Prof Helen McShane
|Keywords:||Tuberculosis, Vaccine, Immunisation and Clinical Trial|
The HIV epidemic and the emergence of multi and extensively drug-resistant strains of Mycobacterium tuberculosis mean that global control of TB, particularly adult pulmonary TB, remains inadequate. The current vaccine, BCG confers protection against disseminated disease in childhood, but does not protect against pulmonary disease. It is known that Class II-restricted CD4+ T cells are essential for protective immunity and that class I-restricted CD8+ T lymphocytes may play a role in maintaining the latent state. Over the last 12 years my group has developed a new TB vaccine, called MVA85A, which is designed to enhance the protective immunity conferred by BCG. This strategy improves BCG induced protection in preclinical models.
Since 2002 we have conducted a series of Phase I and Phase IIa clinical trials with MVA85A in the UK, The Gambia, South Africa and Senegal. In all of these clinical trials we find that MVA85A is safe and highly immunogenic. In April 2009, a Phase IIb proof-of-concept efficacy trial commenced in South African infants. This clinical trial will allow us to evaluate the protective efficacy of this strategy in humans, and is the first of the new generation of TB vaccines to enter into efficacy testing.
Current projects within my group include the development of a BCG challenge model in humans, evaluating the contribution of pre-existing exposure to environmental mycobacteria on vaccine induced immune responses, evaluation of the protective efficacy of new antigens in viral vectors and evaluating mucosal routes of vaccine delivery, in both preclinical and clinical models.
|Gregory Hussey||University of Cape Town||South Africa|
|Martin Ota||MRC Laboratories, The Gambia||The Gambia|
|Sally Sharpe||Health Protection Agency, Porton Down||UK|
|Souleymane MBoup||University of Dakar||Senegal|
|Glyn Hewinson||VLA, Weybridge||UK|
|Mario Roederer||Vaccine Research Center, NIH||USA|
|Willem Hanekom||South African TB Vaccine Initiative (SATVI), Cape Town||South Africa|
|Ann Rawkins||Health Protection Agency, Porton Down||UK|
|John Fulkerson||Aeras Global TB Foundation, Rockville||USA|
An effective new tuberculosis (TB) vaccine regimen must be safe in individuals with latent TB infection (LTBI) and is a priority for global health care. Hide abstract
Continuous high global tuberculosis (TB) mortality rates and variable vaccine efficacy of Mycobacterium bovis Bacille Calmette-Guérin (BCG) motivate the search for better vaccine regimes. Relevant models are required to downselect the most promising vaccines entering clinical efficacy testing and to identify correlates of protection. Hide abstract
Interferon gamma (IFNgamma) is a critical component of the pro-inflammatory immune response that provides protection against Mycobacterium tuberculosis. In the absence of an immunological correlate of protection, antigen-specific production of IFNgamma is a commonly used marker of a protective immune response. To facilitate the evaluation of tuberculosis candidate vaccines three different IFNgamma detection methods were compared. The cultured whole blood ELISA, ex vivo IFNgamma ELISpot and whole blood ex vivo intracellular cytokine staining (ICS) assays were performed head-to-head during a Phase I clinical trial using the candidate vaccine MVA85A. Whilst all three assays detected significant increases in IFNgamma production immediately following vaccination, distinctions between the assays were apparent. Higher baseline IFNgamma responses were detected using the cultured whole blood ELISA, whereas the ex vivo ELISpot assay was the most sensitive in detecting long-term (52 weeks) post-vaccination responses. The whole blood ex vivo ICS assay provided novel information by dissecting the IFNgamma response into responding CD4, CD8 and gamma/delta T cell subsets. Future tuberculosis vaccine trials and immunology studies should ideally include a combination of ex vivo and cultured assays to ensure a thorough and multifaceted evaluation of the immune response is achieved. Hide abstract
In clinical trials recombinant-modified vaccinia virus Ankara expressing the Mycobacterium tuberculosis antigen 85A (MVA85A) induces approximately 10 times more effector T cells than any other recombinant MVA vaccine. We have found that in BCG primed subjects MVA85A vaccination reduces transforming growth factor beta 1 (TGF-beta1) mRNA in peripheral blood lymphocytes and reduces TGF-beta1 protein in the serum, but increases IFN-gamma ELISPOT responses to the recall antigen SK/SD. TGF-beta1 is essential for the generation of regulatory T cells and we see a correlation across vaccinees between CD4+CD25hiFoxP3+ cells and TGF-beta1 serum levels. This apparent ability to counteract regulatory T cell effects suggests a potential use of MVA85A as an adjuvant for less immunogenic vaccines. Hide abstract
