The political economy of bovine tuberculosis in Great Britain.

A brief history of bovine tuberculosis (bTB) and its control in Great Britain (GB) is presented. Numerous diverse policies to control the disease in humans, cattle and wildlife have been pursued over the last 100 years and many millions of pounds have been spent. After notable success in reducing the incidence and prevalence of bTB in cattle in GB from the 1950s to the mid-1980s, the geographical spread of the disease and the number of cattle slaughtered have increased continually since that time, with a high point of bTB incidence in 2008. This increase appeared to coincide with changing policy regarding the control of the disease in badgers, with a more humane approach adopted and with strengthened protection for badgers through legislation. Indeed, there has been much controversy in the debate on the role of badgers in disease transmission to cattle and the need for their control as vectors of the disease. The issue has attracted the attention of the media and there have been various commissioned research projects, trials and public consultations. The findings of two social science investigations presented as examples showed that citizens generally believed that bTB in cattle is an important issue that needs to be tackled, but objected to badgers being killed, whilst cattle farmers were willing to pay around £17/animal/year for a bTB cattle vaccine. It is noted that successes regarding the control of bTB in other countries have combined both cattle and wildlife controls and involved industry working in close partnership with government.

L'auteur retrace brièvement l'histoire de la tuberculose bovine et de la lutte contre cette maladie en Grande-Bretagne. Diverses mesures sanitaires ont été appliquées au cours des cent dernières années afin de maîtriser la maladie chez l'homme, chez les bovins et dans la faune sauvage, pour une dépense totale de plusieurs millions de livres. Après la chute remarquable de l'incidence et de la prévalence de la tuberculose bovine en Grande-Bretagne enregistrée depuis les années 50, la situation s'est inversée au milieu des années 80 et tant la distribution géographique de la maladie que le nombre de bovins abattus n'ont cessé de croître depuis cette date, l'année 2008 marquant le pic de l'incidence de la tuberculose bovine. Il est désormais établi que cette hausse a coïncidé avec l'évolution des politiques de lutte contre la tuberculose chez les blaireaux, à la faveur d'une approche plus respectueuse du bien-être animal qui s'est traduite par une protection renforcée des blaireaux dans la législation. En effet, le rôle des blaireaux dans la transmission de la tuberculose aux bovins et l'impératif de lutter contre les blaireaux en tant que vecteurs ont fait l'objet de très fortes controverses. Cette question a attiré l'attention des médias et il y a eu de nombreux projets de recherche commandités sur le sujet, d'expériences et de consultations publiques. D'après deux enquêtes sociologiques citées par l'auteur, les citoyens étaient généralement convaincus de l'importance de la tuberculose chez les bovins et de la nécessité de s'y attaquer mais ils s'opposaient aux mesures d'abattage des blaireaux, tandis que les éleveurs de bovins étaient disposés à payer environ 17 livres par bovin et par année pour pouvoir vacciner leurs bovins contre la tuberculose bovine. L'auteur fait observer que les succès enregistrés dans d'autres pays dans la lutte contre la tuberculose bovine sont liés à l'application combinée de mesures de contrôle chez les bovins et dans la faune sauvage et à une étroite collaboration entre les éleveurs et le gouvernement.

El autor repasa sucintamente la historia de la tuberculosis bovina y de su control en Gran Bretaña. En los últimos 100 años se han aplicado numerosas y variadas políticas y se han invertido muchos millones de libras para combatir la enfermedad en el ser humano, el ganado vacuno y la fauna silvestre. Entre mediados del decenio de 1950 y mediados del de 1980 se trabajó con notable éxito para reducir la incidencia y prevalencia de la enfermedad en el ganado vacuno británico. Pero a partir de ahí hubo una progresión constante en la propagación geográfica de la enfermedad y en el número de cabezas de ganado sacrificadas, con un máximo de incidencia registrado en 2008. Tal incremento parece coincidir con una inflexión de la política aplicada para luchar contra la enfermedad en los tejones, con la adopción de métodos más clementes y de medidas legislativas que instauraban un mayor nivel de protección de los tejones. Ha habido en efecto una gran controversia acerca del papel de los tejones en los procesos de transmisión de la enfermedad al ganado vacuno y la necesidad de controlar a esos animales como vectores de la infección. El tema ha suscitado gran atención mediática y ha sido objeto de una serie de proyectos de investigación, experimentos y consultas públicas. Según demuestran las conclusiones de dos investigaciones de ciencias sociales presentadas como ejemplo, en general los ciudadanos pensaban que la tuberculosis bovina en el ganado era un problema importante al que había que dar respuesta, pero se oponían al sacrificio de los tejones, a la vez que los ganaderos estaban dispuestos a pagar alrededor de 17 libras/animal/año por la vacunación antituberculosa de sus rebaños vacunos. El autor señala que los éxitos obtenidos en otros países a la hora de combatir la tuberculosis bovina pasan por instaurar controles a la vez en el ganado y en la fauna silvestre y por lograr que la industria trabaje en estrecha asociación con las instancias públicas.

