Theme 1: From bench to bedside (and back)

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Overview

Overview

From bench to bedside (and back) research is centered largely on clinical trials, many conducted through the York Clinical Research Facility (our joint venture with York Hospital), and in association with the Vaccine Institute, St George's London.

Funded by the Bill and Melinda Gates Foundation, the Wellcome Trust, the European Commission and the NIH, we conduct phase 1 trials of mucosal vaccines and microbicides against HIV-1 (Phase I trial to start in 2014), with a focus on finding safe, effective and easily accessible interventions for women in developing countries. 

Other genital tract infections investigated in human volunteers include Chlamydia and HPV (HPV vaccine trial started in 2014). 

A first-in-man trial of a new therapeutic vaccine for visceral leishmaniasis started in 2013, funded by a Wellcome Trust Translation Award.

Projects

Projects

From bench to bedside (and back) research

The year 2011 marks 30 years of AIDS. In that time, AIDS has claimed more than 25 million lives and more than 60 million people have become infected with HIV. Still, each day, more than 7,000 people are newly infected with the virus, including 1,000 children. No country has escaped the devastation of this truly global epidemic. Nevertheless, HIV programmes are now bearing fruit, with global HIV incidence declining, treatment access expanding and an unparalleled global movement mobilized to demand respect for the dignity and human rights of everyone vulnerable to, and affected by, HIV. The next stage in control of this global pandemic is to continue to strive towards the elimination of new infections.

Professor Charles Lacey's group conducts phase 1 clinical trials of vaccines and microbicides against HIV-1. The group has collaborators worldwide and is funded by awards from the Bill and Melinda Gates Foundation, the Wellcome Trust, and the European Commission. The focus of the group is directed towards finding safe, effective and easily accessible preventative interventions against HIV-1 for women in developing countries. We have just completed two phase 1 trials: a novel HIV vaginal vaccine utilising CN54gp140, in conjunction with the Vaccine Institute, St George's, University of London, as part of a Gates Grand Challenges award; and a microbicide trial (MABGEL1) of monoclonal anti-HIV antibodies C2F5, C2G12 and C4E10, both in vaginal gel formulations. We are also taking part in a multicentre trial examining the efficacy of switching to boosted protease inhibitor monotherapy versus continuing combination antiretroviral therapy for the long-term management of HIV-1 infected patients (PIVOT trial). A substudy examining whether this antiviral therapy suppresses viral load in the genital and rectal tracts in these patients, is being led by the Lacey group.

The group has a number of other projects investigating genital tract immunology, including aspects of Chlamydia immunopathogenesis and genetic diversity. Internal collaborations include the development of therapeutic CD8+ T cell-biased vaccines for visceral leishmaniasis with the Kaye groups in the CII, and investigations to determine whether an IgG transporter system, FcRn, is expressed and functional in the female genital tract.

Links:

York Clinical Research Facility (CRF)

Europrise - microbiocides and vaccines

Mucosal HIV Vaccine Project (MUCOVAC)

European Microbiocides Project (EMPRO)

Combined Highly Active Anti-Retroviral Microbiocides project (CHAARM)


Leishmaniasis

Leishmaniasis affects approximately 15m people in 88 countries, results in approximately 100,000 deaths annually, and has a significant impact on health in developing countries. In southern Europe and countries bordering the Mediterranean, leishmaniasis is a major opportunist infection in HIV-infected individuals. Research on leishmaniasis in the Centre is wide ranging and multidisciplinary, including molecular, biochemical and immunological studies.

Research on the immunology of leishmaniasis focuses on disease caused following infection with visceralising species of Leishmania (L. donovani and L. infantum), though comparative research using parasites that cause other forms of disease (cutaneous, mucocutaneous) are also conducted. We have developed novel transgenic lines of Leishmania, that express fluorescent or biophotonic (luciferase) reporter genes and / or defined reporter antigens. These parasites allow us to monitor disease progression non-invasively and by stereo-, confocal and 2-photon microscopy, and to monitor host T cell responses and antigen presenting cell function using TCR transgenic model systems. A major area of research interest is in understanding how immune-mediated pathology contributes to immune-suppression associated with visceral leishmaniasis. Capitalising on the availability of comparative genome sequence data for the major species of Leishmania, we are generating targeted mutant lines to identify survival and virulence factors. Our immunological research into visceral leishmaniasis is funded by Programme Grants from the MRC and the Wellcome Trust. Our vaccine research programme is focused on the development of therapeutic CD8+ T cell-biased vaccines for visceral leishmnaiasis. Funding to develop this work to a first-in- man study in UK volunteers has recently been awarded by the Wellcome Trust.


