From AIDS to TB vaccines — A career in infectious diseases and translational vaccinology

My path toward becoming a Scientific Investigator probably began in my South London Comprehensive, following the advice of a negative maths teacher, who was of the view that I should be a housewife! This comment was like a red rag to a bull and was the final incentive I needed to work hard and get to Medical School. Ironically this was probably the best bit of career advice anyone has given me!

Most of my medical career I believed that I was going to be a GP, spending 6 months in general practice and then realizing that it wasn't the right career for me. I did a U-turn and went back to hospital medicine and from there I went in to infectious diseases. I often get asked the question ‘if you weren't a scientist what would you be?’ and I would reply a doctor! I am fortunate enough to be able to do both.

As a junior doctor I worked in Brighton at the beginning of the AIDS epidemic in this country and this is when I became interested in HIV and infectious diseases. At that time we had no drugs to treat HIV, and all of my patients were dying of late stage AIDS. This was a very eye-opening experience and a fascinating combination of interesting medicine and palliative care. It also allowed me to see first-hand the devastating effects of untreated infectious diseases. My quest to gain further knowledge and experience in HIV and infectious diseases, lead me from Brighton, to Oxford and then to London.

It was in London, when I was learning to do bronchoscopies on patients, that I became interested in TB and decided I wanted to do some basic research in this area. I came to talk to Prof. Adrian Hill in Oxford, who had established a big program of research in malaria vaccine development, and I persuaded him to let me start working on TB vaccine development in parallel. I have since led the TB vaccine research group at Oxford University for 14 years.

The geographical overlap between the TB and the HIV epidemic has really had a devastating impact, particularly in sub-Saharan Africa. We know that people who are infected with HIV have a 10% annual risk of reactivating their latent M. tuberculosis infection, compared with people who are HIV negative who have a 10% lifetime risk. In addition we know that people who are HIV-infected are significantly more likely to become infected with M. tuberculosis. Furthermore we know that people who are infected with HIV who then develop TB disease can get an acceleration of their HIV disease so these 2 pathogens really do have a devastating synergy.

TB remains a very significant cause of disease and death throughout the world – worldwide, TB is second only to HIV as the greatest global infectious killer; in 2013, 9 million people were infected with TB and 1.5 million died from the disease. The emergence of drug resistance makes it harder to treat this disease and co-infection with HIV increases susceptibility. There is an urgent need for better control measures, and the most cost-effective way to control any infectious disease epidemic is with effective vaccination. In my group in Oxford, we developed the first new TB vaccine to enter into clinical testing, the first to be tested in latently infected subjects, the first vaccine to enter into human efficacy testing and now the first to be delivered by aerosol in humans.

Since 2002, we have run a series of UK clinical trials to investigate the safety and immunogenicity of candidate TB vaccines, including MVA85A (recombinant modified vaccinia Ankara expressing antigen 85A) and ChAdOx1 85A (chimp adenovirus expressing antigen 85A) (both developed at the Jenner), and a number of industry partners' vaccines. MVA85A and ChAdOx1 85A are used as boost vaccines for BCG-primed subjects; heterologous prime-boost vaccination regimens provide an effective way to induce high levels of cellular immunity, while the inclusion of BCG in a new regimen allows the retention of the protective effects of BCG in childhood against severe disease. Both vaccines have been shown to be safe and immunogenic in healthy adult volunteers (e.g. ref. 1). MVA85A has been further studied in M. tuberculosis latently infected individuals, and HIV-infected individuals, and the vaccine is safe and immunogenic in these groups.^2,3

As a result of our successful UK trials, we have been working closely with African collaborators to run clinical trials of MVA85A in target populations in Africa. Successful healthy-adult studies in South Africa, in collaboration with SATVI, were followed by age de-escalation studies that demonstrated safety in children and infants,⁴ while a trial in The Gambia, with the MRC Laboratories, Fajara, showed that co-administration of MVA85A and routine EPI vaccinations did not result in interference of the EPI vaccines.⁵ In Senegal, with CHU Le Dantec, Dakar, MVA85A vaccination of HIV-infected adults on and off antiretroviral therapy (ART) demonstrated that subjects on ART had higher responses than ART-naïve subjects, but that responses were comparable after a second dose of MVA85A 6–12 months later.⁶ An ongoing trial in Uganda with the UVRI, Entebbe, is investigating the effect of helminth infection on vaccine immunogenicity.

