All Wales Genetics Laboratory, Cardiff. Samples with >70ng DNA were assessed for 28 oncogenes using Next Genuine Sequencing on the Illumina SMP2 panel. Results: 116 patients were consented from 6/10/14–1/10/15 referred from 12 oncologists. The data on patient/sample flow is shown in Fig 1. Median survival was 161 days from consent. The 1st sample was sent to Cardiff on 28/1/15 as the Illumina panel was undergoing fi- nal validation. 50 samples have been sent; 11 had insufficient DNA; these samples had lower cell number (but with no impact of necrosis/tumour proportion); The most commonly altered gene was K-Ras (13 of 22 adenocarcinomas). Only 2 patients with results from >25 of the 28 genes had no tier 1 or 2 ie potentially treatable molecular abnormalities. The median time from consent to result was 109 days (range 45–250) with delays occurring throughout the pathway. Conclusion: Patients and oncologists are keen to be involved in molecular profiling; but patients need to be consented early to allow results to guide therapy. Prioritisation of samples is key. Not all samples are suitable for analysis due to small cell number or low tumour proportion. Molecular analysis may require extra resource in pathology, if it is to become standard of care. The first 4 patients to start treatment on MATRIX were enrolled from 27/8/15 in Newcastle. Disclosure: All authors have declared no conflicts of interest

Lysine 53 Acetylation of Cytochrome c in Prostate Cancer: Warburg Metabolism and Evasion of Apoptosis

Prostate cancer is the second leading cause of cancer-related death in men. Two classic cancer hallmarks are a metabolic switch from oxidative phosphorylation (OxPhos) to glycolysis, known as the Warburg effect, and resistance to cell death. Cytochrome c (Cytc) is at the intersection of both pathways, as it is essential for electron transport in mitochondrial respiration and a trigger of intrinsic apoptosis when released from the mitochondria. However, its functional role in cancer has never been studied. Our data show that Cytc is acetylated on lysine 53 in both androgen hormone-resistant and -sensitive human prostate cancer xenografts. To characterize the functional effects of K53 modification in vitro, K53 was mutated to acetylmimetic glutamine (K53Q), and to arginine (K53R) and isoleucine (K53I) as controls. Cytochrome c oxidase (COX) activity analyzed with purified Cytc variants showed reduced oxygen consumption with acetylmimetic Cytc compared to the non-acetylated Cytc (WT), supporting the Warburg effect. In contrast to WT, K53Q Cytc had significantly lower caspase-3 activity, suggesting that modification of Cytc K53 helps cancer cells evade apoptosis. Cardiolipin peroxidase activity, which is another proapoptotic function of the protein, was lower in acetylmimetic Cytc. Acetylmimetic Cytc also had a higher capacity to scavenge reactive oxygen species (ROS), another pro-survival feature. We discuss our experimental results in light of structural features of K53Q Cytc, which we crystallized at a resolution of 1.31 Å, together with molecular dynamics simulations. In conclusion, we propose that K53 acetylation of Cytc affects two hallmarks of cancer by regulating respiration and apoptosis in prostate cancer xenografts