Biomedical subjects

Helen McShane

Publications and source records attributed to Helen McShane.

16 recordsLinked to original sources

PubMed2006

Impaired IFN-gamma-secreting capacity in mycobacterial antigen-specific CD4 T cells during chronic HIV-1 infection despite long-term HAART.

OBJECTIVE: To determine whether long-term HAART in chronic HIV-1 infection restores fully functional Mycobacterium tuberculosis (MTB)-specific CD4 T-cell responses. DESIGN: A cross-sectional study of HIV-1-seropositive subjects on continuous HAART for over one year with CD4 cell counts greater than 300 cells/microl and undetectable viraemia, antiretroviral-naive individuals with primary HIV-1 infection (PHI), and healthy bacillus Calmette-Guérin-vaccinated low-risk controls. METHODS: Purified protein derivative (PPD)-specific cytokine-secreting CD4 T cells were quantified ex vivo by enzyme-linked immunospot assay and intracellular cytokine staining. Lymphoproliferation was detected by [3H]-thymidine incorporation. RESULTS: PPD-specific IFN-gamma-secreting CD4 T cells were markedly reduced in chronic HAART-treated HIV-1-positive and PHI subjects compared with healthy controls [medians 30, 155 and 582 spot-forming cells/million peripheral blood mononuclear cells (PBMC), respectively, P < 0.0001 and P < 0.002], but the frequency of these cells was, nonetheless, significantly greater in viraemic PHI subjects than in aviraemic chronic HIV-1-positive subjects (P < 0.01). In the latter, low frequencies of PPD-specific IL-2 and IL-4-secreting CD4 T cells were also observed. However, lymphoproliferation was evident after the in-vitro stimulation of PBMC with PPD, indicating that MTB-specific T cells were present. The defect in IFN-gamma secretion could be overcome by culture with IL-12. CONCLUSION: Despite an improvement in CD4 T-cell counts after HAART, MTB-specific CD4 T cells from chronically infected patients have impaired IFN-gamma-secreting capacity. The early initiation of HAART might preserve functional CD4 T-cell responses to MTB, and warrants evaluation in populations with a high risk of dual infection.

Adult↗

PubMed2006

Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis-endemic countries: issues in study design.

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.

Acyltransferases↗

PubMed2006

Tuberculosis vaccines: current status and future prospects.

There is an urgent need to develop more effective tuberculosis vaccines as chemotherapy and Bacille Calmette-Guérin (BCG) have failed to control the current epidemic. BCG does have some protective effect in childhood, so using a second vaccine to boost BCG would be the most ethical and logistically feasible strategy. The cost of tuberculosis efficacy trials will be high and return on investment into the development of a tuberculosis vaccine will be low. Incentives such as orphan drug status could encourage industrial interest. As more vaccines enter into early clinical trials, there is an urgent need for the identification of correlates of protection to aid decisions about which vaccines should go forward into efficacy testing. Research efforts that focus on reducing the cost and risk of conducting clinical trials will be of direct benefit to tuberculosis vaccine development.

Animals↗

PubMed2005

Phase I clinical trial safety of DNA- and modified virus Ankara-vectored human immunodeficiency virus type 1 (HIV-1) vaccines administered alone and in a prime-boost regime to healthy HIV-1-uninfected volunteers.

DNA- and modified virus Ankara (MVA)-vectored candidate vaccines expressing human immunodeficiency virus type 1 (HIV-1) clade A-derived p24/p17 gag fused to a string of HLA class I epitopes, called HIVA, were tested in phase I trials in healthy, HIV-1/2-uninfected adults in Oxford, United Kingdom. Eighteen volunteers were vaccinated with pTHr.HIVA DNA (IAVI-001) alone, 8 volunteers received MVA.HIVA (IAVI-003) alone and 9 volunteers from study IAVI-001 were boosted with MVA.HIVA 9-14 months after DNA priming (IAVI-005). Immunogenicity results observed in these trials was published previously [Mwau M, Cebere I, Sutton J, Chikoti P, Winstone N, Wee EG-T, et al. An HIV-1 clade A vaccine in clinical trials: stimulation of HIV-specific T cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans. J Gen Virol 2004;85:911-9]. Here, we report on the safety of the two vaccines and the vaccine regimes. Overall, both candidate vaccines were safe and well tolerated. There were no reported vaccine-related adverse events over the 6-month period of the study and up to 2 years after the last vaccination. There were no moderate or severe local symptoms recorded after the pTHr.HIVA DNA intramuscular administration. Almost all participants experienced local reactogenicity events such as redness and induration after MVA.HIVA intradermal injection. Thus, the results from these initial small phase I trials administering the pTHr.HIVA DNA and MVA.HIVA vaccines either alone or in a prime-boost regime to healthy HIV-1/2-negative adults indicated that the vaccines were safe and warranted further testing of this approach in larger phase I/II studies.

