Intradermal administration of synthetic DNA vaccines induce robust cellular and humoral immune responses

There has long been an interest by health agencies such as Program for Appropriate Technology in Health (PATH) and the World Health Organization (WHO) to deliver vaccines by the intradermal route (ID). The skin is full of immunological cells, most notably antigen presenting cells. Therefore, ID injection may be an efficient means of inducing an immune response to vaccines. Inovio has developed ID injection followed by a shallow in vivo electroporation (ID-EP) for synthetic DNA vaccine delivery. We have tested a number of our vaccines in clinical trials using the ID-EP delivery system including vaccines targeted against HIV, ZIKA virus and EBOLA virus. The success of the ID method takes on particular importance for a vaccine that will be used in an emergency setting such as during a possible Ebola virus outbreak. Such a vaccine will need to quickly induce robust, protective immune responses. INO-4201, our DNA based Zaire Ebolavirus (EBOV) vaccine, was analyzed following ID delivery. Immune responses generated by INO-4201 after the 2mg intradermal administration using the Cellectra in vivo electroporation device in volunteers revealed the induction of robust Ebola virus GP-specific antibodies, CD4+ as well as CD8+ T cell responses. Specifically, 100% seroconversion, as gauged by binding ELISA, was detected after two doses of INO-4201. The reciprocal geometric mean endpoint titer at that time was 39,664.20 and was boosted by administration of the third dose to 46,968.00. Examination of the EBOLA virus GP specific T cell response as assessed by Interferon gamma (IFNγ) ELISpot revealed a mean peak response magnitude of 295.3 SFU per 10^6 PBMCs. Importantly, the induction of robust immune response by ID-EP was mirrored in the ZIKA virus and HIV DNA vaccine clinical trials. These results indicate that ID methods to deliver DNA-based vaccines are important for further clinical development

Parasitic Infection and the Polarized Th2 Immune Response Can Alter a Vaccine-Induced Immune Response

The AIDS epidemic in the Developing World represents a major global crisis. It is imperative that we develop an effective vaccine. Vaccines are economically the most efficient means of controlling viral infections. However, the development of a vaccine against HIV-1 has been a formidable task, and in developing countries chronic parasitic infection adds another level of complexity to AIDS vaccine development. Helminthic and protozoan infections, common in developing countries, can result in a constant state of immune activation that is characterized by a dominant Th2 type of cytokine profile, high IgE levels, and eosinophilia. Such an immune profile may have an adverse impact on the efficacy of vaccines, in particular, an HIV-1 vaccine. Indeed, the CD8 cellular immune response and the corresponding Th1 type cytokines that enhance the CD8 cellular immune response are important for clearing many viral infections. It is believed that an antigen specific CD8 cellular immune response will be an important component of an HIV-1 vaccine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63250/1/104454903767650685.pd

Integrated results from the COPERNICUS and GALILEO studies.

OBJECTIVES: To report on the efficacy and safety of intravitreal aflibercept in patients with macular edema secondary to central retinal vein occlusion (CRVO) in an integrated analysis of COPERNICUS and GALILEO. PATIENTS AND METHODS: Patients were randomized to receive intravitreal aflibercept 2 mg every 4 weeks or sham injections until week 24. From week 24 to week 52, all intravitreal aflibercept-treated patients in both studies and sham-treated patients in COPERNICUS were eligible to receive intravitreal aflibercept based on prespecified criteria. In GALILEO, sham-treated patients continued to receive sham treatment through week 52. RESULTS: At week 24, mean gain in best-corrected visual acuity and mean reduction in central retinal thickness were greater for intravitreal aflibercept-treated patients compared with sham, consistent with individual trial results. At week 52, after 6 months of intravitreal aflibercept as-needed treatment in COPERNICUS, patients originally randomized to sham group experienced visual and anatomic improvements but did not improve to the extent of those initially treated with intravitreal aflibercept, while the sham group in GALILEO did not improve over week 24 mean best-corrected visual acuity scores. Ocular serious adverse events occurred in CONCLUSION: This analysis of integrated data from COPERNICUS and GALILEO confirmed that intravitreal aflibercept is an effective treatment for macular edema following CRVO

Heat Transfer in Buildings: Application to Solar Air Collector and Trombe Wall Design

The aim of this paper is to briefly recall heat transfer modes and explain their integration within a software dedicated to building simulation (CODYRUN). Detailed elements of the validation of this software are presented and two applications are finally discussed. One concerns the modeling of a flat plate air collector and the second focuses on the modeling of Trombe solar walls. In each case, detailed modeling of heat transfer allows precise understanding of thermal and energetic behavior of the studied structures. Recent decades have seen a proliferation of tools for building thermal simulation. These applications cover a wide spectrum from very simplified steady state models to dynamic simulation ones, including computational fluid dynamics modules (Clarke, 2001). These tools are widely available in design offices and engineering firms. They are often used for the design of HVAC systems and still subject to detailed research, particularly with respect to the integration of new fields (specific insulation materials, lighting, pollutants transport, etc.). Available from: http://www.intechopen.com/books/evaporation-condensation-and-heat-transfer/heat-transfer-in-buildings-application-to-solar-air-collector-and-trombe-wall-designComment: Available from: http://www.intechopen.com/books/evaporation-condensation-and-heat-transfer/heat-transfer-in-buildings-application-to-solar-air-collector-and-trombe-wall-desig

Laser impulse coupling measurements at 400 fs and 80 ps using the LULI facility at 1057 nm wavelength

