A prime-boost immunisation regimen using recombinant BCG and Pr55 gag virus-like particle vaccines based on HIV type 1 subtype C successfully elicits Gag-specific responses in baboons

Mycobacterium bovis BCG is considered an attractive live bacterial vaccine vector. In this study, we investigated the immune response of baboons to a primary vaccination with recombinant BCG (rBCG) constructs expressing the gag gene from a South African HIV-1 subtype C isolate, and a boost with HIV-1 subtype C Pr55 gag virus-like particles (Gag VLPs). Using an interferon enzyme-linked immunospot assay, we show that although these rBCG induced only a weak or an undetectable HIV-1 Gag-specific response on their own, they efficiently primed for a Gag VLP boost, which strengthened and broadened the immune responses. These responses were predominantly CD8+ T cell-mediated and recognised similar epitopes as those targeted by humans with early HIV-1 subtype C infection. In addition, a Gag-specific humoral response was elicited. These data support the development of HIV-1 vaccines based on rBCG and Pr55 gag VLPs. © 2009 Elsevier Ltd. All rights reserved.

Synthesis of biodegradable polymer-mesoporous silica composite microspheres for DNA prime-protein boost vaccination

DNA vaccines or proteins are capable of inducing specific immunity; however, the translation to the clinic has generally been problematic, primarily due to the reduced magnitude of immune response and poor pharmacokinetics. Herein we demonstrate a composite microsphere formulation, composed of mesoporous silica spheres (MPS) and poly(d,l-lactide-co-glycolide) (PLGA), enables the controlled delivery of a prime-boost vaccine via the encapsulation of plasmid DNA (pDNA) and protein in different compartments. Method with modified dual-concentric-feeding needles attached to a 40 kHz ultrasonic atomizer was studied. These needles focus the flow of two different solutions, which passed through the ultrasonic atomizer. The process synthesis parameters, which are important to the scale-up of composite microspheres, were also studied. These parameters include polymer concentration, feed flowrate, and volumetric ratio of polymer and pDNA-PEI/MPS-BSA. This fabrication technique produced composite microspheres with mean D[4,3] ranging from 6 to 34 μm, depending upon the microsphere preparation. The resultant physical morphology of composite microspheres was largely influenced by the volumetric ratio of pDNA-PEI/MPS-BSA to polymer, and this was due to the precipitation of MPS at the surface of the microspheres. The encapsulation efficiencies were predominantly in the range of 93-98% for pDNA and 46-68% for MPS. In the in vitro studies, the pDNA and protein showed different release kinetics in a 40 day time frame. The dual-concentric-feeding in ultrasonic atomization was shown to have excellent reproducibility. It was concluded that this fabrication technique is an effective method to prepare formulations containing a heterologous prime-boost vaccine in a single delivery system.

Human immunodeficiency virus type 1 subtype C Gag virus-like particle boost substantially improves the immune response to a subtype C gag DNA vaccine in mice

Human immunodeficiency virus type 1 (HIV-1) subtype C is the predominant HIV in southern Africa, and is the target of a number of recent vaccine candidates. It has been proposed that a heterologous prime/boost vaccination strategy may result in stronger, broader and more prolonged immune responses. Since HIV-1 Gag Pr55 polyprotein can assemble into virus-like particles (VLPs) which have been shown to induce a strong cellular immune response in animals, we showed that a typical southern African subtype C Pr55 protein expressed in insect cells via recombinant baculovirus could form VLPs. We then used the baculovirus-produced VLPs as a boost to a subtype C HIV-1 gag DNA prime vaccination in mice. This study shows that a low dose of HIV-1 subtype C Gag VLPs can significantly boost the immune response to a single subtype C gag DNA inoculation in mice. These results suggest a possible vaccination regimen for humans. © 2004 SGM.

HIV-1 sub-type C chimaeric VLPs boost cellular immune responses in mice

Several approaches have been explored to eradicate HIV; however, a multigene vaccine appears to be the best option, given their proven potential to elicit broad, effective responses in animal models. The Pr55 Gagprotein is an excellent vaccine candidate in its own right, given that it can assemble into large, enveloped, virus-like particles (VLPs) which are highly immunogenic, and can moreover be used as a scaffold for the presentation of other large non-structural HIV antigens. In this study, we evaluated the potential of two novel chimaeric HIV-1 Pr55 Gag-based VLP constructs - C-terminal fusions with reverse transcriptase and a Tat::Nef fusion protein, designated GagRT and GagTN respectively - to enhance a cellular response in mice when used as boost components in two types of heterologous prime-boost vaccine strategies. A vaccine regimen consisting of a DNA prime and chimaeric HIV-1 VLP boosts in mice induced strong, broad cellular immune responses at an optimum dose of 100 ng VLPs. The enhanced cellular responses induced by the DNA prime-VLP boost were two- to three-fold greater than two DNA vaccinations. Moreover, a mixture of GagRT and GagTN VLPs also boosted antigen-specific CD8+ and CD4+ T-cell responses, while VLP vaccinations only induced predominantly robust Gag CD4+ T-cell responses. The results demonstrate the promising potential of these chimaeric VLPs as vaccine candidates against HIV-1. © 2010 Pillay et al; licensee BioMed Central Ltd.

