Cynomolgus macaques as a translational model of human immune responses to yellow fever 17D vaccination.

The non-human primate (NHP) model (specifically rhesus and cynomolgus macaques) has facilitated our understanding of the pathogenic mechanisms of yellow fever (YF) disease and allowed the evaluation of the safety and efficacy of YF-17D vaccines. However, the accuracy of this model in mimicking vaccine-induced immunity in humans remains to be fully determined. We used a systems biology approach to compare hematological, biochemical, transcriptomic, and innate and antibody-mediated immune responses in cynomolgus macaques and human participants following YF-17D vaccination. Immune response progression in cynomolgus macaques followed a similar course as in adult humans but with a slightly earlier onset. Yellow fever virus neutralizing antibody responses occurred earlier in cynomolgus macaques [by Day 7[(D7)], but titers > 10 were reached in both species by D14 post-vaccination and were not significantly different by D28 [plaque reduction neutralization assay (PRNT)50 titers 3.6 Log vs 3.5 Log in cynomolgus macaques and human participants, respectively; P = 0.821]. Changes in neutrophils, NK cells, monocytes, and T- and B-cell frequencies were higher in cynomolgus macaques and persisted for 4 weeks versus less than 2 weeks in humans. Low levels of systemic inflammatory cytokines (IL-1RA, IL-8, MIP-1α, IP-10, MCP-1, or VEGF) were detected in either or both species but with no or only slight changes versus baseline. Similar changes in gene expression profiles were elicited in both species. These included enriched and up-regulated type I IFN-associated viral sensing, antiviral innate response, and dendritic cell activation pathways D3-D7 post-vaccination in both species. Hematological and blood biochemical parameters remained relatively unchanged versus baseline in both species. Low-level YF-17D viremia (RNAemia) was transiently detected in some cynomolgus macaques [28% (5/18)] but generally absent in humans [except one participant (5%; 1/20)].IMPORTANCECynomolgus macaques were confirmed as a valid surrogate model for replicating YF-17D vaccine-induced responses in humans and suggest a key role for type I IFN.

The evolution of pharmacovigilance ecosystems: Does Moore's law invite the use of Occam's razor?

AIMS: Moore's law predicts the doubling of complexity of integrated circuits every 2 years; Kryder's corollary assumes a doubling of data storage every 13 months. With the increasing volume of legislation, pharmacovigilance systems today are inherently complex, and the emphasis has shifted from reactive (responding to emerging risks) to planned, active, risk-proportionate approaches operating throughout the life cycle of medicines. METHODS: Exploration of the drivers for increasing complexity of pharmacovigilance systems, focusing on regulatory environment, data management and evaluation. RESULTS: Evaluation of postmarketing data plays an increasingly important role in pharmacovigilance. There is great interest on the part of all stakeholders in optimizing the use of these data. Innovative approaches, including pharmacogenetics and passive measures (sensors), will lead to increased complexity and volumes of data and inevitably to an increase in the volume of case reports. There is a multiplicity of regulations and guidelines on how to manage these data, with an inherent lack of harmonization. CONCLUSION: We summarize the current characterization of safety data types, sources and the classification of these data. Using this benchmark, we discuss the future requirements of an effective pharmacovigilance ecosystem, keeping the principle of parsimony in mind. In this complex, continuously and rapidly changing environment, there is a need for a return to simplicity and pragmatism. The application of Occam's razor could help to support the rapid provision of new, affordable medicines with a positive benefit to risk profile.

Quantum Confined High-Entropy Lanthanide Oxysulfide Colloidal Nanocrystals.

We have synthesized the first reported example of quantum confined high-entropy (HE) nanoparticles, using the lanthanide oxysulfide, Ln2SO2, system as the host phase for an equimolar mixture of Pr, Nd, Gd, Dy, and Er. A uniform HE phase was achieved via the simultaneous thermolysis of a mixture of lanthanide dithiocarbamate precursors in solution. This was confirmed by powder X-ray diffraction and high-resolution scanning transmission electron microscopy, with energy dispersive X-ray spectroscopic mapping confirming the uniform distribution of the lanthanides throughout the particles. The nanoparticle dispersion displayed a significant blue shift in the absorption and photoluminescence spectra relative to our previously reported bulk sample with the same composition, with an absorption edge at 330 nm and a λmax at 410 nm compared to the absorption edge at 500 nm and a λmax at 450 nm in the bulk, which is indicative of quantum confinement. We support this postulate with experimental and theoretical analysis of the bandgap energy as a function of strain and surface effects (ligand binding) as well as calculation of the exciton Bohr radiii of the end member compounds.