R&D in Vaccines Targeting Neglected Diseases: An Exploratory Case Study Considering Funding for Preventive Tuberculosis Vaccine Development from 2007 to 2014.

Based on an exploratory case study regarding the types of institutions funding the research and development to obtain new tuberculosis vaccines, this article intends to provoke discussion regarding the provision of new vaccines targeting neglected disease. Although our findings and discussion are mainly relevant to the case presented here, some aspects are more generally applicable, especially regarding the dynamics of development in vaccines to prevent neglected diseases. Taking into account the dynamics of innovation currently seen at work in the vaccine sector, a highly concentrated market dominated by few multinational pharmaceutical companies, we feel that global PDP models can play an important role throughout the vaccine development cycle. In addition, the authors call attention to issues surrounding the coordination of actors and resources in the research, development, manufacturing, and distribution processes of vaccine products arising from PDP involvement.

Systematic review of mathematical models exploring the epidemiological impact of future TB vaccines.

Mathematical models are useful for assessing the potential epidemiological impact of future tuberculosis (TB) vaccines. We conducted a systematic review of mathematical models estimating the epidemiological impact of future human TB vaccines. PubMed, Embase and WHO Global Health Library were searched, 3-stage manual sifted, and citation- and reference-tracked, identifying 23 papers. An adapted quality assessment tool was developed, with a resulting median study quality score of 20/28. The literature remains divided as to whether vaccines effective pre- or post-infection would provide greatest epidemiological impact. However, all-age or adolescent/adult targeted prevention of disease vaccines achieve greater and more rapid impact than neonatal vaccines. Mass campaigns alongside routine neonatal vaccination can have profound additional impact. Economic evaluations found TB vaccines overwhelmingly cost-effective, particularly when targeted to adolescents/adults. The variability of impact by setting, age group and vaccine characteristics must be accounted for in the development and delivery of future TB vaccines.

DNA Vaccines: A Strategy for Developing Novel Multivalent TB Vaccines.

Multivalent DNA vaccines that are delivered by electroporation (EP) through muscle tissue provide a novel method for eliciting immunity against tuberculosis (TB) as well as a broad range of diseases including HIV and cancers. Proper plasmid construction containing suitable protective TB antigens capable of evoking desired vaccine-induced responses would lead to the appropriate induction of both humoral and cellular immunity. DNA vaccines are safe and of low cost in comparison to traditional vaccines while also providing potentially effective prophylactic or therapeutic modalities against currently untreatable diseases. Here, we describe the steps for developing a rational multivalent TB DNA vaccine delivered with intramuscular EP in mice.

Drug-resistant TB: deadly, costly and in need of a vaccine.

TB is an underappreciated public health threat in developed nations. In 2014, an estimated 9.6 million TB cases and 1.5 million deaths occurred worldwide; 3.3% of these cases resulted from multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) strains. These figures underestimate the economic burden associated with MDR-TB and XDR-TB, as the cost of treating disease caused by these strains can be 9-25 times higher than treating drug-susceptible TB. Developing new drugs, improved diagnostics and new TB vaccines are critical components of a strategy to combat TB in general, and drug-resistant TB in particular. Because Mycobacterium tuberculosis (MTB) has demonstrated a capacity to develop resistance to drugs developed to combat it, it is unlikely that drug-resistant MTB would be 'resistant' to vaccines capable of preventing disease or established infection with drug-sensitive MTB strains. Accordingly, the development of TB vaccines represents an important long-term investment in preventing the spread of drug-resistant TB and achieving WHO's goal of ending the global TB epidemic by 2035. Our current understanding of the epidemiology of drug-resistant TB and the interventions needed to limit its spread, reviewed in this article, illustrates the need for increased financial support for developing new TB drugs, diagnostics and vaccines to meet the WHO goal of TB elimination by 2035.

