Potent Immunity to Low Doses of Influenza Vaccine by Probabilistic Guided Micro-Targeted Skin Delivery in a Mouse Model

Background: Over 14 million people die each year from infectious diseases despite extensive vaccine use [1]. The needle and syringe-first invented in 1853-is still the primary delivery device, injecting liquid vaccine into muscle. Vaccines could be far more effective if they were precisely delivered into the narrow layer just beneath the skin surface that contains a much higher density of potent antigen-presenting cells (APCs) essential to generate a protective immune response. We hypothesized that successful vaccination could be achieved this way with far lower antigen doses than required by the needle and syringe

Improving the reach of vaccines to low-resource regions, with a needle-free vaccine delivery device and long-term thermostabilization

Dry-coated microprojections can deliver vaccine to abundant antigen-presenting cells in the skin and induce efficient immune responses and the dry-coated vaccines are expected to be thermostable at elevated temperatures. In this paper, we show that we have dramatically improved our previously reported gas-jet drying coating method and greatly increased the delivery efficiency of coating from patch to skin to from 6.5% to 32.5%, by both varying the coating parameters and removing the patch edge. Combined with our previous dose sparing report of influenza vaccine delivery in a mouse model, the results show that we now achieve equivalent protective immune responses as intramuscular injection (with the needle and syringe), but with only 1/30th of the actual dose. We also show that influenza vaccine coated microprojection patches are stable for at least 6 months at 23 degrees C. inducing comparable immunogenicity with freshly coated patches. The dry-coated microprojection patches thus have key and unique attributes in ultimately meeting the medical need in certain low-resource regions with low vaccine affordability and difficulty in maintaining "cold-chain" for vaccine storage and transport. (C) 2011 Elsevier B.V. All rights reserved

The timing and origin of orogenic gold mineralisation in the western Lachlan Orogen, southeast Australia: constraints from 40Ar/39Ar dating and halogen and noble gas geochemistry

© 2012 Dr. Alison Maree FairmaidThe Ballarat East gold deposit (408t) is the second largest orogenic gold deposit in the Western Lachlan Orogen, southeast Australia. The western Lachlan Orogen is characterised by a thick package of Ordovician turbiditic sedimentary rocks overlying Cambrian oceanic volcanic sequences. The region was variably affected by multiple major deformation/metamorphism and magmatism events during the Cambrian to Devonian. The Ballarat East gold deposit is located in the Bendigo structural zone of the Western Lachlan Orogen and is hosted in Ordovician sediments of the Castlemaine Supergroup. Gold mineralisation in the Ballarat East deposit is sited in quartz and quartz-carbonate veins within goldfield-scale, west-dipping reverse faults. Two major lode types are present: 1) lode type ‘1’ is characterised by arsenopyrite-dominated quartz veins associated with early movement on reverse faults, whereas 2) lode type ‘2’ is related to structurally later, shallow east-dipping, pyrite-sphalerite-galena-white-mica dominated veins, emanating from reverse faults. Previous studies have suggested that gold mineralisation in the Western Lachlan Orogen occurred at ~440Ma, as a result of metamorphic devolatilisation reactions in the lower crust. However the age of mineralisation at the Ballarat East deposit is only broadly constrained to a period between 460 and 370 Ma, and the source of the gold-bearing fluids could include metamorphosed volcanic rocks, sedimentary rocks and/or granites. In order to provide a more robust chronological framework for gold mineralisation at the Ballarat East deposit, several samples of detrital and hydrothermal potassium-rich minerals were collected and analysed by 40Ar/39Ar dating. In addition, fluid inclusions in portions of quartz and quartz-carbonate veins were characterised by micro-thermometry and halogen/noble gas isotopic tracer methods to further constrain the source(s) of the gold mineralising fluids. The 40Ar/39Ar data obtained from detrital muscovite grains yield ages between 530 – 460 Ma and are concordant with previously published detrital ages. The vein muscovite/sericite ages fall into three age groupings as follows: 445 – 435 Ma (lode type ‘1’), 420 – 415 Ma (lode type ‘2a’) and 380 – 370 Ma (lode type ‘2b’). The gold-bearing quartz veins (from both lode types) contain low salinity (average 4 wt.% NaCl eq.) aqueous H2O inclusions and mixed H2O-CO2 fluid inclusions. Fluid inclusion 40Ar/36Ar values range from 322 (close to Air Saturated Water; ~296) up to a maximum of 4503, and 40Ar/36Ar is strongly correlated with Cl/36Ar. Fluid inclusions have variable Br/Cl values between 1.66 10-3 and 2.91 × 10-3 and I/Cl values between 153 × 10-6 and 501 × 10-6, with a strong correlation between Br/Cl and I/Cl. The fluid inclusion 84Kr/36Ar and 129Xe/36Ar values are variable but show a systematic enrichment in the heavier noble gases. The 40Ar/39Ar ages suggest gold mineralisation at the Ballarat East deposit occurred in three main episodes at ca. 445 Ma, ca. 420 Ma and ca. 380 – 370 Ma. All episodes of mineralisation are associated with fluid inclusions of similar composition. This fluid is suggested to reflect a deeply sourced fluid, possibly originating by devolatilisation of altered volcanic rocks (e.g. basalts). In this scenario, the fluid would have acquired additional noble gases and organic Br plus I by interaction with sedimentary rocks, including organic-rich shales that are found beneath and surrounding the deposit. The data are compatible with genetic models for orogenic Au in which gold mineralisation was initiated by metamorphic devolatilisation in the lower crust, linked to Lachlan Orogenesis at ca. 440 Ma