Investigating the Effect of Steric Hindrance within CdS Single-Source Precursors on the Material Properties of AACVD and Spin-Coat-Deposited CdS Thin Films.

Cadmium sulfide (CdS) is an important semiconductor for electronic and photovoltaic applications, particularly when utilized as a thin film for window layers in CdTe solar cells. Deposition of thin-film CdS through the decomposition of single-source precursors is an attractive approach due to the facile, low-temperature, and rapid nature of this approach. Tailoring the precursor to affect the decomposition properties is commonly employed to tune desirable temperatures of decomposition. However, altering the precursor structure and the effect this has on the nature of the deposited material is an area far less commonly investigated. Here, we seek to investigate this by altering the ligands around the Cd metal center to increase the steric hindrance of the precursor and investigate the effect this has on the decomposition properties and the properties of deposited thin-film CdS from these precursors. For this, we report the synthesis of four CdS precursors with xanthate and pyridyl ligands ([Cd(n-ethyl xanthate)2(3-methyl pyridine)2] [1], [Cd(n-ethyl xanthate)2(3,5-lutidine)2] [2], [(Cd2(isopropyl xanthate)4(3-methyl pyridine)2)n] [3], and [Cd(isopropyl xanthate)2(3,5-lutidine)2] [4]). These single-source precursors for CdS were fully characterized by elemental analysis, NMR spectroscopy, single-crystal X-ray diffraction (XRD), and thermogravimetric analysis. It was found that even with subtle alterations in the xanthate (n-ethyl to isopropyl) and pyridine (3-methyl and 3,5-dimethyl) ligands, a range of hexa-coordinate precursors were formed (two with cis configuration, one with trans configuration, and one as a one-dimensional (1D) polymer). These four precursors were then used in aerosol-assisted chemical vapor deposition (AACVD) and spin-coating experiments to deposit eight thin films of CdS, which were characterized by Raman spectroscopy, powder X-ray diffraction, and scanning electron microscopy. Comparative quantitative information concerning film thickness and surface roughness was also determined by atomic force microscopy. Finally, the optical properties of all thin films were characterized by ultraviolet-visible (UV-Vis) absorption spectroscopy, from which the band gap of each deposited film was determined to be commensurate with that of bulk CdS (ca. 2.4 eV).

Adverse events in the digital age and where to find them.

Exponential growth of health-related data collected by digital tools is a reality within pharmaceutical and medical device research and development. Data generated through digital tools may be categorized as relevant to efficacy and/or safety. The enormity of these data requires the adoption of new approaches for processing and evaluation. Recognition of patterns within the safety data is vital for sponsors seeking regulatory approval for their new products. Nontraditional data sources may contain relevant safety information; early evaluation of these data will help to determine the product safety profile. Advanced technologies have allowed the development of digital tools to screen these data, which in some situations are classified as software as a medical devices and subject to clinical evaluation and post-marketing surveillance. Artificial intelligence may help to reduce or even eliminate noise from within these data, allowing safety experts to focus on the most pertinent evidence. We propose a data typology and provide considerations on how to define adverse events within different types of data, even where no human reporter exists. Proposals are made for the automation of screening processes. We consider validation aspects to support solutions that are proven to produce reliable results, and to deliver trusted outputs to stakeholders.

Synthesis of High Entropy Lanthanide Oxysulfides via the Thermolysis of a Molecular Precursor Cocktail.