Developing vaccines to prevent sustained infection with Mycobacterium tuberculosis: Conference proceedings: National Institute of Allergy and Infectious Diseases, Rockville, Maryland USA, November 7, 2014.

On November 7, 2014, Aeras and the National Institute of Allergy and Infectious Diseases convened a conference entitled "Vaccine Prevention of Sustained Mycobacterium tuberculosis Infection." The purpose of this meeting was to explore the biologic plausibility, potential public health and economic impact, and regulatory feasibility in attempting to develop a vaccine to prevent sustained infection with Mycobacterium tuberculosis (Mtb). Currently there are two main goals for tuberculosis (TB) vaccine development, to develop a vaccine that could serve as a booster to Bacille Calmette-Guérin (BCG) vaccination and prevent active TB in adolescents and adults, and to develop an improved vaccine to replace BCG in infants. Although prevention of sustained Mtb infection is being used as a proof of biological activity for vaccines in mid-Phase 2 development, there currently are no plans for pursuing a prevention of Mtb infection licensure indication for TB vaccines. Ultimately, pursuing a prevention of sustained Mtb infection indication for TB vaccines, in parallel with ongoing efforts to develop vaccines to prevent active TB disease, was deemed a potentially important effort, but would require further resources, particularly to improve diagnostic assays, to increase the regulatory feasibility of this endeavor.

Impact and cost-effectiveness of new tuberculosis vaccines in low- and middle-income countries.

To help reach the target of tuberculosis (TB) disease elimination by 2050, vaccine development needs to occur now. We estimated the impact and cost-effectiveness of potential TB vaccines in low- and middle-income countries using an age-structured transmission model. New vaccines were assumed to be available in 2024, to prevent active TB in all individuals, to have a 5-y to lifetime duration of protection, to have 40-80% efficacy, and to be targeted at "infants" or "adolescents/adults." Vaccine prices were tiered by income group (US $1.50-$10 per dose), and cost-effectiveness was assessed using incremental cost per disability adjusted life year (DALY) averted compared against gross national income per capita. Our results suggest that over 2024-2050, a vaccine targeted to adolescents/adults could have a greater impact than one targeted at infants. In low-income countries, a vaccine with a 10-y duration and 60% efficacy targeted at adolescents/adults could prevent 17 (95% range: 11-24) million TB cases by 2050 and could be considered cost-effective at $149 (cost saving to $387) per DALY averted. If targeted at infants, 0.89 (0.42-1.58) million TB cases could be prevented at $1,692 ($634-$4,603) per DALY averted. This profile targeted at adolescents/adults could be cost-effective at $4, $9, and $20 per dose in low-, lower-middle-, and upper-middle-income countries, respectively. Increased investments in adult-targeted TB vaccines may be warranted, even if only short duration and low efficacy vaccines are likely to be feasible, and trials among adults should be powered to detect low efficacies.

Optimal control for a tuberculosis model with reinfection and post-exposure interventions.

We apply optimal control theory to a tuberculosis model given by a system of ordinary differential equations. Optimal control strategies are proposed to minimize the cost of interventions, considering reinfection and post-exposure interventions. They depend on the parameters of the model and reduce effectively the number of active infectious and persistent latent individuals. The time that the optimal controls are at the upper bound increase with the transmission coefficient. A general explicit expression for the basic reproduction number is obtained and its sensitivity with respect to the model parameters is discussed. Numerical results show the usefulness of the optimization strategies.

Key issues in the clinical development and implementation of TB vaccines in South Africa.