AIDS Vaccines↗

PubMed2005

Synergistic DNA-MVA prime-boost vaccination regimes for malaria and tuberculosis.

T-cell-mediated responses against the liver-stage of Plasmodium falciparum are critical for protection in the human irradiated sporozoite model and several animal models. Heterologous prime-boost approaches, employing plasmid DNA and viral vector delivery of malarial DNA sequences, have proved particularly promising for maximising T-cell-mediated protection in animal models. The T-cell responses induced by this prime-boost regime, in animals and humans, are substantially greater than the sum of the responses induced by DNA or MVA vaccines used alone, leading to the term introduced here of "synergistic" prime-boost immunisation. The insert in our first generation clinical constructs is known as multiple epitope-thrombospondin-related adhesion protein (ME-TRAP). We have performed an extensive series of phase I/II trials evaluating various prime-boost combination regimens for delivery of ME-TRAP in over 500 malaria-naïve and malaria-exposed individuals. The three delivery vectors are DNA, modified vaccinia virus Ankara (MVA) and, more recently, fowlpox strain 9 (FP9). Administration was intra-epidermal and intramuscular for DNA and intradermal for MVA and FP9. Doses of DNA ranged from 4 microg to 2mg. Doses of MVA were up to 1.5 x 10(8) plaque forming units (pfu) and of FP9, up to 1.0 x 10(8)pfu. Further trials employing bacille Calmette-Guérin (BCG) as the priming agent and MVA expressing antigen 85A of Mycobacterium tuberculosis as the boosting agent has extended the scope of synergistic prime-boost vaccination. In this review we summarise the safety, immunogenicity and efficacy results from these malaria and tuberculosis vaccine clinical trials.

Adult↗

PubMed2005

Prime-boost immunisation strategies for tuberculosis.

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.

Humans↗

PubMed2005

Boosting BCG with MVA85A: the first candidate subunit vaccine for tuberculosis in clinical trials.

There is an urgent need for an improved vaccine against tuberculosis. Heterologous prime-boost immunization regimes induce higher levels of cellular immunity than homologous boosting with the same vaccine. Using BCG as the priming immunization in such a regime allows for the retention of the beneficial protective effects of BCG against disseminated disease in childhood. Recombinant poxviruses are powerful boosting agents, for both CD4+ and CD8+ T cells. Here we review the preclinical data from a BCG prime-recombinant modified vaccinia virus Ankara expressing antigen 85A (MVA85A) boost strategy. MVA85A is now in clinical trials in the UK and Africa and the design of these trials, including the ethical and regulatory issues are discussed.

BCG Vaccine↗

PubMed2005

Evaluation of vaccines in the EU TB Vaccine Cluster using a guinea pig aerosol infection model of tuberculosis.

The TB Vaccine Cluster project funded by the EU Fifth Framework programme aims to provide novel vaccines against tuberculosis that are suitable for evaluation in humans. This paper describes the studies of the protective efficacy of vaccines in a guinea pig aerosol-infection model of primary tuberculosis. The objective was to conduct comparative evaluations of vaccines that had previously demonstrated efficacy in other animal models. Groups of 6 guinea pigs were immunized with vaccines provided by the relevant EU Vaccine Cluster partners. Survival over 17 or 26 weeks was used as the principal measure of vaccine efficacy following aerosol challenge with H37Rv. Counts of mycobacteria in lungs and spleens, and histopathological changes in the lungs, were also used to provide evidence of protection. A total of 24 vaccines were evaluated in 4 experiments each of a different design. A heterologous prime-boost strategy of DNA and MVA, each expressing Ag85A and a fusion protein of ESAT-6 and Ag85B in adjuvant, protected the guinea pigs to the same extent as BCG. Genetically modified BCG vaccines and boosted BCG strategies also protected guinea pigs to the same extent as BCG but not statistically significantly better. A relatively high aerosol-challenge dose and evaluation over a protracted time post-challenge allowed superior protection over BCG to be demonstrated by BCG boosted with MVA and fowl pox vectors expressing Ag85A.

Aerosols↗

PubMed2005

Co-infection with HIV and TB: double trouble.

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.

Antiretroviral Therapy, Highly Active↗

PubMed2004

Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans.

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.

Acyltransferases↗

PubMed2004

A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans.

The immunogenicities of candidate DNA- and modified vaccinia virus Ankara (MVA)-vectored human immunodeficiency virus (HIV) vaccines were evaluated on their own and in a prime-boost regimen in phase I clinical trials in healthy uninfected individuals in the United Kingdom. Given the current lack of approaches capable of inducing broad HIV-neutralizing antibodies, the pTHr.HIVA DNA and MVA.HIVA vaccines focus solely on the induction of cell-mediated immunity. The vaccines expressed a common immunogen, HIVA, which consists of consensus HIV-1 clade A Gag p24/p17 proteins fused to a string of clade A-derived epitopes recognized by cytotoxic T lymphocytes (CTLs). Volunteers' fresh peripheral blood mononuclear cells were tested for HIV-specific responses in a validated gamma interferon enzyme-linked immunospot (ELISPOT) assay using four overlapping peptide pools across the Gag domain and three pools of known CTL epitopes present in all of the HIVA protein. Both the DNA and the MVA vaccines alone and in a DNA prime-MVA boost combination were safe and induced HIV-specific responses in 14 out of 18, seven out of eight and eight out of nine volunteers, respectively. These results are very encouraging and justify further vaccine development.