High entropy (HE) materials have received significant attention in recent years, due to their intrinsically high levels of configurational entropy. While there has been significant work exploring HE alloys and oxides, new families of HE materials are still being revealed. In this work we present the synthesis of a novel family of HE materials based on lanthanide oxysulfides. Here, we implement lanthanide dithiocarbamates as versatile precursors that can be mixed at the molecular scale prior to thermolysis in order to produce the high entropy oxysulfide. The target of our synthesis is the HE Ln2SO2 phase, where Ln = Pr, Nd, Gd, Dy, Er and where Ln = Pr, Nd, Gd, Dy for 5 and 4 lanthanide samples, respectively. We confirmed the structure of samples produced by powder X-ray diffraction, electron microscopy, and high-resolution energy dispersive X-ray spectroscopy. Optical spectroscopy shows a broad emission feature centered around 450 nm as well as a peak in absorption at around 280 nm. From this data we calculate the band gap and Urbach energies of the materials produced.

PI3Kδ inhibition prevents IL33, ILC2s and inflammatory eosinophils in persistent airway inflammation.

BACKGROUND: Phosphoinositide-3-kinase-delta (PI3Kδ) inhibition is a promising therapeutic approach for inflammatory conditions due to its role in leucocyte proliferation, migration and activation. However, the effect of PI3Kδ inhibition on group 2 innate lymphoid cells (ILC2s) and inflammatory eosinophils remains unknown. Using a murine model exhibiting persistent airway inflammation we sought to understand the effect of PI3Kδ inhibition, montelukast and anti-IL5 antibody treatment on IL33 expression, group-2-innate lymphoid cells, inflammatory eosinophils, and goblet cell metaplasia. RESULTS: Mice were sensitised to house dust mite and after allowing inflammation to resolve, were re-challenged with house dust mite to re-initiate airway inflammation. ILC2s were found to persist in the airways following house dust mite sensitisation and after re-challenge their numbers increased further along with accumulation of inflammatory eosinophils. In contrast to montelukast or anti-IL5 antibody treatment, PI3Kδ inhibition ablated IL33 expression and prevented group-2-innate lymphoid cell accumulation. Only PI3Kδ inhibition and IL5 neutralization reduced the infiltration of inflammatory eosinophils. Moreover, PI3Kδ inhibition reduced goblet cell metaplasia. CONCLUSIONS: Hence, we show that PI3Kδ inhibition dampens allergic inflammatory responses by ablating key cell types and cytokines involved in T-helper-2-driven inflammatory responses.

Molecular Precursor Route to Bournonite (CuPbSbS3) Thin Films and Powders.

Quaternary metal chalcogenides have attracted attention as candidates for absorber materials for inexpensive and sustainable solar energy generation. One of these materials, bournonite (orthorhombic CuPbSbS3), has attracted much interest of late for its properties commensurate with photovoltaic energy conversion. This paper outlines the synthesis of bournonite for the first time by a discrete molecular precursor strategy. The metal dithiocarbamate complexes bis(diethyldithiocarbamato)copper (II) (Cu(S2CNEt2)2, (1)), bis(diethyldithiocarbamato)lead (II) (Pb(S2CNEt2)2, (2)), and bis(diethyldithiocarbamato)antimony (III) (Sb(S2CNEt2)3, (3)) were prepared, characterized, and employed as molecular precursors for the synthesis of bournonite powders and the thin film by solvent-less pyrolysis and spray-coat-pyrolysis techniques, respectively. The polycrystalline powders and thin films were characterized by powder X-ray diffraction (p-XRD), which could be indexed to orthorhombic CuPbSbS3. The morphology of the powder at the microscale was studied using scanning electron microscopy (SEM). Energy-dispersive X-ray spectroscopy (EDX) was used to elucidate an approximately 1:1:1:3 Cu/Pb/Sb/S elemental ratio. An optical band gap energy of 1.55 eV was estimated from a Tauc plot, which is close to the theoretical value of 1.41 eV.

Synthesis, X-ray Single-Crystal Structural Characterization, and Thermal Analysis of Bis(O-alkylxanthato)Cd(II) and Bis(O-alkylxanthato)Zn(II) Complexes Used as Precursors for Cadmium and Zinc Sulfide Thin Films.

