Summary This article summarises the consensus arrived at a meeting of South African and international stakeholders on specific late phase clinical trial design issues integrating the investigation of ...immune correlates as an integral part of a phase III protocol for a preventative TB vaccine in an adolescent/adult population. The challenge ahead is to optimize the planning for phase 3 TB vaccine preventative trials, under resource constraints, given that there are no known correlates of protection to shorten and increase the efficiencies of efficacy trials. An adaptive, multi-arm, group sequentially designed trial protocol is proposed incorporating design features that address uncertainties arising from both advances in the field and dynamic study populations and disease states. Such a design allows modifications that protect research subjects, save time, and maximize the impact of scarce financial resources. Further, the protocol underwent joint review by regulators from several African nations at a meeting of the African Vaccine Regulatory Forum (AVAREF), a regional regulatory harmonization initiative, and recommendations are included.
TB remains a very significant global health burden. There is an urgent need for better tools for TB control, which include an effective vaccine. Bacillus Calmette–Guérin (BCG), the currently licensed ...vaccine, confers highly variable protection against pulmonary TB, the main source of TB transmission. Replacing BCG completely or boosting BCG with another vaccine are the two current strategies for TB vaccine development. Delivering a vaccine by aerosol represents a way to match the route of vaccination to the route of infection. This route of immunisation offers not only the scientific advantage of delivering the vaccine directly to the respiratory mucosa, but also practical and logistical advantages. This review summarises the state of current TB vaccine candidates in the pipeline, reviews current progress in aerosol administration of vaccines in general and evaluates the potential for TB vaccine candidates to be administered by the aerosol route.
Co-infection with HIV and Mycobacterium tuberculosis is common, particularly in the developing world. Tuberculosis (TB) is the commonest co-infection in HIV-positive individuals, who are at increased ...risk of both reactivation of latent infection and acquisition of new infection. As the degree of immunosuppression increases, the risks of developing TB disease also increase. The patho-physiology, clinical picture, differential diagnosis and diagnostic tests are discussed, together with the interactions between antiretroviral therapy and anti-tuberculous chemotherapy. Indications for chemoprophylaxis and vaccination against TB are reviewed.
Niobium aluminides have been considered as a potential high temperature structural material. They are expected to exhibit high elastic stiffness, strength and creep resistance at elevated ...temperatures. One of the notable advantages of niobium aluminides are the high melting points compared to those of other, more commonly considered aluminide systems. Titanium and nickel alumindes are generally limited to structural applications below 1000 DGC, however, niobium aluminides can have extremely high strength even above 1200 DGC and the incorporation of ductile reinforcements of metallic niobium can be used to lower the ductile to brittle transition temperatures and increase room temperature fracture toughness.
The development of an effective TB vaccine remains paramount to achieving the goal of global eradication of TB by 2050. The only licensed vaccine, BCG, has variable efficacy and is poorly effective ...in high burden countries. The development of promising candidate vaccines to either 'boost' a BCG primed immune system or replace BCG altogether is a key area for innovative research. Here, we discuss some of the issues encountered in the development of potential candidate vaccines and the future challenges.
Protective immunity against Mycobacterium tuberculosis depends on the generation of a TH1-type cellular immune response, characterized by the secretion of interferon-γ (IFN-γ) from antigen-specific T ...cells. The induction of potent cellular immune responses by vaccination in humans has proven difficult. Recombinant viral vectors, especially poxviruses and adenoviruses, are particularly effective at boosting previously primed CD4+ and CD8+ T-cell responses against a number of intracellular pathogens in animal studies. In the first phase 1 study of any candidate subunit vaccine against tuberculosis, recombinant modified vaccinia virus Ankara (MVA) expressing antigen 85A (MVA85A) was found to induce high levels of antigen-specific IFN-γ-secreting T cells when used alone in bacille Calmette-Guérin (BCG)-naive healthy volunteers. In volunteers who had been vaccinated 0.5-38 years previously with BCG, substantially higher levels of antigen-specific IFN-γ-secreting T cells were induced, and at 24 weeks after vaccination these levels were 5-30 times greater than in vaccinees administered a single BCG vaccination. Boosting vaccinations with MVA85A could offer a practical and efficient strategy for enhancing and prolonging antimycobacterial immunity in tuberculosis-endemic areas.
