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Ellis R.D.,405 Research Boulevard | Hatherill M.,University of Cape Town | Tait D.,The Warehouse | Snowden M.,405 Research Boulevard | And 5 more authors.
Tuberculosis | Year: 2015

A recent trial of a leading tuberculosis (TB) vaccine candidate in 3000 South African infants failed to show protection over that from BCG alone, and highlights the difficulties in clinical development of TB vaccines. Progression of vaccine candidates to efficacy trials against TB disease rests on demonstration of safety and immunogenicity in target populations and protection against challenge in preclinical models, but immunologic correlates of protection are unknown, and animal models may not be predictive of results in humans. Even in populations most heavily affected by TB the sample sizes required for Phase 2b efficacy trials using TB disease as an endpoint are in the thousands. Novel clinical trial models have been developed to evaluate candidate TB vaccines in selected populations using biologically relevant outcomes and innovative statistical approaches. Such proof of concept studies can be used to more rationally select vaccine candidates for advancement to large scale trials against TB disease. © 2015 Elsevier Ltd.


Colaco C.A.,ImmunoBiology Ltd | Bailey C.R.,ImmunoBiology Ltd | Walker K.B.,405 Research Boulevard | Keeble J.,UK National Institute for Biological Standards and Control
BioMed Research International | Year: 2013

Adjuvants were reintroduced into modern immunology as the dirty little secret of immunologists by Janeway and thus began the molecular definition of innate immunity. It is now clear that the binding of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) on antigen presenting cells (APCs) activates the innate immune response and provides the host with a rapid mechanism for detecting infection by pathogens and initiates adaptive immunity. Ironically, in addition to advancing the basic science of immunology, Janeway's revelation on induction of the adaptive system has also spurred an era of rational vaccine design that exploits PRRs. Thus, defined PAMPs that bind to known PRRs are being specifically coupled to antigens to improve their immunogenicity. However, while PAMPs efficiently activate the innate immune response, they do not mediate the capture of antigen that is required to elicit the specific responses of the acquired immune system. Heat shock proteins (HSPs) are molecular chaperones that are found complexed to client polypeptides and have been studied as potential cancer vaccines. In addition to binding PRRs and activating the innate immune response, HSPs have been shown to both induce the maturation of APCs and provide chaperoned polypeptides for specific triggering of the acquired immune response. © 2013 Camilo A. Colaco et al.


PubMed | Bill and Melinda Gates Foundation, University of Witwatersrand, 405 Research Boulevard, The Warehouse and University of Cape Town
Type: Journal Article | Journal: Tuberculosis (Edinburgh, Scotland) | Year: 2015

A recent trial of a leading tuberculosis (TB) vaccine candidate in 3000 South African infants failed to show protection over that from BCG alone, and highlights the difficulties in clinical development of TB vaccines. Progression of vaccine candidates to efficacy trials against TB disease rests on demonstration of safety and immunogenicity in target populations and protection against challenge in preclinical models, but immunologic correlates of protection are unknown, and animal models may not be predictive of results in humans. Even in populations most heavily affected by TB the sample sizes required for Phase 2b efficacy trials using TB disease as an endpoint are in the thousands. Novel clinical trial models have been developed to evaluate candidate TB vaccines in selected populations using biologically relevant outcomes and innovative statistical approaches. Such proof of concept studies can be used to more rationally select vaccine candidates for advancement to large scale trials against TB disease.


Barker L.,405 Research Boulevard | Hessel L.,Consultant in Vaccinology | Walker B.,UK National Institute for Biological Standards and Control
Tuberculosis | Year: 2012

A rational process is clearly needed and can be extremely helpful for selection, assessing and advancing TB vaccine candidates from entry into preclinical and clinical development and for advancing candidates from early safety and immunogenicity clinical trials to proof-of-concept and pivotal efficacy trials. A joint effort between Aeras and the Tuberculosis Vaccine Initiative has focused on the development of objective criteria for a number of key general vaccine characteristics which can be assessed at critical stages of development. In order to maximize development efficiency, increase likelihood of success, and optimize use of scarce resources, this process includes establishment of gates for moving TB vaccine candidates through progressive development stages based on meeting the established criteria for specific vaccine candidates. © 2012 Elsevier Ltd. All rights reserved.


Brennan M.J.,Aeras | Clagett B.,Aeras | Clagett B.,University of Pennsylvania | Fitzgerald H.,Aeras | And 7 more authors.
Vaccine | Year: 2012

In this review, published peer-reviewed preclinical studies using prime-boost tuberculosis (TB) vaccine regimens in animal challenge models for tuberculosis have been evaluated. These studies have been divided into groups that describe prime-boost vaccine combinations that performed better than, equivalent to, or worse than the currently used BCG vaccine. Review of the data has revealed interesting findings, including that more than half of the published studies using BCG as a prime combined with a novel boost vaccine give better efficacy than BCG alone and that the greatest reduction in Mycobacterium tuberculosis (M.tb.) colonization of animal tissues is provided by viral vectored vaccines delivered intranasally. Careful evaluation of these data should assist in defining the value of prime-boost regimens for advancement into human TB vaccine trials and stimulate the development of criteria for choosing which vaccine candidates should be studied further. © 2012 Elsevier Ltd.


