|
Principal areas of research
MVA85A Tuberculosis Vaccine (BCG booster vaccine).
Biography
Helen McShane obtained an intercalated BSc in 1988, and then a degree in medicine in 1991; both from the University of London. After junior hospital posts during which she obtained MRCP in 1994, she worked as a registrar in Infectious Diseases and HIV/GU medicine for 3 years. She then began a PhD with Adrian Hill in 1997, and was awarded a PhD in 2001, also from the University of London. In 2001 she was awarded a Wellcome Clinician Scientist Fellowship to establish a translational programme of vaccine research evaluating new TB vaccines in the clinic. This fellowship also allowed her to complete her clinical training and she was awarded a CCST in HIV and GU Medicine in 2003. In 2005, she was awarded a Wellcome Senior Clinical Fellowship, which she took up in 2006. Her research team continues with the programme of translational vaccinology, and is involved in developing new assays for monitoring vaccination induced cellular immune responses, developing a BCG challenge model in humans and the aerosol delivery of vaccines.
Research
There are 2 million deaths each year from TB, and 8 million new cases. In addition, it is estimated that 2 billion people are latently infected with TB, and are at risk of reactivation of that latent infection. The HIV epidemic is compounding the problem. The currently available vaccine, Mycobacterium bovis Bacille Calmette-Guerin (BCG), is largely ineffective at protecting against pulmonary disease and a more effective TB vaccine is a major global public health priority. However, as BCG does confer reliable protection against disseminated disease in childhood, it may be unethical and impractical to test and deploy a vaccine strategy that does not include BCG. An immunisation strategy that includes BCG is attractive because the populations in which a vaccine candidate will need to be tested will already have been immunised with BCG. The leading explanation for the failure of BCG to protect against TB disease in the developing world is that pre-existing exposure to environmental mycobacteria either masks the effects of subsequent vaccination with BCG or inhibits (blocks) the replication of BCG. It is important to determine the effects of exposure to environmental mycobacteria on any new candidate vaccine.
A new vaccine will need to induce the relevant arm of the host immune response. M.tb is an intracellular organism and protective immunity is entirely dependent on an intact cellular immune system. Th1-type, MHC class II-restricted CD4+ T cells are essential for protective immunity, and class I-restricted CD8+ T lymphocytes probably also have a role, perhaps in maintaining the latent state. When used in heterologous prime-boost strategies, recombinant pox viruses and recombinant adenoviral constructs are particularly good at boosting previously primed T cell responses. Incorporating BCG into such heterologous prime-boost regimes allows the beneficial protective effects of BCG to be retained. We have developed an immunisation strategy using BCG as the priming immunisation and a recombinant MVA (rMVA) expressing antigen 85A (MVA85A) as the boost. Antigen 85A forms part of the immunodominant antigen 85 complex and is an enzyme, mycolyl transferase, which is involved in cell wall biosynthesis. It has long been considered a leading choice of candidate antigen for use in a TB vaccine.
Since 2001, we have conducted a series of small scale clinical trials to evaluate the safety and immunogenicity of MVA85A. We found that MVA85A was safe and highly immunogenic in BCG naïve subjects, and significantly more immunogenic in BCG primed subjects. We have since shown that this vaccine is also safe and highly immunogenic in M.tb latently infected subjects. We have established collaborations with the MRC Laboratories in The Gambia and the University of Cape Town, in South Africa. MVA85A is now in clinical trials in infants in the Gambia and adolescents in South Africa.
In the UK we have been utilizing techniques in polychromatic flow cytometry to comprehensively characterize the vaccine induced immune responses and we find that the vaccine induces highly polyfunctional CD4+ T cells which are not terminally differentiated. We are also utilizing molecular methods and microarrays to characterize the vaccine induced immune responses. Clinically, we are also working on a BCG challenge model in humans which will aid the identification of immunological correlates of protection.
Key publications
Ibanga HB, Brookes RH, Hill PC, Owiafe PK, Fletcher HA, Lienhardt C, Hill AVS, Adegbola R, McShane H. Early clinical trials with a new tuberculosis vaccine, MVA85A, in tuberculosis endemic countries: issues in study design. The Lancet Infectious Diseases 2006; 6:522-28.
Williams A, Goonetilleke NP, McShane H, Griffiths K, Gilbert SC and Hill AVS. Boosting with Poxviruses Enhances BCG Efficacy against Tuberculosis in Guinea-Pigs. Infection & Immunity 2005. 73(6):3814-6.
McShane H, Pathan AA, Sander CR, Keating SM, Gilbert SC, Huygen K, Fletcher HA, Hill AVSH. Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG primed and naturally acquired anti-mycobacterial immunity in humans. Nature Medicine 2004. 10(11):1240-4.
McShane H, Pathan AA, Sander CR, Goonetilleke NP, Fletcher HA, Hill AVSH. Boosting BCG with MVA85A, the first candidate subunit vaccine for tuberculosis in clinical trials. Tuberculosis (Edinb). 2005;85(1-2):47-52. Epub 2005 Jan 21.
Goonetilleke N, McShane H, Hannan C, Anderson R, Brookes R, Hill AVSH. 2003. Enhanced immunogenicity and protective efficacy of the BCG vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus. J. Immunol 171: 1602-1609.
McShane H, Behboudi S, Goonetilleke N, Brookes R, Hill AVS. 2002. Protective immunity against M. tuberculosis induced by dendritic cells pulsed with both CD8+ and CD4+ T cell epitopes from antigen 85A. Infection & Immunity Mar;70(3):1623-6.
Back to main Investigators page
|
|