HIV-1 subtype C Pr55gag virus-like particle vaccine efficiently boosts baboons primed with a matched DNA vaccine

A DNA vaccine expressing human immunodeficiency virus type 1 (HIV-1) southern African subtype C Gag (pTHGag) and a recombinant baculovirus Pr55gag virus-like particle prepared using a subtype C Pr55gag protein (Gag VLP) was tested in a prime-boost inoculation regimen in Chacma baboons. The response of five baboons to Gag peptides in a gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay after three pTHGag immunizations ranged from 100 to 515 spot-forming units (s.f.u.) per 106 peripheral blood mononuclear cells (PBMCs), whilst the response of two baboons to the Gag VLP vaccine ranged from 415 to 465 s.f.u. per 106 PBMCs. An increase in the Gag-specific response to a range of 775-3583 s.f.u. per 106 PBMCs was achieved by boosting with Gag VLPs the five baboons that were primed with pTHGag. No improvement in Gag responses was achieved in this prime-boost inoculation regimen by increasing the number of pTHGag inoculations to six. IFN-γ responses were mapped to several peptides, some of which have been reported to be targeted by PBMCs from HIV-1 subtype C-infected individuals. Gag VLPs, given as a single-modality regimen, induced a predominantly CD8+ T-cell IFN-γ response and interleukin-2 was a major cytokine within a mix of predominantly Th1 cytokines produced by a DNA-VLP prime-boost modality. The prime-boost inoculation regimen induced high serum p24 antibody titres in all baboons, which were several fold above that induced by the individual vaccines. Overall, this study demonstrated that these DNA prime/VLP boost vaccine regimens are highly immunogenic in baboons, inducing high-magnitude and broad multifunctional responses, providing support for the development of these products for clinical trials. © 2008 SGM.

Engineering a financial bloodbath: how sub-prime securitization destroyed the legitimacy of financial capitalism

"This book investigates the origins and implications of the securitization crisis, described by the chief executive of ANZ as a "financial services bloodbath". Based on extensive interviews it offers an integrated series of case studies drawn from the United States, the United Kingdom and Australia. A central purpose is to not only chart what went wrong with the investment houses and why the regulatory systems failed, but also provide policy guidance. The book therefore combines the empirical with the normative. In so doing, it provides a route map to navigate one of the most significant financial and regulatory failures in modern times."

Application of Dynamic Hysteresis Band Height Control to Improve Output Voltage Transient in Boost and Positive Buck-Boost Converters

This paper presents dynamic hysteresis band height control to reduce the overshoot and undershoot issue on output voltage caused by load change. The converters in this study are Boost and Positive Buck-Boost (PBB) converters. PBB has been controlled to work in a step up conversion and avoid overshoot when load is changed. Simulation and experimental results have been presented to verify the proposed method.

Utilizing robustness of positive buck-boost converter against input voltage and load current disturbances

A Positive Buck- Boost (PBB) converter is a known DC-DC converter that can operate in step up and step down modes. Unlike Buck, Boost, and Inverting Buck Boost converters, the inductor current of a PBB can be controlled independently of its voltage conversion ratio. In other words, the inductor of PBB can be utilised as an energy storage unit in addition to its main function of energy transfer. In this paper, the capability of PBB to store energy has been utilised to achieve robustness against input voltage fluctuations and output current changes. The control strategy has been developed to keep accuracy, affordability, and simplicity acceptable. To improve the efficiency of the system a Smart Load Controller (SLC) has been suggested. Applying SLC extra current storage occurs when there is sudden loads change otherwise little extra current is stored.

Can Risk Management boost the supply of Affordable Housing Development and Management?