This work investigates tuning of the molecular structure of a series of O-alkylxanthato zinc and cadmium precursor complexes to enhance production of ZnS and CdS materials. The structures of several bis(O-alkylxanthato) cadmium(II) complexes (8-13) and bis(O-alkyl xanthato)zinc(II) complexes (18 and 19) are reported based on single crystal X-ray diffraction data. CdS and ZnS films were produced by the spin-coating of these metal complexes followed by their thermal decomposition to the corresponding metal sulfides. Thin films of CdS were deposited by spin-coating the bis(O-alkylxanthato) cadmium(II) precursors (7-13) on glass substrates, followed by annealing at 300 °C for 60 min. Thin films of ZnS were deposited by spin-coating bis(O-alkylxanthato) zinc(II) (14-20), followed by annealing at 200 °C for 60 min. The molecular complexes and solid state materials are characterized using a range of techniques including single-crystal X-ray diffraction, pXRD, EDS and XPS, DSC and TGA, UV-vis and PL spectroscopies, and electron microscopy. These techniques provided information on the influence of alkyl chain length on the thermal conditions required to fabricate metal sulfide films as well as film properties such as film quality, and morphology. For example, the obtained crystallite size of metal sulfide films formed is correlated to the hydrocarbon chain length of xanthate ligands in the precursor. The behavior of the complexes under thermal stress was therefore studied in detail. DTA and TGA profiles explain the relationship between hydrocarbon chain length, decomposition temperatures, and the energies required for decomposition. A higher decomposition temperature for complexes with longer hydrocarbon chains is observed compared to complexes with shorter hydrocarbon chains. Band-gap energies calculated from the optical absorption spectra alongside steady state and time-resolved photoluminescence studies are reported for CdS films.

Reporting rates of adverse reactions to specialty care medicines exhibit a direct positive correlation with patient exposure: A lack of evidence for the Weber effect.

AIMS: The classical Weber effect describes an increase in adverse reaction (AR) reports after medicinal product authorisation, with a peak in AR reporting at the end of the second year followed by a decline, despite increasing patient exposure. The present study aimed to evaluate the validity of the Weber effect in the context of authorised medicines in a specialty care setting. METHODS: Using 6-monthly sales data as a proxy for exposure, the exposure-adjusted reporting rates for AR reports for 10 selected specialty care medicines were plotted against time. These data were also evaluated based on the source of report (solicited or unsolicited) and the nature of the AR contained within the reports (listed or unlisted). Unsolicited reports were analysed against sales volumes. Goodness of fit (R2 ) was calculated and the trend representing the highest R2 was selected. RESULTS: Study data comprised a total of 1 222 852 AR reports for 10 specialty care medicines. Amongst all of the products evaluated, none of the associated data represented reporting patterns entirely consistent with the classical Weber effect (see Figure 1). The results, however, showed a systemic direct correlation between AR reporting and sales volumes, especially throughout the first 5 years post-authorisation. CONCLUSION: The study not only presents evidence of the absence of the Weber effect with specialty care medicines but also provides a substantial evidence of linear AR reporting correlating with sales volumes, especially during the first 5 years after marketing.

Heterometallic 3d-4f Complexes as Air-Stable Molecular Precursors in Low Temperature Syntheses of Stoichiometric Rare-Earth Orthoferrite Powders.

Four 3d-4f hetero-polymetallic complexes [Fe2Ln2((OCH2)3CR)2(O2CtBu)6(H2O)4] (where Ln = La (1 and 2) and Gd (3 and 4); and R = Me (1 and 3) and Et (2 and 4)) are synthesized and analyzed using elemental analysis, Fourier transform infrared spectroscopy, thermogravimetric analysis, and SQUID magnetometry. Crystal structures are obtained for both methyl derivatives and show that the complexes are isostructural and adopt a defective dicubane topology. The four heavy metals are connected with two alkoxide bridges. These four precursors are used as single-source precursors to prepare rare-earth orthoferrite pervoskites of the form LnFeO3. Thermal decomposition in a ceramic boat in a tube furnace gives orthorhombic LnFeO3 powders using optimized temperatures and decomposition times: LaFeO3 formed at 650 °C over 30 min, whereas GdFeO3 formed at 750 °C over 18 h. These materials are structurally characterized using powder X-ray diffraction, Raman spectroscopy, scanning electron microscopy, energy-dispersive X-ray map spectroscopy, and SQUID magnetometry. EDX spectroscopy mapping reveals a homogeneous spatial distribution of elements for all four materials consistent with LnFeO3. Magnetic measurements on complexes 1-4 confirm the presence of weak antiferromagnetic coupling between the central Fe(III) ions of the clusters and negligible ferromagnetic interaction with peripheral Gd(III) ions in 3 and 4. Zero-field-cooled and field-cooled measurements of magnetization of LaFeO3 and GdFeO3 in the solid-state suggest that both materials are ferromagnetic, and both materials show open magnetic hysteresis loops at 5 and 300 K, with Msat higher than previously reported for these nanomaterials. We conclude that this is a new and facile low temperature route to these important magnetic materials that is potentially universal, limited only by what metals can be programmed into the precursor complexes.