A current area of interest to our group is whether delivering a TB vaccine via the aerosol route (through nebulisation directly into the lungs) is a more effective method of vaccination. There is some evidence from mouse models to suggest that the best, most protective way of giving a TB vaccine is to deliver the vaccine directly into the lungs. To do this the vaccine is administered using an aerosol. This is something that is generating a lot of interest in the field - since TB enters the body through the lungs this delivery method makes intuitive sense. In the last few years we have started clinical trials investigating aerosol delivery of MVA85A and have shown this route to be both safe and immunogenic. We have just published results from a Phase I clinical trial comparing the safety and immunogenicity of the MV85A vaccine, delivered either by a needle or an aerosol, in individuals who had previously been vaccinated with BCG.⁷ This was a very successful study as it showed that the aerosol delivery was safe and also generated stronger immune responses in the lungs than the conventional delivery of the vaccine using a needle. As well as stimulating superior immune responses in the lungs, the aerosol delivery method also had comparable, if not trending toward higher, immune responses in the blood than the needle delivery method. We are now running a second trial to look at whether you can give repeated doses of the vaccine using different routes of immunisation.

MVA85A was the first new TB candidate vaccine to reach efficacy trial since BCG over 100 years ago. The first efficacy trial, from 2009–2012, in collaboration with SATVI and supported by Aeras and the Wellcome Trust, enrolled 2797 South African infants who were randomized to receive BCG alone at birth or BCG followed by MVA85A boost at 4–6 months of age. MVA85A vaccination was safe but did not improve upon BCG-induced protection.⁸ A second double-blind, placebo-controlled, randomized efficacy trial has taken place in South Africa and Senegal in HIV-infected adults, with the collaboration of UCT and CHU Le Dantec and support from Aeras and EDCTP. This trial started in 2011 and the 650 adults completed follow up in late 2014.⁹

In terms of major career achievements, developing the first new TB vaccine to enter clinical testing and the first vaccine to enter efficacy testing is extremely high up there. Being awarded a Wellcome Senior Clinical Research Fellowship in 2005 is also a notable success for me, especially because during my first Wellcome Senior Clinical Research Fellowship I had my third child! I was elated, when my Fellowship was then renewed in 2011.

Being a mother to 3 wonderful children is a personal highlight and managing to balance motherhood alongside my career has been challenging, but I believe that it has made me a more tolerant, determined and focused investigator. My work and travel schedule is packed, especially having such well-established partnerships outside of the UK. But you learn to be creative and we've even made family holidays around my work trips so my children have all been to Senegal, The Gambia and South Africa! Research is a lot more flexible than clinical work and this allows me to “Box and Cox” my time accordingly, e.g., attending a school play in the afternoon and catching up on emails in the evening.

Managing my TB group is often like an extension of motherhood. You have these bright, young researchers and clinicians who you want to nurture and help succeed in their careers. Mentoring is one of the aspects of being a Principal Investigator that I love and I have supervised 18 PhD students, co-supervised 4 MSc students and am an Academic Foundation Programme Lead to oversee young academic clinicians in training.

I actively try to inspire budding scientists by giving public engagement talks to schools and encouraging work experience within my TB group. However, on reflection, maybe all a child needs is that ‘negative maths teacher’, in order to inspire them to strive to reach their goals.

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Helen McShane

About Helen McShane. Prof. McShane has extensive experience in TB immunology and vaccinology. She is currently a Professor of Vaccinology at Oxford University, Wellcome Senior Clinical Research Fellow, Honorary Consultant physician in HIV medicine and an Academic Foundation Programme Lead. She also chairs the TuBerculosis Vaccine Initiative Advisory Committee. Prof. McShane obtained an intercalated BSc in 1988, followed by a degree in medicine in 1991 (both University of London). In 1997 she was awarded an MRC Clinical Training Fellowship to undertake a PhD with Adrian Hill in Oxford, and was later awarded a PhD in 2001 (University of London). In 2001 she received a Wellcome Clinician Scientist Fellowship, allowing her to complete her clinical training and subsequently awarded a CCST in HIV and GU Medicine in 2003. In 2005, she was awarded a Wellcome Senior Clinical Research Fellowship; this Fellowship was renewed in 2011. Helen has led the TB vaccine research group at Oxford University for 14 y and notably headed the development of MVA85A, one of the most clinically advanced new TB vaccine candidates and the first to enter human efficacy testing. She collaborates with several research groups in Africa in the conduct of clinical trials. Her current interests are in immunomonitoring in clinical trials, the development of human mycobacterial challenge models and aerosol delivery of vaccines. Helen chairs the Wellcome Trust Clinical Interview Committee and sits on the Wellcome Trust Translational Fund committee. She is a member of the GLOBVAC board for the Norwegian Research Council. Helen has published over 100 peer-reviewed publications and has an H-index of 39.