A shortage of affordable housing is a major problem in Australia today. This is mainly due to the limited supply of affordable housing that is provided by the non-government housing sector. Some private housing developers see the provision of affordable housing for lower income people as a high risk investment which offers a lower return than broader market-based housing. The scarcity of suitable land, a limited government ‘subsidy’, and increasing housing costs have not provided sufficient development incentives to encourage their investment despite the existing high demand for affordable housing. This study analyses the risk management process conducted by some private and not-for-profit housing providers in South East Queensland, and draws conclusions about the relationship between risk assessments/responses and past experiences. In-depth interviews of selected non-government housing providers have been conducted to facilitate an understanding of their approach to risk assessment/response in developing and in managing affordable housing projects. These developers use an informal risk management process as part of their normal business process in accordance with industry standards. A simple qualitative matrix has been used to analyse probability and impacts using a qualitative scale - low, medium and high. For housing providers who have considered investing in affordable housing but have not yet implemented any such projects, affordable housing development is seen as an opportunity that needs to be approached with caution. The risks associated with such projects and the levels of acceptance of these are not consistently identified by current housing providers. Many interviewees agree that the recognition of financial risk and the fear of community rejection of such housing projects have restrained them from committing to such investment projects. This study suggests that implementing improvements to the risk mitigation and management framework may assist in promoting the supply of affordable housing by non-government providers.

Can risk management boost the supply of affordable housing development and management?

Purpose: The purpose of this paper is to analyse the risk management process conducted by some private and not-for-profit affordable housing providers in South East Queensland, and draw conclusions about the relationship between risk assessments/responses and past experiences.----- Design/methodology/approach: In-depth interviews of selected non-government housing providers have been conducted to facilitate an understanding of their approach to risk assessment in developing and in managing affordable housing projects. Qualitative data are analysed using thematic analysis to find emerging themes suggested by interview participants.----- Findings: The paper finds that informal risk management process is used as part of normal business process in accordance with industry standards. Many interviewees agree that the recognition of financial risk and the fear of community rejection of such housing projects have restrained them from committing to such investment projects. The levels of acceptance of risk are not always consistent across housing providers which create opportunities to conduct multi-stakeholder partnership to reduce overall risk.----- Research limitations/implications: The paper has implications for developers or investors who seek to include affordable housing as part of their portfolio. However, data collected in the study are a cross-section of interviews that will not include the impact on recent tax incentives offers by the Australian Commonwealth Government.----- Practical implications: The study suggests that implementing improvements to the risk mitigation and management framework may assist in promoting the supply of affordable housing by non-government providers.----- Originality/value: The focus of the study is the interaction between partnerships and risk management in development and management of affordable rental housing.

Cross voltage control with inner hysteresis current control for multi-output boost converter

Multi-output boost (MOB) converter is a novel DC-DC converter unlike the regular boost converter, has the ability to share its total output voltage and to have different series output voltage from a given duty cycle for low and high power applications. In this paper, discrete voltage control with inner hysteresis current control loop has been proposed to keep the simplicity of the control law for the double-output MOB converter, which can be implemented by a combination of analogue and logical ICs or simple microcontroller to constrain the output voltages of MOB converter at their reference voltages against variation in load or input voltage. The salient features of the proposed control strategy are simplicity of implementation and ease to extend to multiple outputs in the MOB converter. Simulation and experimental results are presented to show the validity of control strategy.

A general approach to control a positive buck-boost converter to achieve robustness against input voltage fluctuations and load changes

A Positive Buck-Boost converter is a known DC-DC converter which may be controlled to act as Buck or Boost converter with same polarity of the input voltage. This converter has four switching states which include all the switching states of the above mentioned DC-DC converters. In addition there is one switching state which provides a degree of freedom for the positive Buck-Boost converter in comparison to the Buck, Boost, and inverting Buck-Boost converters. In other words the Positive Buck-Boost Converter shows a higher level of flexibility for its inductor current control compared to the other DC-DC converters. In this paper this extra degree of freedom is utilised to increase the robustness against input voltage fluctuations and load changes. To address this capacity of the positive Buck-Boost converter, two different control strategies are proposed which control the inductor current and output voltage against any fluctuations in input voltage and load changes. Mathematical analysis for dynamic and steady state conditions are presented in this paper and simulation results verify the proposed method.

Multi-output buck-boost converter with enhanced dynamic response to load and input voltage changes

This paper presents a new multi-output DC/DC converter topology that has step-up and step-down conversion capabilities. In this topology, several output voltages can be generated which can be used in different applications such as multilevel converters with diode-clamped topology or power supplies with several voltage levels. Steady state and dynamic equations of the proposed multi-output converter have been developed, that can be used for steady state and transient analysis. Two control techniques have been proposed for this topology based on constant and dynamic hysteresis band height control to address different applications. Simulations have been performed for different operating modes and load conditions to verify the proposed topology and its control technique. Additionally, a laboratory prototype is designed and implemented to verify the simulation results.