Safety and Immunogenicity of a Heterologous Prime-Boost Ebola Virus Vaccine Regimen in Healthy Adults in the United Kingdom and Senegal.

BACKGROUND: The 2014 West African outbreak of Ebola virus disease highlighted the urgent need to develop an effective Ebola vaccine. METHODS: We undertook 2 phase 1 studies assessing safety and immunogenicity of the viral vector modified vaccinia Ankara virus vectored Ebola Zaire vaccine (MVA-EBO-Z), manufactured rapidly on a new duck cell line either alone or in a heterologous prime-boost regimen with recombinant chimpanzee adenovirus type 3 vectored Ebola Zaire vaccine (ChAd3-EBO-Z) followed by MVA-EBO-Z. Adult volunteers in the United Kingdom (n = 38) and Senegal (n = 40) were vaccinated and an accelerated 1-week prime-boost regimen was assessed in Senegal. Safety was assessed by active and passive collection of local and systemic adverse events. RESULTS: The standard and accelerated heterologous prime-boost regimens were well-tolerated and elicited potent cellular and humoral immunogenicity in the United Kingdom and Senegal, but vaccine-induced antibody responses were significantly lower in Senegal. Cellular immune responses measured by flow cytometry were significantly greater in African vaccinees receiving ChAd3 and MVA vaccines in the same rather than the contralateral limb. CONCLUSIONS: MVA biomanufactured on an immortalized duck cell line shows potential for very large-scale manufacturing with lower cost of goods. This first trial of MVA-EBO-Z in humans encourages further testing in phase 2 studies, with the 1-week prime-boost interval regimen appearing to be particularly suitable for outbreak control. CLINICAL TRIALS REGISTRATION: NCT02451891; NCT02485912.

A Free-Standing and Self-Healable 2D Supramolecular Material Based on Hydrogen Bonding: A Nanowire Array with Sub-2-nm Resolution.

In many 2D materials reported thus far, the forces confining atoms in a 2D plane are often strong interactions, such as covalent bonding. Herein, the first demonstration that hydrogen (H)-bonding can be utilized to assemble polydiacetylene (a conductive polymer) toward a 2D material, which is stable enough to be free-standing, is shown. The 2D material is well characterized by a large number of techniques (mainly different microscopy techniques). The H-bonding allows splitting of the material into ribbons, which can reassemble, similar to a zipper, leading to the first example of a healable 2D material. Moreover, such technology can easily create 2D, organic, conductive nanowire arrays with sub-2-nm resolution. This material may have potential applications in stretchable electronics and nanowire cross-bar arrays.

In depth comparative phenotyping of blood innate myeloid leukocytes from healthy humans and macaques using mass cytometry.

Comparative immune-profiling of innate responses in humans and non-human primates is important to understand the pathogenesis of infectious and chronic inflammatory diseases as well as for the preclinical development of vaccines and immune therapies. However, direct comparisons of the two species are rare and were never performed using mass cytometry. Here, whole-blood-derived leukocytes from healthy humans and cynomolgus macaques were analyzed with mass cytometry. Two similar panels of around 30 monoclonal antibodies targeting human markers associated with innate myeloid cells to stain fixed human and macaque leukocytes were constructed. To compare the circulating innate cells from the two primate species, an analysis pipeline combining a clustering analysis by the Spanning-tree Progression Analysis of Density-normalized Events (SPADE) algorithm with a two-step hierarchical clustering of cells nodes and markers was used. Identical SPADE settings were applied to both datasets, except for the 20 clustering markers which slightly differed. A correlation analysis designed to compare the phenotypes of human and macaque cell nodes and based on 16 markers, including 15 shared clustering markers and CD19 for humans or CD20 for macaques, revealed similarities and differences between staining patterns. This study unique by the number of individuals (26 humans and 5 macaques) and the use of mass cytometry certainly contributes to better assess the advantages and limits of the use of non-human primates in preclinical research. © 2017 International Society for Advancement of Cytometry.

