Inhibition of mycobacterial growth in vitro following primary but not secondary vaccination with Mycobacterium bovis BCG.

Despite the widespread use of the Mycobacterium bovis BCG vaccine, there are more than 9 million new cases of tuberculosis (TB) every year, and there is an urgent need for better TB vaccines. TB vaccine candidates are selected for evaluation based in part on the detection of an antigen-specific gamma interferon (IFN-γ) response. The measurement of mycobacterial growth in blood specimens obtained from subjects immunized with investigational TB vaccines may be a better in vitro correlate of in vivo vaccine efficacy. We performed a clinical study with 30 United Kingdom adults who were followed for 6 months to evaluate the abilities of both a whole-blood- and a novel peripheral blood mononuclear cell (PBMC)-based mycobacterial growth inhibition assay to measure a response to primary vaccination and revaccination with BCG. Using cryopreserved PBMCs, we observed a significant improvement in mycobacterial growth inhibition following primary vaccination but no improvement in growth inhibition following revaccination with BCG (P < 0.05). Mycobacterial growth inhibition following primary BCG vaccination was not correlated with purified protein derivative (PPD) antigen-specific IFN-γ enzyme-linked immunospot (ELISPOT) responses. We demonstrate that a mycobacterial growth inhibition assay can detect improved capacity to control growth following primary immunization, but not revaccination, with BCG. This is the first study to demonstrate that an in vitro growth inhibition assay can identify a difference in vaccine responses by comparing both primary and secondary BCG vaccinations, suggesting that in vitro growth inhibition assays may serve as better surrogates of clinical efficacy than the assays currently used for the assessment of candidate TB vaccines.

The blueprint for vaccine research & development: walking the path for better TB vaccines.

Much progress has been made in TB vaccine research over the past ten years, and a series of new live genetically altered mycobacterial vaccines, viral-vectored vaccines and sub-unit vaccines composed of recombinant antigens are presently in clinical development phases. A series of challenges remain, however, to be addressed in order to develop new and better candidate TB vaccines, especially an expansion of our knowledge of what constitutes protective immunity in TB, the identification of the most suitable vaccination strategies, the capacity and infrastructure to conduct large-scale trials in endemic countries, the investment in vaccine manufacturing capacity, and the development of effective regulatory pathways that shorten review timelines. In this brief paper, we review how the Vaccine Blueprint places itself in the continuation and expansion of two groundbreaking initiatives taking place over the last two years, that is, an invigorated Global Plan to Stop TB 2011-2015 that gives a clear emphasis on Research and Development, and the International Roadmap for TB Research, that identifies key priorities for research on TB vaccines, spanning from the most fundamental research aspects to the more field-based epidemiological aspects.

Considerations regarding efficacy endpoints in HIV vaccine trials: executive summary and recommendations of an expert consultation jointly organized by WHO, UNAIDS and ANRS in support of the Global HIV Vaccine Enterprise.

HIV vaccines of the first generation are, in contrast to most currently licensed vaccines, unlikely to provide sterilizing immunity against infection with HIV. However, they are expected to exert a beneficial effect on the maintenance of CD4 T-cell counts by reducing viral load. There is a recognized need for clarifying the path to licensure of such novel vaccines and defining the clinical trial endpoints. This was the focus of discussions of a 2-day workshop organized by the WHO, UNAIDS and the ANRS, in support of the Global HIV Vaccine Enterprise, which took place in Paris, France (5-6 September 2007). This expert consultation, the proceedings of which are presented here, was intended to review the fundamental principles and approaches to validate surrogate markers in clinical research, as well as the significance of viral load for the individual course of disease and for secondary transmission. Recommendations were also made for additional research to inform decision-making regarding potential licensure and delivery of vaccines which do not prevent HIV acquisition but do reduce viral load.

Planning to improve global health: the next decade of tuberculosis control.

The Global Plan to Stop TB 2006-2015 is a road map for policy-makers and managers of national programmes. It sets out the key actions needed to achieve the targets of the Millennium Development Goals relating to tuberculosis (TB): to halve the prevalence and deaths by 2015 relative to 1990 levels and to save 14 million lives. Developed by a broad coalition of partners, the plan presents a model approach combining interventions that can feasibly be supplied on the ground. The main areas of activity set out in the plan are: scaling up interventions to control tuberculosis; promoting the research and development of improved diagnostics, drugs and vaccines; and engaging in related activities for advocacy, communications and social mobilization. Scenarios for the planning process were developed; these looked at issues both globally and in seven epidemiological regions. The scenarios made ambitious but realistic assumptions about the pace of scale-up and implementation coverage of the activities. A mathematical model was used to estimate the impact of scaling up current interventions based on data from studies of tuberculosis biology and from experience with tuberculosis control in diverse settings. The estimated costs of the activities set out in the Global Plan were based on implementing interventions and researching and developing drugs, diagnostics and vaccines; these costs were US$ 56 billion over 10 years. When translated into cost per disability adjusted life year averted, these costs compare favourably with those of other public health interventions. This approach to planning for global tuberculosis control is a valuable example of developing plans to improve global health that has relevance for other health issues.

A review of vaccine research and development: tuberculosis.

Substantial progress has been made during the past 15 years towards the development of improved vaccines for tuberculosis. This is due to advances in the characterization of genes and antigens of Mycobacterium tuberculosis (M. tb), aided by the availability of genome sequences of different mycobacterial species and M. tb isolates and to greater understanding of protective immune responses to the pathogen in both animals and humans. More than one hundred candidate vaccines have been tested in animal models, representing all of the major vaccine design strategies, and some have now moved into clinical trials. This review summarizes recent advances in tuberculosis vaccine development.

New live mycobacterial vaccines: the Geneva consensus on essential steps towards clinical development.

As the disease caused by Mycobacterium tuberculosis continues to be a burden, which the world continues to suffer, there is a concerted effort to find new vaccines to combat this problem. Of the various vaccines strategies, one viable option is the development of live mycobacterial vaccines. A meeting with researchers, regulatory bodies, vaccines developers and manufactures was held to consider the challenges and progress, which has been achieved with live mycobacterial vaccines (either modified BCG or attenuated M. tuberculosis). Discussion led to the production of a consensus document of the proposed entry criteria for Phase I clinical trials of candidate live mycobacterial vaccines. The vaccine must be characterised thoroughly to prove identity and consistency, as clinical trial lots are prepared. In pre-clinical studies, greater protective efficacy as well as improved safety potential relative to BCG should be considered when assessing potential vaccine candidates. A standard way to measure the protective efficacy to facilitate comparison between vaccine candidates was suggested. Additional safety criteria and verification of attenuation must be considered for attenuated M. tuberculosis. Two non-reverting independent mutations are recommended for such vaccines. When entering Phase I trials, enrollment should be based upon an acceptable characterisation of the study population regarding mycobacterium status and exclude HIV(+) individuals. BCG could be used as a comparator for blinding during the trials and to properly assess vaccine-specific adverse reactions, while assays are being developed to assess immunogenicity of vaccines. The proposed criteria suggested in this consensus document may facilitate the movement of the most promising vaccine candidates to the clinic and towards control of tuberculosis.