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TB Vaccine Development Impact Objectives • Work towards developing an effective vaccine against tuberculosis (TB) • Confirm the safety and immunogenicity of delivering the MVA85A vaccine by aerosol direct to the respiratory mucosa • Ultimately produce an effective, safe and accessible vaccine for the global prevention of TB Overcoming the challenges of tuberculosis (TB) vaccine development Clinician and Professor of Vaccinology at the University of Oxford in the UK, Helen McShane is using her 26 years of expertise to lead a research team in their quest to develop, assess and apply a new TB vaccine Could you give Could you expand on your own previous significantly less immunogenic in South a brief overview work into the effectiveness of the BCG African infants than it had been in UK adults. of TB in terms vaccination and the work you have led of prevalence developing a booster vaccine? Despite these results, we have learnt a huge of the disease amount from the conduct of this trial, and today, current In 2002, we started a clinical trial programme nine additional papers have been published treatments and with MVA85A, the first subunit vaccine from the data arising from this trial. We their effectiveness, and any drawbacks? candidate TB vaccine to be tested in clinical have gained important insights into immune trials. This vaccine was designed to boost the correlates of risk of TB disease from samples Tuberculosis kills more people today than any effects of BCG. After a careful programme of taken during this trial, how to diagnose other infectious pathogen. The emergence trials in the UK, including testing this vaccine TB in infants, and the role of Quantiferon of multi and extensively drug-resistant in M tb latently infected people, we then testing in infants exposed to TB. strains of Mycobacterium tuberculosis began trials in The Gambia and South Africa. (M tb) makes this problem worse. The World All these trials showed the vaccine to be safe Is your work into MVA85A ongoing and if Health Organization (WHO) has described and well tolerated, and to induce a strong cell so what stage is the project at? extensively drug-resistant TB as virtually mediated immune response – the immune untreatable. People with HIV are more likely response considered important for protection Yes. Since our efficacy trial result in 2013, to get TB and the geographical overlap against TB. In 2009, we started a phase IIb we have been pursuing three independent between the HIV and TB epidemics has efficacy trial in 2797 BCG-vaccinated South ways to improve MVA85A. First, to combine further contributed to this global epidemic. African infants, in collaboration with the it with another viral vector called ChAdOx1 It is also estimated that 25 per cent of the South African TB Vaccine Initiative (SATVI), expressing the same antigen; second to global population are latently infected with M Aeras and Emergent BioSolutions. The evaluate the effect of delivering MVA85A by tb, and these people are at risk of reactivation aim of this trial was to see whether infants aerosol direct to the respiratory mucosa, of this latent infection if they become that received MVA85A, as a boost to BCG, and third, to identify novel protective immunosuppressed for any reason. There are were more protected than infants who only antigens. The overarching aim of this work many causes of immunosuppression from the received BCG. is to put these three strategies together immune senescence that happens with old and develop a novel vaccination regimen age, cancer chemotherapy, and some of the In 2013, 10 working days after we first that includes several antigens from TB and new biological treatments for autoimmune received the results of this trial, we published involves two different vaccinations, one of diseases. However, globally the commonest the data in The Lancet. In this trial, we found which is likely delivered by aerosol. At the cause of immunosuppression is co-infection that MVA85A was safe, confirming results moment these three different strategies are with HIV. Even in an era of antiretroviral of the previous trials. However, we also being evaluated in my lab and in trials in therapy and effective treatment for HIV, people found that it did not improve efficacy over the UK. The next step will be to test some of with well-controlled HIV are still more likely to BCG alone. This disappointing result may these ideas in trials with my collaborators get TB than their HIV-uninfected counterparts. have been in part because the vaccine was in South Africa and Uganda. www.impact.pub 85 From bench to bedside Through clinical trials, Professor Helen McShane and her team are continuing to translate their research from bench to high burden tuberculosis (TB) countries with the goal of providing the global population with an effective and safe TB vaccine Tuberculosis (TB) remains one of the major ‘Most of the burden of disease is lung Through her research, McShane is interested causes of death and disease worldwide. With disease and BCG does not work well in the strong link between HIV and TB. In one third of the global population infected against lung disease in most of the world.’ geographical areas such as Sub-Saharan with Mycobacterium tuberculosis (M tb) and Additionally, giving patients BCG boosters, Africa, the two diseases overlap tremendously. over one million deaths annually from the or numerous injections, does not increase Due to HIV’s immunosuppression, HIV- disease, there is an urgent need to develop protection against TB. infected patients have a far higher likelihood an effective vaccine. Leading the charge on of contracting TB than healthy individuals. As TB vaccination development is Professor Due to BCG’s inconsistent success against McShane describes it: ‘these two pathogens Helen McShane at Oxford University’s pulmonary diseases and its inability to really do have a devastating synergy.’ Nuffield Department of Medicine in the protect patients long term in most settings, UK. Since 2001, McShane has directed the the development of a new vaccine is To address the inadequate global control of TB vaccine research group with a goal of paramount. McShane’s translational research HIV and TB, McShane and her team have developing and evaluating new TB vaccine aims to move data from the laboratory to developed several new vaccines, the first of candidates. In doing so, McShane has the clinic, thus providing countries with a TB which is called Modified Vaccinia Ankara conducted a series of clinical trials in the UK vaccine that is safe, affordable and effective. virus expressing antigen 85A (MVA85A). and high burden TB countries including The MVA85A was developed as a BCG boost to Gambia, South Africa, Senegal and Uganda. DEVELOPING A NEW VACCINE improve BCG-induced protection against TB McShane’s passion for TB grew from a deep bacteria. Any new vaccine regimen needs to Currently, TB vaccination is limited. For the interest in HIV treatment. With a background undergo extensive testing. Once found to be past 100 years, Bacille Calmette-Guerin (BCG) in clinical medicine, she treated patients effective, a new regimen will be licensed and has been the only licensed vaccine available during the beginning of the HIV epidemic in made available to the public. to the public. BCG is routinely given to the UK. Although this experience was a tragic infants in order to protect against TB during one, it provided McShane with: ‘experience THE LONG ROAD OF CLINICAL TRIALS the first 10 years of life and is effective in of a fascinating mix of interesting and rare The first efficacy trial for MVA85A was preventing the disease in areas outside of opportunistic infections and palliative care conducted by McShane’s group from 2009 the lungs. However, as McShane explains: medicine,’ she explains. to 2012 in collaboration with the South 86 www.impact.pub It is critical that new TB vaccines are tested in the populations where such vaccines will ultimately be deployed Project Insights and that when an effective vaccine is developed, it is made FUNDING Professor Helen McShane’s research available at an affordable price to these populations programme has been funded by: the Wellcome Trust; Aeras; The Bill and Melinda Gates Foundation; The European Commission; and The European and Africa TB Vaccine Initiative (SATVI). In a lavage cell samples, which are used to predict Developing Countries Clinical Trial double-blind, randomised, placebo-controlled immune responses in the lungs. Participants Partnership. study, McShane and her team enrolled 2797 who received aerosol MVA85A had a higher healthy South African infants aged four to response in important immune-helper cells COLLABORATORS six months. All of the infants had received called Ag85A-specific CD4 T cells. CD8 T cells, The South African TB Vaccine Initiative • BCG within seven days of birth and were which are thought to help with the defense MRC Unit – Entebbe, Uganda • MRC Unit – Fajara, The Gambia • Mboup Group, Chu then randomly split into two groups, with against TB, were expressed equally in both Le Dantec – Dakar, Senegal • Lewinsohn 1399 allocated to the MVA85A booster and the aerosol and intradermal groups. Group – OHSU, Portland, Oregon • 1398 allocated to a placebo. Although well Fletcher Group – LSHTM, UK • Dockrell tolerated by the infants, results indicated that MORE QUESTIONS TO ANSWER Group – LSHTM, UK • Ottenhoff Group – MVA85A did not boost the infants’ BCG- McShane’s work in developing improved TB LUMC, Netherlands induced TB protection as expected. prevention does not stop there. Questions regarding the protective immune response, CONTACT Professor Helen McShane However, it is important to note that the the development of an effective vaccine and Professor of Vaccinology, majority of TB transmission does not occur the use of such a vaccine in HIV-infected University of Oxford through infants, but adults.
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