At the École Polytechnique « LULI » facility, we have measured the impulse coupling coefficient Cm (target momentum per joule of incident laser light) with several target materials in vacuum, at 1057 nm and 400 fs and 80 ps pulse duration. A total of 64 laser shots were completed in a two-week experimental campaign, divided between the two pulse durations and among the materials. Our main purpose was to resolve wide discrepancies among reported values for Cm in the 100 ps region, where many applications exist. A secondary purpose was to compare Cm at 400 fs and 80 ps pulse duration. The 80 ps pulse was obtained by partial compression. Materials were Al, Ta, W, Au, and POM (polyoxymethylene, trade name Delrin). One application of these results is to pulsed laser ablation propulsion in space, including space debris re-entry, where narrow ranges in Cm and specific impulse Isp spell the difference between dramatic and uneconomical performance. We had difficulty measuring mass loss from single shots. Imparted momentum in single laser shots was determined using pendulum deflection and photonic Doppler velocimetry. Cm was smaller at the 400 fs pulse duration than at 80 ps. To our surprise, Cm for Al at 80 ps was at most 30 N/MW with 30 kJ/m2 incident fluence. On the other extreme, polyoxymethylene (POM, trade name Delrin) demonstrated 770 N/MW under these conditions. Together, these results offer the possibility of designing a Cm value suited to an application, by mixing the materials appropriately

Numerical models of irrotational binary neutron stars in general relativity

We report on general relativistic calculations of quasiequilibrium configurations of binary neutron stars in circular orbits with zero vorticity. These configurations are expected to represent realistic situations as opposed to corotating configurations. The Einstein equations are solved under the assumption of a conformally flat spatial 3-metric (Wilson-Mathews approximation). The velocity field inside the stars is computed by solving an elliptical equation for the velocity scalar potential. Results are presented for sequences of constant baryon number (evolutionary sequences). Although the central density decreases much less with the binary separation than in the corotating case, it still decreases. Thus, no tendency is found for the stars to individually collapse to black hole prior to merger.Comment: Minor corrections, improved figure, 5 pages, REVTeX, Phys. Rev. Lett. in pres

A two-mass expanding exact space-time solution

In order to understand how locally static configurations around gravitationally bound bodies can be embedded in an expanding universe, we investigate the solutions of general relativity describing a space-time whose spatial sections have the topology of a 3-sphere with two identical masses at the poles. We show that Israel junction conditions imply that two spherically symmetric static regions around the masses cannot be glued together. If one is interested in an exterior solution, this prevents the geometry around the masses to be of the Schwarzschild type and leads to the introduction of a cosmological constant. The study of the extension of the Kottler space-time shows that there exists a non-static solution consisting of two static regions surrounding the masses that match a Kantowski-Sachs expanding region on the cosmological horizon. The comparison with a Swiss-Cheese construction is also discussed.Comment: 15 pages, 5 figures. Replaced to match the published versio

DNA prime Listeria boost induces a cellular immune response to SIV antigens in the rhesus macaque model that is capable of limited suppression of SIV239 viral replication

AbstractDNA vaccines and recombinant Listeria monocytogenes that express and secrete SIV Gag and Env antigens were combined in a nonhuman primate prime-boost immunogenicity study followed by a challenge with SIV239. We report that recombinant DNA vaccine delivered intramuscularly, and recombinant L. monocytogenes delivered orally each individually have the ability to induce CD8+ and CD4+ T cell immune responses in a nonhuman primate. Four rhesus monkeys were immunized at weeks 0, 4, 8, and 12 with the pCSIVgag and pCSIVenv DNA plasmids and boosted with SIV expressing L. monocytogenes vaccines at weeks 16, 20, and 28. Four rhesus monkeys received only the L. monocytogenes vaccines at weeks 16, 20, and 28. A final group of monkeys served as a control group. Blood samples were taken before vaccination and 2 weeks post each injection and analyzed by ELISPOT for CD4+ and CD8+ T cell responses. Moderate vaccine induced SIV-specific cellular immune responses were observed following immunization with either DNA or L. monocytogenes vectors. However, the SIV antigen-specific immune responses were significantly increased when Rhesus macaques were primed with SIV DNA vaccines and boosted with the SIV expressing L. monocytogenes vectors. In addition, the combined vaccine was able to impact SIV239 viral replication following an intrarectal challenge. This study demonstrates for the first time that oral L. monocytogenes can induce a cellular immune response in a nonhuman primate and is able to enhance the efficacy of a DNA vaccine as well as provide modest protection against SIV239 challenge

Dust and gas in the magellanic clouds from the heritage Herschel Key Project. I. Dust properties and insights into the origin of the submillimeter excess emission

The dust properties in the Large and Small Magellanic clouds (LMC/SMC) are studied using the HERITAGE Herschel Key Project photometric data in five bands from 100 to 500 μm. Three simple models of dust emission were fit to the observations: a single temperature blackbody modified by a power-law emissivity (SMBB), a single temperature blackbody modified by a broken power-law emissivity (BEMBB), and two blackbodies with different temperatures, both modified by the same power-law emissivity (TTMBB). Using these models, we investigate the origin of the submillimeter excess, defined as the submillimeter emission above that expected from SMBB models fit to observations <200 μm. We find that the BEMBB model produces the lowest fit residuals with pixel-averaged 500 μm submillimeter excesses of 27% and 43% for the LMC and SMC, respectively. Adopting gas masses from previous works, the gas-to-dust ratios calculated from our fitting results show that the TTMBB fits require significantly more dust than are available even if all the metals present in the interstellarmedium (ISM) were condensed into dust. This indicates that the submillimeter excess ismore likely to be due to emissivity variations than a second population of colder dust. We derive integrated dust masses of (7.3 ± 1.7) × 105 and (8.3 ± 2.1) × 104 M⊙ for the LMC and SMC, respectively. We find significant correlations between the submillimeter excess and other dust properties; further work is needed to determine the relative contributions of fitting noise and ISM physics to the correlation