The origin and evolution of mineralizing fluids in a sediment-hosted orogenic-gold deposit, Ballarat East, Southeastern Australia

The hydrothermal fluids responsible for gold mineralization at the Ballarat East gold deposit (the second largest orogenic gold deposit in the western Lachlan orogen) are thought to have links to a variety of processes, including metamorphism, sedimentation, and/or magmatism. In the current study, noble gases and halogens have been used as fluid tracers to reevaluate the origin and evolution of the gold-related fluids at the Ballarat East deposit. Gold-bearing quartz and carbonate veins from the Ballarat East contain low salinity (∼4 wt % NaCl equiv) aqueous (H2O) and mixed H2O-CO2 fluid inclusions. These fluid inclusions have variable molar Br/Cl values of between 1.2 × 10-3 and 2.9 × 10-3 and I/Cl values between 150 × 10-6 and 500 × 10-6, and Br is strongly correlated with I, defining a mixing line with a Br/I ratio of 5.6. The fluid inclusions have40Ar/36Ar ratios ranging from 322 (close to the atmospheric40Ar/36Ar ratio of ∼296) up to a maximum of 4503.40Ar is strongly correlated with Cl and defines a mixing line with a 40ArE/Cl ratio of 4.6 × 10-4 (40ArE denotes excess 40Ar). The fluid inclusions contain 5.1 to 32 ppm40ArE (by mass) and exhibit minimum 36Ar concentrations ranging from 3.1 to 11 ppb, which exceed air-saturated water (ASW) levels by several parts per billion (ASW = 1.3-2.7 ppb). Fluid inclusion84Kr/36Ar and130Xe/36Ar values are uniformly enriched in Kr and Xe relative to air, but exhibit limited variation. These data provide strong evidence for the involvement of two noble gas and halogen reservoirs. This data is compatible with a deeply sourced fluid, possibly originating by devolatilization of altered volcanic rocks (e.g., basalts) that acquired additional noble gases and organic Br plus I by interaction with sedimentary rocks, including organic-rich shales that are found beneath and surrounding the deposit. The data are also consistent with mixing deeply sourced metamorphic fluids with sedimentary formation waters; however, both interpretations favor the involvement of metamorphic fluids and sedimentary components and highlight the significance of fluid-rock interaction as controls on fluid compositions in Victorian deposits. The data are compatible with genetic models for orogenic gold in which gold mineralization was initiated by metamorphic devolatilization in the lower crust, and was linked to Lachlan orogenesis at ca. 440 Ma

Timing of gold mineralisation in the western Lachlan Orogen, SE Australia: a critical overview

The western sub-province of the Paleozoic Lachlan Orogen in Victoria is dominated by thick turbidite sequences overlying Cambrian basement volcanics. The region was subjected to multiple Cambrian to Late Devonian regional deformation events, followed by extensive post-tectonic granitic magmatism. The western Lachlan Orogen is considered a typical 'orogenic' gold province and hosts a large number of goldfields, including the world-class Bendigo-Ballarat goldfields. A variety of geochronological methods (e.g. U-Pb zircon; Re-Os sulfide; Ar/ Ar whole-rock, mica) have been used to constrain the timing of gold mineralisation, and the relationship to metamorphism/deformation/ magmatism. Regional granitic magmatism is relatively well constrained from U-Pb zircon dating, with the timing of deformation/metamorphism and gold mineralisation reliant largely on Ar/ Ar dating results. Owing to inconsistencies in the available Ar/ Ar data and recent revisions to Ar/ Ar monitor ages and decay constants, we recalculate and re-evaluate all existing Ar/ Ar age results. These revisions confirm that the western Lachlan Orogen is characterised by multiple deformation/ metamorphism events, with the Stawell structural zone deformed during the ca 500 Ma Delamarian and ca 445 Ma Benambran orogenies, the Bendigo Zone deformed during the Benambran orogeny (with minor Tabberabberan overprinting), and the Melbourne Zone affected by the ca 380-370 Ma Tabberabberan orogeny. Post-tectonic granitic magmatism occurred in two main time intervals, the Early Devonian (ca 400 Ma) and the Late Devonian (ca 380-370 Ma), with the former limited to the Stawell and northwest Bendigo Zones, and the latter distributed throughout the Bendigo and Melbourne Zones and southeast Stawell Zone. Gold mineralisation occurred in two main episodes at ca 445 Ma and ca 380-370 Ma, with another possible (minor) event at ca 410-400 Ma. The ca 445 Ma event is prevalent across the Stawell and Bendigo Zones, with Late Devonian gold mineralisation restricted to the Melbourne and eastern Bendigo Zones. The timing of the two main events is supported by geological constraints, the reproducibility of Ar/ Ar results and, in the case of the Bendigo goldfield, coincidence with Re-Os data. Suggestions of a single Devonian age gold mineralisation event are not supported by the available data. The two main gold mineralisation episodes (ca 445 Ma; ca 380-370 Ma) coincide with the waning stages of the Benambran and Tabberabberan orogenies, respectively. Crustal thickening and consequent metamorphic devolatilisation during the Benambran orogeny may have been the main cause of fluid flow related to gold mineralisation at ca 445 Ma. In contrast, crustal anatexis is considered responsible for metamorphic fluid generation and Early Devonian gold mineralisation

