Model evaluation of target product profiles of an infant vaccine against respiratory syncytial virus (RSV) in a developed country setting

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract disease in children worldwide and is a significant cause of hospital admissions in young children in England. No RSV vaccine has been licensed but a number are under development. In this work, we present two structurally distinct mathematical models, parameterized using RSV data from the UK, which have been used to explore the effect of introducing an RSV paediatric vaccine to the National programme. We have explored different vaccine properties, and dosing regimens combined with a range of implementation strategies for RSV control. The results suggest that vaccine properties that confer indirect protection have the greatest effect in reducing the burden of disease in children under 5 years. The findings are reinforced by the concurrence of predictions from the two models with very different epidemiological structure. The approach described has general application in evaluating vaccine target product profiles

The last man standing is the most resistant: eliminating artemisinin-resistant malaria in Cambodia.

BACKGROUND: Artemisinin combination therapy (ACT) is now the recommended first-line treatment for falciparum malaria throughout the world. Initiatives to eliminate malaria are critically dependent on its efficacy. There is recent worrying evidence that artemisinin resistance has arisen on the Thai-Cambodian border. Urgent containment interventions are planned and about to be executed. Mathematical modeling approaches to intervention design are now integrated into the field of malaria epidemiology and control. The use of such an approach to investigate the likely effectiveness of different containment measures with the ultimate aim of eliminating artemisinin-resistant malaria is described. METHODS: A population dynamic mathematical modeling framework was developed to explore the relative effectiveness of a variety of containment interventions in eliminating artemisinin-resistant malaria in western Cambodia. RESULTS: The most effective intervention to eliminate artemisinin-resistant malaria was a switch of treatment from artemisinin monotherapy to ACT (mean time to elimination 3.42 years (95% CI 3.32-3.60 years). However, with this approach it is predicted that elimination of artemisinin-resistant malaria using ACT can be achieved only by elimination of all malaria. This is because the various forms of ACT are more effective against infections with artemisinin-sensitive parasites, leaving the more resistant infections as an increasing proportion of the dwindling parasite population. CONCLUSION: Containment of artemisinin-resistant malaria can be achieved by elimination of malaria from western Cambodia using ACT. The "last man standing" is the most resistant and thus this strategy must be sustained until elimination is truly achieved

Predicting the relative impacts of maternal and neonatal respiratory syncytial virus (RSV) vaccine target product profiles: A consensus modelling approach

AbstractBackgroundRespiratory syncytial virus (RSV) is the major viral cause of infant and childhood lower respiratory tract disease worldwide. Defining the optimal target product profile (TPP) is complicated due to a wide range of possible vaccine properties, modalities and an incomplete understanding of the mechanism of natural immunity. We report consensus population level impact projections based on two mathematical models applied to a low income setting.MethodTwo structurally distinct age-specific deterministic compartmental models reflecting uncertainty associated with the natural history of infection and the mechanism by which immunity is acquired and lost were constructed. A wide range of vaccine TPPs were explored including dosing regime and uptake, and effects in the vaccinated individual on infectiousness, susceptibility, duration of protection, disease severity and interaction with maternal antibodies and natural induced immunity. These were combined with a range of vaccine implementation strategies, targeting the highest priority age group and calibrated using hospitalization data from Kilifi County Hospital, Kenya.FindingsBoth models were able to reproduce the data. The impact predicted by the two models was qualitatively similar across the range of TPPs, although one model consistently predicted higher impact than the other. For a proposed realistic range of scenarios of TPP combinations, the models predicted up to 70% reduction in hospitalizations in children under five years old. Vaccine designs which reduced the duration and infectiousness of infection were predicted to have higher impacts. The models were sensitive to the coverage and rate of loss of vaccine protection but not to the interaction between vaccine and maternal/naturally acquired immunity.ConclusionThe results suggest that vaccine properties leading to reduced virus circulation by lessening the duration and infectiousness of infection upon challenge are of major importance in population RSV disease control. These features should be a focus for vaccine development

Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.

BACKGROUND: Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria. METHODS AND FINDINGS: We conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials. CONCLUSIONS: Adjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options

Hyperparasitaemia and low dosing are an important source of anti-malarial drug resistance