Background. A new vaccine is urgently needed to combat tuberculosis. However, without a correlate of protection, selection of the vaccines to take forward into large-scale efficacy trials is ...difficult. Use of bacille Calmette-Guérin (BCG) as a surrogate for human Mycobacterium tuberculosis challenge is a novel model that could aid selection. Methods. Healthy adults were assigned to groups A and B (BCG-naive) or groups C and D (BCG-vaccinated). Groups B and D received candidate tuberculosis vaccine MVA85A. Participants were challenged with intradermal BCG 4 weeks after those who received MVA85A. Skin biopsies of the challenge site were taken 2 weeks post challenge and BCG load quantified by culture and quantitative polymerase chain reaction (qPCR). Results. Volunteers with a history of BCG showed some degree of protective immunity to challenge, having lower BCG loads compared with volunteers without prior BCG, regardless of MVA85A status. There was a significant inverse correlation between antimycobacterial immunity at peak response after MVA85A and BCG load detected by qPCR. Conclusion. Our results support previous findings that this BCG challenge model is able to detect differences in antimycobacterial immunity induced by vaccination and could aid in the selection of candidate tuberculosis vaccines for field efficacy testing.
Processing defects in hot extrusion reaction synthesis Morsi, K; McShane, H.B; McLean, M
Materials science & engineering. A, Structural materials : properties, microstructure and processing,
10/2000, Volume:
290, Issue:
1
Journal Article
Peer reviewed
Experiments were conducted on a miniature and a larger extrusion press to simultaneously form and extrude nickel aluminides (Ni
3Al, NiAl) and nickel aluminide composites from elemental powders using ...a novel process called hot extrusion reaction synthesis. An overview of macroscopic and microscopic processing defects that can arise in this process is presented as well as strategies for overcoming these defects. Extrusion cracking was found to significantly increase with increased nickel content. Higher extrusion die exit temperatures promoted both a reaction converting elemental powders to the desired intermetallic or intermetallic composites and reduced cracking of NiAl extrusions. Processing defects in the form of matrix micro-cracking and reaction layers between intermetallic matrix and SiC reinforcements were also present in the composite material. The reaction always occurs seconds after the material had been extruded, thus bypassing the consolidation stage of extrusion resulting in the presence of reaction induced porosity. A novel high temperature transient window has been identified for the production of
pore-free intermetallic and intermetallic composite rods and wires.
The research presented here describes the results of production trials of various nickel, iron and titanium aluminides, using the method of hot extrusion reaction synthesis (HERS). Billets of the ...elemental powder mixtures have undergone HERS in a specially designed experimental scale extrusion rig. The ease of processing was highly dependant on the container (tooling) temperature, the heating time of the billet, the ram speed during extrusion, the composition and the aluminide system in question. HERS has been successful with aluminides based on the stoichiometric ratios of FeAl and Ni3Al at relatively low container temperatures (less than 600°C). The extruded microstructures consisted of a mixture of intermetallic phases. The short processing cycle led to fine grain sizes and high values of mechanical properties, such as yield strength.
Vaccines against intracellular pathogens such as
Mycobacterium tuberculosis need to induce strong cellular immune responses. Heterologous prime-boost immunisation strategies induce higher levels of ...both CD4+ and CD8+ T cells than homologous boosting with the same vector. Recombinant pox-viruses are particularly good at boosting previously primed T cell responses. Using BCG as the priming immunisation in such a heterologous prime-boost strategy is a practical solution, which allows the beneficial effects of BCG in children to be maintained.
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