The efficacy of bacille Calmette-Guérin (BCG) may be enhanced by heterologous vaccination strategies that boost the BCG-primed immune response. One leading booster vaccine, MVA85A (where "MVA" denotes "modified vaccinia virus Ankara"), has shown promising safety and immunogenicity in human trials performed in the United Kingdom. We investigated the safety and immunogenicity of MVA85A in mycobacteria-exposed--but Mycobacterium tuberculosis-uninfected--healthy adults from a region of South Africa where TB is endemic. Hide abstract
In the search for effective vaccines against intracellular pathogens such as HIV, tuberculosis and malaria, recombinant viral vectors are increasingly being used to boost previously primed T cell responses. Published data have shown prime-boost vaccination with BCG-MVA85A (modified vaccinia virus Ankara expressing antigen 85A) to be highly immunogenic in humans as measured by ex vivo IFN-gamma ELISPOT. Here, we used polychromatic flow cytometry to investigate the phenotypic and functional profile of these vaccine-induced Mycobacterium tuberculosis (M.tb) antigen 85A-specific responses in greater detail. Promisingly, antigen 85A-specific CD4(+) T cells were found to be highly polyfunctional, producing IFN-gamma, TNF-alpha, IL-2 and MIP-1beta. Surface staining showed the responding CD4(+) T cells to be relatively immature (CD45RO(+) CD27(int)CD57(-)); this observation was supported by the robust proliferative responses observed following antigenic stimulation. Furthermore, these phenotypic and functional properties were independent of clonotypic composition and epitope specificity, which was maintained through the different phases of the vaccine-induced immune response. Overall, these data strongly support the use of MVA85A in humans as a boosting agent to expand polyfunctional M.tb-specific CD4(+) T cells capable of significant secondary responses. Hide abstract
Tuberculosis remains a substantial global health problem despite effective drug treatments. The efficacy of BCG, the only available vaccine, is variable, especially in tuberculosis-endemic regions. Recent advances in the development of new vaccines against tuberculosis mean that the first of these are now entering into early clinical trials. A recombinant modified vaccinia virus Ankara expressing a major secreted antigen from Mycobacterium tuberculosis, antigen 85A, was the first new tuberculosis vaccine to enter into clinical trials in September 2002. This vaccine is known as MVA85A. In a series of phase I clinical trials in the UK, MVA85A had an excellent safety profile and was highly immunogenic. MVA85A was subsequently evaluated in a series of phase I trials in The Gambia, a tuberculosis-endemic area in west Africa. This vaccine is the only new subunit tuberculosis vaccine to enter into clinical trials in Africa to date. Here, we discuss some of the issues that were considered in the protocol design of these studies including recruitment, inclusion and exclusion criteria, reimbursement of study participants, and HIV testing. These issues are highly relevant to early clinical trials with all new tuberculosis vaccines in the developing world. Hide abstract
Protective immunity against Mycobacterium tuberculosis depends on the generation of a T(H)1-type cellular immune response, characterized by the secretion of interferon-gamma (IFN-gamma) 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-gamma-secreting T cells when used alone in bacille Calmette-Guerin (BCG)-naive healthy volunteers. In volunteers who had been vaccinated 0.5-38 years previously with BCG, substantially higher levels of antigen-specific IFN-gamma-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. Hide abstract
Human mycobacterial challenge models
Human challenge models have greatly facilitated the field of vaccine research, particularly for malaria vaccine research. A human mycobacterial challenge model would aid in the down selection of new TB vaccine candidates. It would not be ethical to challenge human subjects with virulent Mycobacterium tuberculosis, but BCG provides a safe alternative. BCG is a replicating mycobacteria, licensed for human use. We are developing a human BCG challenge model where BCG is administered intradermally ...