Implementing the optimal provision of ecosystem services.

Many ecosystem services are public goods whose provision depends on the spatial pattern of land use. The pattern of land use is often determined by the decisions of multiple private landowners. Increasing the provision of ecosystem services, though beneficial for society as a whole, may be costly to private landowners. A regulator interested in providing incentives to landowners for increased provision of ecosystem services often lacks complete information on landowners' costs. The combination of spatially dependent benefits and asymmetric cost information means that the optimal provision of ecosystem services cannot be achieved using standard regulatory or payment for ecosystem services approaches. Here we show that an auction that sets payments between landowners and the regulator for the increased value of ecosystem services with conservation provides incentives for landowners to truthfully reveal cost information, and allows the regulator to implement the optimal provision of ecosystem services, even in the case with spatially dependent benefits and asymmetric information.

Projected land-use change impacts on ecosystem services in the United States.

Providing food, timber, energy, housing, and other goods and services, while maintaining ecosystem functions and biodiversity that underpin their sustainable supply, is one of the great challenges of our time. Understanding the drivers of land-use change and how policies can alter land-use change will be critical to meeting this challenge. Here we project land-use change in the contiguous United States to 2051 under two plausible baseline trajectories of economic conditions to illustrate how differences in underlying market forces can have large impacts on land-use with cascading effects on ecosystem services and wildlife habitat. We project a large increase in croplands (28.2 million ha) under a scenario with high crop demand mirroring conditions starting in 2007, compared with a loss of cropland (11.2 million ha) mirroring conditions in the 1990s. Projected land-use changes result in increases in carbon storage, timber production, food production from increased yields, and >10% decreases in habitat for 25% of modeled species. We also analyze policy alternatives designed to encourage forest cover and natural landscapes and reduce urban expansion. Although these policy scenarios modify baseline land-use patterns, they do not reverse powerful underlying trends. Policy interventions need to be aggressive to significantly alter underlying land-use change trends and shift the trajectory of ecosystem service provision.

Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica Vaccine and PATRICIA Trials.

BACKGROUND: There is some evidence to suggest that one or two doses of the HPV vaccine provides similar protection to the three-dose regimen. The main aim of the study was to ascertain HPV-16/18 vaccine efficacy in both full and naive cohorts and to explore protection conferred against non-vaccine HPV types, by number of doses received. METHODS: Summary data from the Costa Rica Vaccine Trial (CVT; NCT00128661) and ~the PATRICIA trial (NCT001226810), two phase 3, double-blind, randomised controlled clinical trials of the HPV-16/18 AS04-adjuvanted vaccine in young women, were combined in a post-hoc analysis (GlaxoSmithKline [GSK] e-track number 202142) to investigate the efficacy of fewer than three doses of the HPV-16/18 vaccine after 4 years of follow-up. Women were randomly assigned to receive three doses of the HPV-16/18 vaccine or to a control vaccine; yet, some received fewer doses. After exclusion of women with less than 12 months of follow-up or those who were HPV-16/18 DNA-positive at enrolment (for the HPV-16/18 endpoint), we calculated vaccine efficacy against one-time detection of incident HPV infections after three, two, and one dose(s). The primary study endpoint was one-time detection of first incident HPV-16/18 infections accumulated during the follow-up phase. FINDINGS: We assessed vaccine efficacy against incident HPV-16/18 infection in the modified total vaccinated cohort (22 327 received three doses, 1185 two doses, 543 one dose). Vaccine efficacy against incident HPV-16/18 infections for three doses was 77·0% (95% CI 74·7-79·1), two doses was 76·0% (62·0-85·3), and one dose was 85·7% (70·7-93·7). Vaccine efficacy against incident HPV-31/33/45 infections for three doses was 59·7% (56·0-63·0), two doses was 37·7% (12·4-55·9), and one dose was 36·6% (-5·4 to 62·2). Vaccine efficacy against incident HPV-16/18 infection for two-dose women who received their second dose at 1 month was 75·3% (54·2-87·5) and 82·6% (42·3-96·1) for those who received the second dose at 6 months (CVT data only). Vaccine efficacy against HPV-31/33/45 for two-dose women who received their second dose at 6 months (68·1%, 27·0-87·0; CVT data only), but not those receiving it at one month (10·1%, -42·0 to 43·3), was similar to the three-dose group. INTERPRETATION: 4 years after vaccination of women aged 15-25 years, one and two doses of the HPV-16/18 vaccine seem to protect against cervical HPV-16/18 infections, similar to the protection provided by the three-dose schedule. Two doses separated by 6 months additionally provided some cross-protection. These data argue for a direct assessment of one-dose efficacy of the HPV-16/18 vaccine. FUNDING: US National Cancer Institute, National Institutes of Health Office of Research on Women's Health, and Ministry of Health of Costa Rica (CVT); GlaxoSmithKline Biologicals SA (PATRICIA).