Wang Y.,U.S. National Cancer Institute | Sui Y.,U.S. National Cancer Institute | Kato S.,U.S. National Cancer Institute | Hogg A.E.,U.S. National Cancer Institute | And 5 more authors.
Nature Communications | Year: 2015

The structured lymphoid tissues are considered the only inductive sites where primary T-cell immune responses occur. The naïve T cells in structured lymphoid tissues, once being primed by antigen-bearing dendritic cells, differentiate into memory T cells and traffic back to the mucosal sites through the bloodstream. Contrary to this belief, here we show that the vaginal type-II mucosa itself, despite the lack of structured lymphoid tissues, can act as an inductive site during primary CD8 + T-cell immune responses. We provide evidence that the vaginal mucosa supports both the local immune priming of naïve CD8 + T cells and the local expansion of antigen-specific CD8 + T cells, thereby demonstrating a different paradigm for primary mucosal T-cell immune induction. © 2015 Macmillan Publishers Limited. All rights reserved.


Nunes J.K.,PATH Malaria Vaccine Initiative | Cardenas V.,PATH Malaria Vaccine Initiative | Cardenas V.,405 Research Boulevard | Loucq C.,PATH Malaria Vaccine Initiative | And 11 more authors.
BMC Infectious Diseases | Year: 2013

Background: Efforts to develop malaria vaccines show promise. Mathematical model-based estimates of the potential demand, public health impact, and cost and financing requirements can be used to inform investment and adoption decisions by vaccine developers and policymakers on the use of malaria vaccines as complements to existing interventions. However, the complexity of such models may make their outputs inaccessible to non-modeling specialists. This paper describes a Malaria Vaccine Model (MVM) developed to address the specific needs of developers and policymakers, who need to access sophisticated modeling results and to test various scenarios in a user-friendly interface. The model's functionality is demonstrated through a hypothetical vaccine.Methods: The MVM has three modules: supply and demand forecast; public health impact; and implementation cost and financing requirements. These modules include pre-entered reference data and also allow for user-defined inputs. The model includes an integrated sensitivity analysis function. Model functionality was demonstrated by estimating the public health impact of a hypothetical pre-erythrocytic malaria vaccine with 85% efficacy against uncomplicated disease and a vaccine efficacy decay rate of four years, based on internationally-established targets. Demand for this hypothetical vaccine was estimated based on historical vaccine implementation rates for routine infant immunization in 40 African countries over a 10-year period. Assumed purchase price was $5 per dose and injection equipment and delivery costs were $0.40 per dose.Results: The model projects the number of doses needed, uncomplicated and severe cases averted, deaths and disability-adjusted life years (DALYs) averted, and cost to avert each. In the demonstration scenario, based on a projected demand of 532 million doses, the MVM estimated that 150 million uncomplicated cases of malaria and 1.1 million deaths would be averted over 10 years. This is equivalent to 943 uncomplicated cases and 7 deaths averted per 1,000 vaccinees. In discounted 2011 US dollars, this represents $11 per uncomplicated case averted and $1,482 per death averted. If vaccine efficacy were reduced to 75%, the estimated uncomplicated cases and deaths averted over 10 years would decrease by 14% and 19%, respectively.Conclusions: The MVM can provide valuable information to assist decision-making by vaccine developers and policymakers, information which will be refined and strengthened as field studies progress allowing further validation of modeling assumptions. © 2013 Nunes et al.; licensee BioMed Central Ltd.


Kennell M.,405 Research Boulevard | Woolley J.,405 Research Boulevard
Tuberculosis | Year: 2012

The success of global efforts to develop new TB vaccines will rely on both addressing the scientific challenges identified throughout this Blueprint and mobilizing sufficient support and resources to sustain and advance the TB vaccine pipeline. As outlined in the TB Vaccine Blueprint, activities over the next decade will include expanding financing to provide sufficient resources, raising awareness of the need for new TB vaccines, and broadening the base of advocates, allies and champions for TB vaccine R&D. These activities will only be successful if advocates and researchers - including scientists, clinicians and product developers - work together. Researchers and advocates play an essential role in promoting the advancement of TB vaccine research and development (R&D), but have too often operated independently of each other, with researchers focusing on the science and advocates and civil society focused on advocacy, communications and resource mobilization. As we look toward the next decade of TB vaccine development, it will be critical for the research and advocacy communities to work more closely together to support the common goal of developing new, more effective TB vaccines. © 2012 Elsevier Ltd. All rights reserved.


Brennan M.J.,405 Research Boulevard | Stone M.R.,405 Research Boulevard | Stone M.R.,Liquidia Technologies | Evans T.,405 Research Boulevard
International Journal of Tuberculosis and Lung Disease | Year: 2012

The development of tuberculosis (TB) vaccines is at a turning point, with the promise of new vaccines on the horizon. Over the next few years, it is possible that we will see a phase III multi-site clinical trial of at least one new TB vaccine and perhaps the introduction of a TB vaccine by the end of the decade. However, many gaps remain in our understanding of TB pathogenesis as well as the host immune responses required to provide protective immunity. A major challenge for TB vaccines is to establish a correlate of vaccine immunity which would greatly facilitate bridging studies needed to approve, license and distribute new TB vaccines in all areas endemic for TB. This will require TB vaccines that are both safe and effective in all populations. It cannot be accomplished without hard work as well as additional resources that match the ambitious goals of the TB community. © 2012 The Union.


PubMed | 405 Research Boulevard
Type: | Journal: Tuberculosis (Edinburgh, Scotland) | Year: 2012

A rational process is clearly needed and can be extremely helpful for selection, assessing and advancing TB vaccine candidates from entry into preclinical and clinical development and for advancing candidates from early safety and immunogenicity clinical trials to proof-of-concept and pivotal efficacy trials. A joint effort between Aeras and the Tuberculosis Vaccine Initiative has focused on the development of objective criteria for a number of key general vaccine characteristics which can be assessed at critical stages of development. In order to maximize development efficiency, increase likelihood of success, and optimize use of scarce resources, this process includes establishment of gates for moving TB vaccine candidates through progressive development stages based on meeting the established criteria for specific vaccine candidates.

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