Intracellular pathogens contribute to a significant proportion of infectious disease morbidity and mortality worldwide. Increasing evidence points to a major role for host genetics in explaining ...inter-individual variation in susceptibility to infectious diseases. A number of monogenic disorders predisposing to infectious disease have been reported, including susceptibility to intracellular pathogens in association with mutations in genes of the interleukin-12/interleukin-23/interferon-γ axis. Common genetic variants have also been demonstrated to regulate susceptibility to intracellular infection, for example the CCR5Δ32 polymorphism that modulates human immunodeficiency virus-1 (HIV-1) disease progression. Genome-wide association study approaches are being increasingly utilized to define genetic variants underlying susceptibility to major infectious diseases. This review focuses on the current state-of-the-art in genetics and genomics as pertains to understanding the genetic contribution to human susceptibility to infectious diseases caused by intracellular pathogens such as tuberculosis, leprosy, HIV-1, hepatitis, and malaria, with a particular emphasis on insights from recent genome-wide approaches. The results from these studies implicate common genetic variants in novel molecular pathways involved in human immunity to specific pathogens.
Vaccines are sensitive biologics that require continuous refrigerated storage to maintain their viability. The vast majority of vaccines are also administered using needles and syringes. The need for ...cold chain storage and the significant logistics surrounding needle-and-syringe vaccination is constraining the success of immunization programs. Recombinant live viral vectors are a promising platform for the development of vaccines against a number of infectious diseases, however these viruses must retain infectivity to be effective. Microneedles offer an effective and painless method for delivery of vaccines directly into skin that in the future could provide solutions to current vaccination issues. Here we investigated methods of coating live recombinant adenovirus and modified vaccinia virus Ankara (MVA) vectors onto solid microneedle arrays. An effective spray-coating method, using conventional pharmaceutical processes, was developed, in tandem with suitable sugar-based formulations, which produces arrays with a unique coating of viable virus in a dry form around the shaft of each microneedle on the array. Administration of live virus-coated microneedle arrays successfully resulted in virus delivery, transcutaneous infection and induced an antibody or CD8+ T cell response in mice that was comparable to that obtained by needle-and-syringe intradermal immunization. To our knowledge, this is the first report of successful vaccination with recombinant live viral vectored vaccines coated on microneedle delivery devices.
Spray-coating microneedle arrays targets the material to the shaft of each microneedle, retains live recombinant viral vectored vaccine viability, resulting in successful transcutaneous antigen expression. Display omitted
The GIRAFFE Inner Bulge Survey (GIBS) Zoccali, M; Vasquez, S; Gonzalez, O A ...
Astronomy and astrophysics (Berlin),
3/2017, Letnik:
599
Journal Article
Recenzirano
Odprti dostop
Context. Several recent studies have demonstrated that the Galactic bulge hosts two components with different mean metallicities, and possibly different spatial distribution and kinematics. As a ...consequence, both the metallicity distribution and the radial velocity of bulge stars vary across different lines of sight. Aims. We present here the metallicity distribution function of red clump stars in 26 fields spread across a wide area of the bulge, with special emphasis on fields close to Galactic plane, at latitudes b= -2degrees and b= -1degrees, that have not been explored before. Methods. This paper includes new metallicities from a sample of approximately 5000 K giant stars, observed at spectral resolution R~ 6500, in the Calcium II Triplet region. These represent the main dataset from the GIRAFFE Inner Bulge Survey. As part of the same survey we have previously published results for a sample of approximately 600 K giant stars, at latitude b~ -4degrees, derived from higher resolution spectra (R= 22 500). Results. The combined sample allows us to trace and characterize the metal poor and metal rich bulge populations down to the inner bulge. We present a density map for each of the two components. Contrary to expectations from previous works, we found the metal poor population to be more centrally concentrated than the metal rich one, and with a more axisymmetric spatial distribution. The metal rich population, on the other hand, is arranged in a boxy distribution, consistent with an edge-on bar. By coupling metallicities and radial velocities we show that the metal poor population has a velocity dispersion that varies rather mildly with latitude. On the contrary, the metal rich population has a low velocity dispersion far from the plane (b= -8.5degrees), yet has a steeper gradient with latitude, becoming higher than the metal poor one in the innermost field (b= -1degrees). Conclusions. This work provides new observational constraints on the actual chemodynamical properties of the Galactic bulge, that will help discrimination between different formation models.