AIDS Vaccines↗

PubMed2004

Developing an improved vaccine against tuberculosis.

Despite the availability of a vaccine for over 80 years, the tuberculosis epidemic continues to be a major cause of mortality and morbidity throughout the world. The factors contributing to the resurgence of tuberculosis and the possible explanations for the failure of the current vaccine, bacille Calmette-Guérin, are discussed. The nature of protective immunity to Mycobacterium tuberculosis and how this relates to the development of new candidate vaccines is then considered. The issues surrounding the progression of the most promising candidates into Phase I clinical trials are also discussed.

Animals↗

PubMed2003

Enhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette-Guérin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus Ankara.

Heterologous prime-boost immunization strategies can evoke powerful T cell immune responses and may be of value in developing an improved tuberculosis vaccine. We show that recombinant modified vaccinia virus Ankara, expressing Mycobacterium tuberculosis Ag 85A (M.85A), strongly boosts bacille Calmette-Guérin (BCG)-induced Ag 85A specific CD4(+) and CD8(+) T cell responses in mice. A comparison of intranasal (i.n.) and parenteral immunization of BCG showed that while both routes elicited comparable T cell responses in the spleen, only i.n. delivery elicited specific T cell responses in the lung lymph nodes, and these responses were further boosted by i.n. delivery of M.85A. Following aerosol challenge with M. tuberculosis, i.n. boosting of BCG with either BCG or M.85A afforded unprecedented levels of protection in both the lungs (2.5 log) and spleens (1.5 log) compared with naive controls. Protection in the lung correlated with the induction of Ag 85A-specific, IFN-gamma-secreting T cells in lung lymph nodes. These findings support further evaluation of mucosally targeted prime-boost vaccination approaches for tuberculosis.

Acyltransferases↗

PubMed2003

CD8+ T cell-mediated suppression of intracellular Mycobacterium tuberculosis growth in activated human macrophages.

Animal models of tuberculosis point to a protective role for MHC class I-restricted CD8(+) T cells, yet it is unclear how these cells protect or whether such findings extend to humans. Here we report that macrophages infected with Mycobacterium tuberculosis, rapidly process and present an early secreted antigenic target (ESAT-6)-specific HLA class I-restricted CD8(+) T cell epitope. When cocultured with CD8(+) T cells restricted through classical HLA class I molecules the growth of bacilli within macrophages is significantly impaired after 7 days. This slow antimycobacterial activity did not correlate with macrophage lysis but required cell contact. We also found that inhibitors of apoptosis either had no effect or augmented the CD8-mediated suppressive activity, suggesting that an activation signal might be involved. Indeed we show that CD8(+) T cells were able to activate macrophages through receptors that include CD95 (Fas). Consistent with these findings the CD8-mediated suppression of mycobacterial growth was partially reversed by Fas blockade. These data identify a previously unrecognized CD8(+) T cell-mediated mechanism used to control an intracellular infection of macrophages.

Cell Communication↗

PubMed2002

Protective immunity against Mycobacterium tuberculosis induced by dendritic cells pulsed with both CD8(+)- and CD4(+)-T-cell epitopes from antigen 85A.

Immunization with DNA followed by modified vaccinia virus Ankara strain, both expressing the antigen 85A, induced both CD4(+)- and CD8(+)-T-cell responses in BALB/c mice. Following challenge with Mycobacterium tuberculosis, this prime-boost regimen produced protection equivalent to that conferred by Mycobacterium bovis BCG. Following immunization with dendritic cells pulsed with an antigen 85A CD4(+)- or CD8(+)-restricted epitope, alone or in combination, copresentation of both epitopes on the same dendritic cell was required for protection, demonstrating that induced CD8(+) T cells can play a protective role against tuberculosis.

Acyltransferases↗

PubMed2002

Prime-boost immunization strategies for infectious diseases.

New vaccination strategies that induce the cellular arm of the immune response are needed for the development of effective prophylactic and therapeutic vaccines against a number of intracellular pathogens. DNA vaccines, recombinant viral vectors and recombinant proteins are all effective antigen delivery systems for inducing cellular immunity; however, when used alone, the levels of specific responses they induce are low. Prime-boost immunization strategies involve using two different vaccines, each encoding the same antigen, some weeks apart. Such strategies have been shown to enhance cellular immunity in several different animal and disease models.

AIDS Vaccines↗