CH4-N2 in the Maldon gold deposit, central Victoria, Australia

The Maldon gold deposit in central Victoria has geological, geochronological and fluid chemistry characteristics that distinguish it from typical vein-hosted, 'orogenic' gold deposits in this region. The deposit lies within the thermal aureole of the Lat

Factors associated with transmission of influenza-like illness in a cohort of households containing multiple children

BACKGROUND: Household studies of influenza-like illness (ILI) afford opportunities to study determinants of respiratory virus transmission. OBJECTIVES: We examined predictors of ILI transmission within households containing at least two children. METHODS: A prospective cohort study recorded ILI symptoms daily for 2712 adult and child participants during the 1998 influenza season in Victoria, Australia. Logistic and Poisson regressions were used to explore predictors of household transmission of ILI and the secondary household attack proportion (SHAP). A date of illness onset during the influenza season was used as a proxy indicator of ILI associated with influenza infection (as opposed to other aetiological causes). RESULTS: A total of 1009 ILI episodes were reported by 781 of 2712 (29%) participants residing in 157 households. Transmission, defined as detection of ILI in one or more household members following identification of an index case, was observed in 206 of 705 (29%) household introductions. Transmission of ILI was significantly associated with the onset of ILI in the index case during the peak influenza season compared with the remainder of the observation period (37% versus 27%, odds ratio = 1·59, 95% CI 1·09, 2·31, P = 0·017). The SHAP was 0·12, higher if the index case was of secondary school age [incidence risk ratio (IRR) = 1·80, 95% CI 1·08, 2·98, P = 0·022]. CONCLUSIONS: Risk of household transmission of ILI was increased during the peak influenza season, indicating an increased burden of disease during the period of influenza circulation. In this cohort, secondary-school-aged children and adults were important transmitters of ILI

Protective efficacy of a bacterially produced modular capsomere presenting M2e from influenza: extending the potential of broadly cross-protecting epitopes

Influenza A viruses drift and shift, emerging as antigenically distinct strains that lead to epidemics and pandemics of varying severity. Even epitopes associated with broad cross-protection against different strains, such as the ectodomain of matrix protein 2 (M2e), mutate unpredictably. Vaccine protective efficacy is only ensured when the emerging virus lies within the vaccine's cross-protective domain, which is poorly defined in most situations. When virus emerges outside this domain it is essential to rapidly re-engineer the vaccine and hence re-center the cross-protective domain on the new virus. This approach of vaccine re-engineering in response to virus change is the cornerstone of the current influenza control system, based on annual prediction and/or pandemic reaction. This system could become more responsive, and perhaps preventative, if its speed could be improved. Here, we demonstrate vaccine efficacy of a rapidly manufacturable modular capsomere presenting the broadly cross-protecting M2e epitope from influenza. M2e inserted into a viral capsomere at the DNA level was expressed in Escherichia coli as a fusion protein (Wibowo et al., 2013). Immunization of mice with this modular capsomere adjuvanted with conventional aluminum hydroxide induced high (more than 10(5) endpoint titer) levels of M2e-specific antibodies that reduced disease severity and viral load in the lungs of challenged mice. The combination of rapid manufacturability of modular capsomere presented in this study, and the established cross-protective efficacy of M2e, allow rapid matching of vaccine to the circulating virus and hence rapid re-centering of the vaccine's cross-protective domain onto the virus. This approach synergizes the discussed benefits of broadly cross-protecting epitopes with rapid scale-up vaccine manufacture using microbial cell factories.Nani Wibowo, Fiona K. Hughes, Emily J. Fairmaid, Linda H.L. Lua, Lorena E. Brown, Anton P.J. Middelber