Poverty in perception : a study of the twentieth-century prime ministers of Australia and New Zealand

Australia and New Zealand, as English-speaking nations with dominant white populations, present an ethnic anomaly not only in South East Asia, but also in the Southern Hemisphere. Colonised by predominantly workingclass British immigrants from the late eighteenth century, an ethnic and cultural connection grew between these two countries even though their indigenous populations and ecological environments were otherwise very different. Building a new life in Australia and New Zealand, the colonists shared similar historic perceptions of poverty – perceptions from their homelands that they did not want to see replicated in their new adopted countries. Dreams of a better life shaped their aspirations, self-identity and nationalistic outlook. By the twentieth century, national independence and self-government had replaced British colonial rule. The inveterate occurrence of poverty in Australia and New Zealand had created new local perspectives and different perceptions of, and about, poverty. This study analyses what relationship existed between the political directions adopted by the twentieth-century prime ministers of Australia and New Zealand and their perceptions of poverty. Using the existential phenomenological theory and methodology of Maurice Merleau-Ponty, the study adds to the body of knowledge about poverty in Australia and New Zealand by revealing the structure and origin of the poverty perceptions of the twentieth-century prime ministers.

Immunogenicity and protective efficacy of an anti-Streptococcus pyogenes vaccine candidate in multiple animal species

Streptococcus pyogenes, also known as Group A Streptococcus (GAS) has been associated with a range of diseases from the mild pharyngitis and pyoderma to more severe invasive infections such as streptococcal toxic shock. GAS also causes a number of non-suppurative post-infectious diseases such as rheumatic fever, rheumatic heart disease and glomerulonephritis. The large extent of GAS disease burden necessitates the need for a prophylactic vaccine that could target the diverse GAS emm types circulating globally. Anti-GAS vaccine strategies have focused primarily on the GAS M-protein, an extracellular virulence factor anchored to GAS cell wall. As opposed to the hypervariable N-terminal region, the C-terminal portion of the protein is highly conserved among different GAS emm types and is the focus of a leading GAS vaccine candidate, J8-DT/alum. The vaccine candidate J8-DT/alum was shown to be immunogenic in mice, rabbits and the non-human primates, hamadryas baboons. Similar responses to J8-DT/alum were observed after subcutaneous and intramuscular immunization with J8-DT/alum, in mice and in rabbits. Further assessment of parameters that may influence the immunogenicity of J8-DT demonstrated that the immune responses were identical in male and female mice and the use of alum as an adjuvant in the vaccine formulation significantly increased its immunogenicity, resulting in a long-lived serum IgG response. Contrary to the previous findings, the data in this thesis indicates that a primary immunization with J8-DT/alum (50ƒÊg) followed by a single boost is sufficient to generate a robust immune response in mice. As expected, the IgG response to J8- DT/alum was a Th2 type response consisting predominantly of the isotype IgG1 accompanied by lower levels of IgG2a. Intramuscular vaccination of rabbits with J8-DT/alum demonstrated that an increase in the dose of J8-DT/alum up to 500ƒÊg does not have an impact on the serum IgG titers achieved. Similar to the immune response in mice, immunization with J8-DT/alum in baboons also established that a 60ƒÊg dose compared to either 30ƒÊg or 120ƒÊg was sufficient to generate a robust immune response. Interestingly, mucosal infection of naive baboons with a M1 GAS strain did not induce a J8-specific serum IgG response. As J8-DT/alum mediated protection has been previously reported to be due to the J8- specific antibody formed, the efficacy of J8-DT antibodies was determined in vitro and in vivo. In vitro opsonization and in vivo passive transfer confirmed the protective potential of J8-DT antibodies. A reduction in the bacterial burden after challenge with a bioluminescent M49 GAS strain in mice that were passively administered J8-DT IgG established that protection due to J8-DT was mediated by antibodies. The GAS burden in infected mice was monitored using bioluminescent imaging in addition to traditional CFU assays. Bioluminescent GAS strains including the ‘rheumatogenic’ M1 GAS could not be generated due to limitations with transformation of GAS, however, a M49 GAS strain was utilized during BLI. The M49 serotype is traditionally a ‘nephritogenic’ serotype associated with post-streptococcal glomerulonephritis. Anti- J8-DT antibodies now have been shown to be protective against multiple GAS strains such as M49 and M1. This study evaluated the immunogenicity of J8-DT/alum in different species of experimental animals in preparation for phase I human clinical trials and provided the ground work for the development of a rapid non-invasive assay for evaluation of vaccine candidates.