HTLV-1 Mucosal studies

Human T lymphotropic virus type 1 (HTLV-1) was the first human retrovirus discovered. HTLV-1 is an oncovirus that causes an aggressive leukaemia/lymphoma, termed adult T cell lymphoma/leukaemia (ATLL) in 4% of carriers, and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in 3%. HTLV -1 infection is a nationally and internationally neglected disease for which there is no vaccine or cure. For ATLL, despite aggressive treatment, the mean survival time after diagnosis is only 8 months. HAM/TSP progresses relentlessly, with 50% wheelchair dependence after 18 years and in rapid progressors, the condition is fatal within months.

An estimated 20 000 people in the UK and 10-20 million worldwide are infected with the virus which is endemic in the West Indies, south-western Japan, South America, many African countries, Melanesia, Iran and Romania. Perhaps because of the relative infrequency of disease in Europe and USA, HTLV-1 has been the Cinderella of the retrovirus family, with comparatively little investment or interest. However every year 20 patients are diagnosed with ATLL in the UK alone and 41% of newly diagnosed HTLV-1 infections in the UK were also acquired here. Although it is transmitted via breastfeeding, unprotected sexual intercourse, contaminated blood products and needles, it seems that sexual transmission is the most common mode worldwide. In addition, the sexual transmission of HTLV-1 seems to be much more efficient than breast feeding, and more so from male to female partners. 

Although HTLV-1 can infect many human cells in vitro, it seems to preferentially target CD4+ T cells. However, cell-free HTLV-1 virions infect CD4+ T cells inefficiently in vivo and in vitro , and cell-free blood products of HTLV-1 positive patients are not infectious. The main route of viral entry into uninfected CD4+ T cells is subject to debate. Viral entry receptors used by HTLV-1 include the glucose transporter Glut1, heparin sulphate proteoglycans and neuropillin-1. The formation of tight junctions between infected and non-infected CD4+ T cells, the active orientation of the microtublar cytoskeleton of the infected T cells towards the junction site , and the shuttling of HTLV-1 viral products to the inter-cellular junction have all led to the concept of direct transmission via the ‘virological synapse’ .  Recently, however, the observation of HTLV-1 virions embedded in a carbohydrate containing matrix on the surface of infected cells,  as a ‘biofilm’ has suggested that cell-cell transmission may still involve a phase where the virions are extracelluar during transmission. Furthermore, dentritic cells, which home in the mucosal epithelium in vivo, have been successfully infected by cell-free HTLV-1 virions and able to infect CD4+ T cells in vitro. These data suggest an alternative pathway for mucosal acquisition of HTLV-1 through seminal fluid. Partially explaining effective sexual transmission, in vitro studies have demonstrated that proteins and enzymes in seminal fluid can enhance HTLV-1 expression and replication.

At the Centre for Immunology and Infection (CII), we are setting up the first comprehensive experimental program for anti-HTLV-1 microbicide/pre exposure prophylaxis/vaccine development and testing, with the aim to rapidly and effectively translate the outcome of research using pre-clinical models into Phase1/2 trials in healthy volunteers. We are currently working with organotypic human explant models aiming to prevent HTLV-1 transmission at the mucosal level and detecting early intracellular biomarkers of cell- to- cell infection.

We are working in collaboration with Dr G.P. Taylor at Imperial College, London.
http://www.htlv1.eu/contacts.html

As members of the International Retrovirology Association’s HAM/TSP Clinical Trial Subgroup we are currently designing a multicentre, international, randomised, double blind, placebo controlled clinical trial in patients with slow progressing HAM/TSP which will take place in Brazil, Japan, UK and USA.
http://htlv.net/ 

Featured publication

Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial Sheena McCormack*, David T Dunn*, Monica Desai, David I Dolling, Mitzy Gafos, Richard Gilson, Ann K Sullivan, Amanda Clarke, Iain Reeves, Gabriel Schembri, Nicola Mackie, Christine Bowman, Charles J Lacey, Vanessa Apea, Michael Brady, Julie Fox, Stephen Taylor, Simone Antonucci, Saye H Khoo, James Rooney, Anthony Nardone, Martin Fisher, Alan McOwan, Andrew N Phillips, Anne M Johnson, Brian Gazzard, Owen N Gill. Lancet 2015 Sep 9.

Research at CII