Tin(II) Sulfide (SnS) Nanosheets by Liquid-Phase Exfoliation of Herzenbergite: IV-VI Main Group Two-Dimensional Atomic Crystals.

The liquid-phase exfoliation of tin(II) sulfide to produce SnS nanosheets in N-methyl-2-pyrrolidone is reported. The material is characterized by Raman spectroscopy, atomic force microscopy, lattice-resolution scanning transmission electron microscope imaging, and energy dispersive X-ray spectrum imaging. Quantum chemical calculations on the optoelectronic characteristics of bulk and 10-layer down to monolayer SnS have been performed using a quantum chemical density functional tight-binding approach. The optical properties of the SnS and centrifugally fractionated SnS nanosheet dispersions were compared to that predicted by theory. Through centrifugation, bilayer SnS nanosheets can be produced size-selectively. The scalable solution processing of semiconductor SnS nanosheets is the key to their commercial exploitation and is potentially an important step toward the realization of a future electronics industry based on two-dimensional materials.

Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial.

BACKGROUND: Meningococcal conjugate vaccines protect individuals directly, but can also confer herd protection by interrupting carriage transmission. We assessed the effects of meningococcal quadrivalent glycoconjugate (MenACWY-CRM) or serogroup B (4CMenB) vaccination on meningococcal carriage rates in 18-24-year-olds. METHODS: In this phase 3, observer-blind, randomised controlled trial, university students aged 18-24 years from ten sites in England were randomly assigned (1:1:1, block size of three) to receive two doses 1 month apart of Japanese Encephalitis vaccine (controls), 4CMenB, or one dose of MenACWY-CRM then placebo. Participants were randomised with a validated computer-generated random allocation list. Participants and outcome-assessors were masked to the treatment group. Meningococci were isolated from oropharyngeal swabs collected before vaccination and at five scheduled intervals over 1 year. Primary outcomes were cross-sectional carriage 1 month after each vaccine course. Secondary outcomes included comparisons of carriage at any timepoint after primary analysis until study termination. Reactogenicity and adverse events were monitored throughout the study. Analysis was done on the modified intention-to-treat population, which included all enrolled participants who received a study vaccination and provided at least one assessable swab after baseline. This trial is registered with ClinicalTrials.gov, registration number NCT01214850. FINDINGS: Between Sept 21 and Dec 21, 2010, 2954 participants were randomly assigned (987 assigned to control [984 analysed], 979 assigned to 4CMenB [974 analysed], 988 assigned to MenACWY-CRM [983 analysed]); 33% of the 4CMenB group, 34% of the MenACWY-CRM group, and 31% of the control group were positive for meningococcal carriage at study entry. By 1 month, there was no significant difference in carriage between controls and 4CMenB (odds ratio 1·2, 95% CI 0·8-1·7) or MenACWY-CRM (0·9, [0·6-1·3]) groups. From 3 months after dose two, 4CMenB vaccination resulted in significantly lower carriage of any meningococcal strain (18·2% [95% CI 3·4-30·8] carriage reduction), capsular groups BCWY (26·6% [10·5-39·9] carriage reduction), capsular groups CWY (29·6% [8·1-46·0] carriage reduction), and serogroups CWY (28·5% [2·8-47·5] carriage reduction) compared with control vaccination. Significantly lower carriage rates were also noted in the MenACWY-CRM group compared with controls: 39·0% (95% CI 17·3-55·0) carriage reduction for serogroup Y and 36·2% (15·6-51·7) carriage reduction for serogroup CWY. Study vaccines were generally well tolerated, with increased rates of transient local injection pain and myalgia in the 4CMenB group. No safety concerns were identified. INTERPRETATION: Although we detected no significant difference between groups at 1 month after vaccine course, MenACWY-CRM and 4CMenB vaccines reduced meningococcal carriage rates during 12 months after vaccination and therefore might affect transmission when widely implemented. FUNDING: Novartis Vaccines.