BACKGROUND: Preventing the emergence of anti-malarial drug resistance is critical for the success of current malaria elimination efforts. Prevention strategies have focused predominantly on qualitative factors, such as choice of drugs, use of combinations and deployment of multiple first-line treatments. The importance of anti-malarial treatment dosing has been underappreciated. Treatment recommendations are often for the lowest doses that produce "satisfactory" results. METHODS: The probability of de-novo resistant malaria parasites surviving and transmitting depends on the relationship between their degree of resistance and the blood concentration profiles of the anti-malarial drug to which they are exposed. The conditions required for the in-vivo selection of de-novo emergent resistant malaria parasites were examined and relative probabilities assessed. RESULTS: Recrudescence is essential for the transmission of de-novo resistance. For rapidly eliminated anti-malarials high-grade resistance can arise from a single drug exposure, but low-grade resistance can arise only from repeated inadequate treatments. Resistance to artemisinins is, therefore, unlikely to emerge with single drug exposures. Hyperparasitaemic patients are an important source of de-novo anti-malarial drug resistance. Their parasite populations are larger, their control of the infection insufficient, and their rates of recrudescence following anti-malarial treatment are high. As use of substandard drugs, poor adherence, unusual pharmacokinetics, and inadequate immune responses are host characteristics, likely to pertain to each recurrence of infection, a small subgroup of patients provides the particular circumstances conducive to de-novo resistance selection and transmission. CONCLUSION: Current dosing recommendations provide a resistance selection opportunity in those patients with low drug levels and high parasite burdens (often children or pregnant women). Patients with hyperparasitaemia who receive outpatient treatments provide the greatest risk of selecting de-novo resistant parasites. This emphasizes the importance of ensuring that only quality-assured anti-malarial combinations are used, that treatment doses are optimized on the basis of pharmacodynamic and pharmacokinetic assessments in the target populations, and that patients with heavy parasite burdens are identified and receive sufficient treatment to prevent recrudescence

MD simulations of complexes consisted of HIV reverse transcriptase and its potental inhibitors

Fyzikální ústav UKInstitute of Physics of Charles UniversityFaculty of Mathematics and PhysicsMatematicko-fyzikální fakult

Assessing the suitability of mitochondrial and nuclear DNA genetic markers for molecular systematics and species identification of helminths

International audienceBackground: Genetic markers are employed widely in molecular studies, and their utility depends on the degree of sequence variation, which dictates the type of application for which they are suited. Consequently, the suitability of a genetic marker for any specific application is complicated by its properties and usage across studies. To provide a yardstick for future users, in this study we assess the suitability of genetic markers for molecular systematics and species identification in helminths and provide an estimate of the cutoff genetic distances per taxonomic level. Methods: We assessed four classes of genetic markers, namely nuclear ribosomal internal transcribed spacers, nuclear rRNA, mitochondrial rRNA and mitochondrial protein-coding genes, based on certain properties that are important for species identification and molecular systematics. For molecular identification, these properties are interspecies sequence variation; length of reference sequences; easy alignment of sequences; and easy to design universal primers. For molecular systematics, the properties are: average genetic distance from order/suborder to species level; the number of monophyletic clades at the order/suborder level; length of reference sequences; easy alignment of sequences; easy to design universal primers; and absence of nucleotide substitution saturation. Estimation of the cutoff genetic distances was performed using the 'K-means' clustering algorithm. Results: The nuclear rRNA genes exhibited the lowest sequence variation, whereas the mitochondrial genes exhibited relatively higher variation across the three groups of helminths. Also, the nuclear and mitochondrial rRNA genes were the best possible genetic markers for helminth molecular systematics, whereas the mitochondrial proteincoding and rRNA genes were suitable for molecular identification. We also revealed that a general gauge of genetic distances might not be adequate, using evidence from the wide range of genetic distances among nematodes

Genetic Variation of Coleosporium plumeriae from Different Provinces in Thailand

Plumeria rust samples were collected from five provinces in Thailand, including Bangkok, Nakhon Pathom, Rayong, Chonburi and Yala. All five isolates produced the uredial stage but only the isolates from Bangkok and Yala also underwent the telial and basidial stages. The morphological characteristics of all three stages present in the life cycle of the isolates were studied under stereo, compound and electron microscopes. Ribosomal DNA (rDNA) sequences at 28S and ITS (internal transcribed spacer) regions were analyzed with those in the GenBank database by Nucleotide BLAST and phylogenetic analyses. Coleosporium plumeriae was identified as the causal agent of plumeria rust by structure morphology and rDNA sequences that revealed genetic variation of the fungus as well. In general, there were significant differences in the morphological characteristics of uredospores, teliospores and basidia among the isolates. However, the variation of spore morphology was not related to the sampling locations. According to the phylogenetic analysis of 28S rDNA sequences, the UPGMA tree grouped all C. plumeriae from Thailand and foreign countries in the same clade as they shared identical sequences. On the other hand, the UPGMA tree inferred from ITS rDNA sequence data detected genetic variation of the isolate from Chonburi and separated it into the distinct tree branch. In this study, structure morphology and ITS rDNA were suitable genetic markers for both interspecific and intraspecific taxonomy of C. plumeriae