Significant progress has been made in advancing the development pipeline for a new and more effective TB vaccine with some candidate vaccines now in late stage clinical evaluation. However, progress has been hampered by an incomplete understanding of the components of a protective immune response and limited animal models, rendering the field unable to reliably predict vaccine efficacy earlier in preclinical development, including by evaluation in animal models, and limiting the predictive utility of comparing immunogenic effects across vaccine candidates in phase I/II studies. Consequently, new candidate vaccines have to be evaluated for efficacy in large-scale phase II/III trials using clinical endpoints. Apart from the technical challenges of characterising TB incidence in target populations at high risk of acquiring TB disease and standardising case definitions in order to improve both the sensitivity and more importantly the specificity of trial endpoints, there is an urgency in expanding and supporting the considerable trial infrastructure that will be required to evaluate and ultimately license a new TB vaccine. In the longer term, implementation strategies are dependent on what policy makers most value. Economic analyses will be essential to guide policy and implementation. This paper outlines the gaps and challenges and identifies solutions for effectively developing and efficiently introducing a new TB vaccine.

Open source drug discovery--a new paradigm of collaborative research in tuberculosis drug development.

It is being realized that the traditional closed-door and market driven approaches for drug discovery may not be the best suited model for the diseases of the developing world such as tuberculosis and malaria, because most patients suffering from these diseases have poor paying capacity. To ensure that new drugs are created for patients suffering from these diseases, it is necessary to formulate an alternate paradigm of drug discovery process. The current model constrained by limitations for collaboration and for sharing of resources with confidentiality hampers the opportunities for bringing expertise from diverse fields. These limitations hinder the possibilities of lowering the cost of drug discovery. The Open Source Drug Discovery project initiated by Council of Scientific and Industrial Research, India has adopted an open source model to power wide participation across geographical borders. Open Source Drug Discovery emphasizes integrative science through collaboration, open-sharing, taking up multi-faceted approaches and accruing benefits from advances on different fronts of new drug discovery. Because the open source model is based on community participation, it has the potential to self-sustain continuous development by generating a storehouse of alternatives towards continued pursuit for new drug discovery. Since the inventions are community generated, the new chemical entities developed by Open Source Drug Discovery will be taken up for clinical trial in a non-exclusive manner by participation of multiple companies with majority funding from Open Source Drug Discovery. This will ensure availability of drugs through a lower cost community driven drug discovery process for diseases afflicting people with poor paying capacity. Hopefully what LINUX the World Wide Web have done for the information technology, Open Source Drug Discovery will do for drug discovery.

Cost-effectiveness of novel vaccines for tuberculosis control: a decision analysis study.

BACKGROUND: The development of a successful new tuberculosis (TB) vaccine would circumvent many limitations of current diagnostic and treatment practices. However, vaccine development is complex and costly. We aimed to assess the potential cost effectiveness of novel vaccines for TB control in a sub-Saharan African country--Zambia--relative to the existing strategy of directly observed treatment, short course (DOTS) and current level of bacille Calmette-Guérin (BCG) vaccination coverage. METHODS: We conducted a decision analysis model-based simulation from the societal perspective, with a 3% discount rate and all costs expressed in 2007 US dollars. Health outcomes and costs were projected over a 30-year period, for persons born in Zambia (population 11,478,000 in 2005) in year 1. Initial development costs for single vaccination and prime-boost strategies were prorated to the Zambian share (0.398%) of global BCG vaccine coverage for newborns. Main outcome measures were TB-related morbidity, mortality, and costs over a range of potential scenarios for vaccine efficacy. RESULTS: Relative to the status quo strategy, a BCG replacement vaccine administered at birth, with 70% efficacy in preventing rapid progression to TB disease after initial infection, is estimated to avert 932 TB cases and 422 TB-related deaths (prevention of 199 cases/100,000 vaccinated, and 90 deaths/100,000 vaccinated). This would result in estimated net savings of $3.6 million over 30 years for 468,073 Zambians born in year 1 of the simulation. The addition of a booster at age 10 results in estimated savings of $5.6 million compared to the status quo, averting 1,863 TB cases and 1,011 TB-related deaths (prevention of 398 cases/100,000 vaccinated, and of 216 deaths/100,000 vaccinated). With vaccination at birth alone, net savings would be realized within 1 year, whereas the prime-boost strategy would require an additional 5 years to realize savings, reflecting a greater initial development cost. CONCLUSIONS: Investment in an improved TB vaccine is predicted to result in considerable cost savings, as well as a reduction in TB morbidity and TB-related mortality, when added to existing control strategies. For a vaccine with waning efficacy, a prime-boost strategy is more cost-effective in the long term.