Aims. We seek to constrain the formation of the Galactic bulge by analysing the detailed chemical composition of a large sample of red clump stars in Baade’s window. These stars were selected to ...minimise the contamination by other Galactic components, so they are good tracers of the bulge metallicity distribution in Baade’s window, at least for stars more metal-rich than ~−1.5. Methods. We used an automatic procedure to measure Fe/H differentially with respect to the metal-rich star μLeo in a sample of 219 bulge red clump stars from R = 20 000 resolution spectra obtained with FLAMES/GIRAFFE at the VLT. For a subsample of 162 stars, we also derived Mg/H from spectral synthesis around the Mg i triplet at λ 6319 Å. Results. The Fe and Mg metallicity distributions are both asymmetric with median values of +0.16 and +0.21, respectively. They show only a small proportion of stars at low metallicities, extending down to Fe/H = −1.1 or Mg/H = −0.7. The iron distribution is clearly bimodal, as revealed both by a deconvolution (from observational errors) and a Gaussian decomposition. The decomposition of the observed Fe and Mg metallicity distributions into Gaussian components yields two populations of equal sizes (50% each): a metal-poor component centred on Fe/H = −0.30 and Mg/H = −0.06 with a large dispersion and a narrow metal-rich component centred on Fe/H = +0.32 and Mg/H = +0.35. The metal-poor component shows high Mg/Fe ratios (around 0.3), while stars in the metal-rich component are found to have nearly solar ratios. Kinematical differences between the two components have also been found: the metal-poor component shows kinematics compatible with an old spheroid, while the metal-rich component is consistent with a population supporting a bar. In view of their chemical and kinematical properties, we suggest different formation scenarii for the two populations: a rapid formation time scale as an old spheroid for the metal-poor component (old bulge) and for the metal-rich component, a formation on a longer time scale driven by the evolution of the bar (pseudo-bulge). The observations are described well by a simple model consisting of two components: a simple closed box model to predict the metal-poor population contribution and a local thin disc metallicity distribution, shifted in metallicity, to represent the metal-rich population. The pseudo-bulge is compatible with its being formed from the inner thin disc, assuming high (but plausible) values of the gradients in the early Galactic disc.
Transmission-blocking vaccines (TBV) target the sexual-stages of the malaria parasite in the mosquito midgut and are widely considered to be an essential tool for malaria elimination. High-titer ...functional antibodies are required against target antigens to achieve effective transmission-blocking activity. We have fused Pfs25, the leading malaria TBV candidate antigen to IMX313, a molecular adjuvant and expressed it both in ChAd63 and MVA viral vectors and as a secreted protein-nanoparticle. Pfs25-IMX313 expressed from viral vectors or as a protein-nanoparticle is significantly more immunogenic and gives significantly better transmission-reducing activity than monomeric Pfs25. In addition, we demonstrate that the Pfs25-IMX313 protein-nanoparticle leads to a qualitatively improved antibody response in comparison to soluble Pfs25, as well as to significantly higher germinal centre (GC) responses. These results demonstrate that antigen multimerization using IMX313 is a very promising strategy to enhance antibody responses against Pfs25, and that Pfs25-IMX313 is a highly promising TBV candidate vaccine.
Vaccines against Ebola virus Venkatraman, Navin; Silman, Daniel; Folegatti, Pedro M. ...