Effect of vaginal immunization with HIVgp140 and HSP70 on HIV-1 replication and innate and T cell adaptive immunity in women.

The international effort to prevent HIV-1 infection by vaccination has failed to develop an effective vaccine. The aim of this vaccine trial in women was to administer by the vaginal mucosal route a vaccine consisting of HIV-1 gp140 linked to the chaperone 70-kDa heat shock protein (HSP70). The primary objective was to determine the safety of the vaccine. The secondary objective was to examine HIV-1 infectivity ex vivo and innate and adaptive immunity to HIV-1. Protocol-defined female volunteers were recruited. HIV-1 CN54gp140 linked to HSP70 was administered by the vaginal route. Significant adverse reactions were not detected. HIV-1 was significantly inhibited ex vivo in postimmunization CD4(+) T cells compared with preimmunization CD4(+) T cells. The innate antiviral restrictive factor APOBEC3G was significantly upregulated, as were CC chemokines which induce downregulation of CCR5 in CD4(+) T cells. Indeed, a significant inverse correlation between the proportion of CCR5(+) T cells and the concentration of CCL-3 or CCL-5 was found. Importantly, the upregulation of APOBEC3G showed a significant inverse correlation, whereas CCR5 exhibited a trend to correlate with inhibition of HIV-1 infection (r = 0.51). Furthermore, specific CD4(+) and CD8(+) T cell proliferative responses were significantly increased and CD4(+) T cells showed a trend to have an inverse correlation with the viral load (r = -0.60). However, HIVgp140-specific IgG or IgA antibodies were not detected. The results provide proof of concept that an innate mechanism consisting of CC chemokines, APOBEC3G, and adaptive immunity by CD4 and CD8 T cells might be involved in controlling HIV-1 infectivity following vaginal mucosal immunization in women. (This study has been registered at ClinicalTrials.gov under registration no. NCT01285141.) Importance: Vaginal immunization of women with a vaccine consisting of HIVgp140 linked to the 70-kDa heat shock protein (HSP70) elicited ex vivo significant inhibition of HIV-1 replication in postimmunization CD4(+) T cells compared with that in preimmunization peripheral blood mononuclear cells. There were no significant adverse events. The vaccine induced the significant upregulation of CC chemokines and the downmodulation of CCR5 expression in CD4(+) T cells, as well as an inverse correlation between them. Furthermore, the level of CCR5 expression was directly correlated with the viral load, consistent with the protective mechanism in which a decrease in CCR5 molecules on CD4(+) T cells decreases HIV-1 envelope binding. Expression of the antiviral restriction factor APOBEC3G was inversely correlated with the viral load, suggesting that it may inhibit intracellular HIV-1 replication. Both CD4(+) and CD8(+) T cells showed HIVgp140- and HSP70-specific proliferation. A strong inverse correlation between the proportion of CC chemokine-modulated CCR5-expressing CD4(+) T cells and the stimulation of CD4(+) or CD8(+) T cell proliferation by HIVgp140 was found, demonstrating a significant interaction between innate and adaptive immunity. This is the first clinical trial of vaginal immunization in women using only HIVgp140 and HSP70 administered by the mucosal route (3 times) in which a dual innate protective mechanism was induced and enhanced by significant adaptive CD4(+) and CD8(+) T cell proliferative responses.