Vaccine,
08/2018, Letnik:
36, Številka:
36
Journal Article
Recenzirano
Odprti dostop
We have just witnessed the largest and most devastating outbreak of Ebola virus disease, which highlighted the urgent need for development of an efficacious vaccine that could be used to curtail ...future outbreaks. Prior to 2014, there had been limited impetus worldwide to develop a vaccine since the virus was first discovered in 1976. Though too many lives were lost during this outbreak, it resulted in the significantly accelerated clinical development of a number of candidate vaccines through an extraordinary collaborative global effort coordinated by the World Health Organisation (WHO) and involving a number of companies, trial centres, funders, global stakeholders and agencies. We have acquired substantial safety and immunogenicity data on a number of vaccines in Caucasian and African populations. The rapid pace of events led to the initiation of the landmark efficacy trial testing the rVSV-vectored vaccine, which showed high level efficacy in an outbreak setting when deployed using an innovative ring vaccination strategy. Though the Public Health Emergency of International Concern (PHEIC) declared by the WHO has now been lifted, the global scientific community faces numerous challenges ahead to ensure that there is a licensed, deployable vaccine available for use in future outbreaks for at least the Zaire and Sudan strains of Ebola virus. There remain several unanswered questions on the durability of protection, mechanistic immunological correlates and preferred deployment strategies. This review outlines a brief history of the development of Ebola vaccines, the significant progress made since the scale of the outbreak became apparent, some lessons learnt and how they could shape future development of vaccines and the management of similar outbreaks.
Background. Influenza A viruses cause occasional pandemics and frequent epidemics. Licensed influenza vaccines that induce high antibody titers to the highly polymorphic viral surface antigen ...hemagglutinin must be reformulated and readministered annually. A vaccine providing protective immunity to the highly conserved internal antigens could provide longer-lasting protection against multiple influenza subtypes. Methods. We prepared a Modified Vaccinia virus Ankara (MVA) vector encoding nucleoprotein and matrix protein 1 (MVA−NP+M1) and conducted a phase I clinical trial in healthy adults. Results. The vaccine was generally safe and well tolerated, with significantly fewer local side effects after intramuscular rather than intradermal administration. Systemic side effects increased at the higher dose in both frequency and severity, with 5 out of 8 volunteers experiencing severe nausea/vomiting, malaise, or rigors. Ex vivo T-cell responses to NP and M1 measured by IFN-γ ELISPOT assay were significantly increased after vaccination (prevaccination median of 123 spot-forming units/million peripheral blood mononuclear cells, postvaccination peak response median 339, 443, and 1443 in low-dose intradermal, low-dose intramuscular, and high-dose intramuscular groups, respectively), and the majority of the antigen-specific T cells were CD8⁺. Conclusions. We conclude that the vaccine was both safe and remarkably immunogenic, leading to frequencies of responding T cells that appear to be much higher than those induced by any other influenza vaccination approach. Further studies will be required to find the optimum dose and to assess whether the increased T-cell response to conserved influenza proteins results in protection from influenza disease.
Prostate cancer possesses several characteristics that make it a suitable candidate for immunotherapy; however, prostate cancer vaccines to date demonstrate modest efficacy and low immunogenicity. ...The goal of the present pre-clinical study was to explore the immunogenic properties and protective efficacy of a novel prostate cancer immunotherapy based on the heterologous prime–boost viral-vectored vaccination platform. The simian adenovirus, ChAdOx1, and modified vaccinia Ankara virus, MVA, encoding a prostate cancer-associated antigen, the six transmembrane epithelial antigen of the prostate 1 (STEAP1), induced strong sustained antigen-specific CD8+ T-cell responses in C57BL/6 and BALB/c male mice. Unexpectedly, the high vaccine immunogenicity translated into relatively low protective efficacy in the murine transplantable and spontaneous models of prostate cancer. A combination of the vaccine with PD-1 blocking antibody significantly improved survival of the animals, with 80 % of mice remaining tumour-free. These results indicate that the ChAdOx1–MVA vaccination regime targeting STEAP1 combined with PD-1 therapy might have high therapeutic potential in the clinic.
This paper compares the chemical evolution of the Large Magellanic Cloud (LMC) to that of the Milky Way (MW) and investigates the relation between the bar and the inner disc of the LMC in the context ...of the formation of the bar. Our results show that the chemical history of the LMC experienced a strong contribution from type Ia supernovae as well as a strong s-process enrichment from metal-poor AGB winds. Massive stars made a smaller contribution to the chemical enrichment compared to the MW. The observed differences between the bar and the disc speak in favour of an episode of enhanced star formation a few Gyr ago, occurring in the central parts of the LMC and leading to the formation of the bar. This is in agreement with recently derived star formation histories.
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