Breakthrough aerosol human infection model gives hope for future tuberculosis vaccine development

15 April 2024

University of Oxford researchers have for the first time established a controlled human infection model for tuberculosis (TB) that infects people via the lungs – the way TB enters the body.

The clinical trial, which used the BCG vaccine delivered via aerosol into participants’ lungs, is a first step towards establishing a challenge model that can be used to test new TB vaccines.

Human challenge models have contributed significantly to the development of vaccines for diseases such as malaria or typhoid, especially in early-phase trials. They help scientists select which vaccines should be taken forward into larger field efficacy studies and could be particularly useful with pathogens like tuberculosis, where vaccine development is very difficult.

Unlike malaria and typhoid, where participants were given the virulent form of the disease, it would not be ethical to give people tuberculosis; while there are effective treatments for malaria and typhoid, no such quick, effective treatment exists for tuberculosis and there is no way of knowing for certain that a person has been cured.

The BCG vaccine was used in this trial because it is a live attenuated strain of Mycobacterium bovis – which is related to Mycobacterium tuberculosis, the bacterium which causes tuberculosis in humans – and BCG is known to be safe in humans.

Previous human challenge studies had administered the BCG in the arm, but this method does not mimic the natural route of TB infection into the lungs, which is why the aerosol method was investigated.

The research team recruited healthy people who had never before had the BCG vaccine. They were given BCG by aerosol using a nebuliser into the lungs, and a control group had BCG injected in the arm.

As this was the first time this approach had been used, the researchers gradually increased the dose to ensure it was safe and found the highest dose that did not induce troublesome side effects. They then compared how much BCG could be recovered after administering it in the lungs and through the skin.

The doses of aerosol-inhaled BCG were found to be well tolerated by the participants and there was no significant difference in the frequency of adverse events between the two groups.

Professor Helen McShane, Professor of Vaccinology in the Nuffield Department of Medicine, who led the study, said: “When we did lung washes of the participants, we recovered BCG, which is a positive sign in a challenge study. When we eventually test a new vaccine using this method, if we can’t find BCG in the lung washings it would suggest that the vaccine has induced protection. If we hadn’t found BCG in the lung fluid, we would not have been able to move forward with this as a model.”

Professor McShane, who is Director of the NIHR Oxford BRC added: “TB is back as the number one killer among infectious diseases. It’s a really difficult pathogen to make a vaccine for, and human challenge models, such as the one we have trialled in this study will undoubtedly play a vital part in helping us to develop a vaccine. For this reason, this is an important first step in establishing that model.”

Earlier this year, Professor McShane launched another study looking at BCG given by aerosol as a vaccine, rather than a challenge agent, and comparing inhalation to vaccination administered through the skin.

The study, whose findings have been published in The Lancet Infectious Diseases, was supported by the Bill and Melinda Gates Foundation and the National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC).

Notes for Editors

  1. For media queries or to schedule interviews please contact Dr Adriaan Louis Taljaard, Manager Strategic Communications (Vaccines), Oxford University: [email protected]
  2. The paper ‘Safety of a controlled human infection model of tuberculosis with aerosolised, live-attenuated Mycobacterium bovis BCG versus intradermal BCG in BCG-naive adults in the UK: a dose-escalation, randomised, controlled, phase 1 trial’ can be accessed at (using the link at the top of the margin on the first page)
  3. The National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre (BRC) is based at the Oxford University Hospitals NHS Foundation Trust and run in partnership with the University of Oxford.

The mission of the National Institute for Health and Care Research (NIHR) is to improve the health and wealth of the nation through research. We do this by:

  • funding high quality, timely research that benefits the NHS, public health and social care;
  • investing in world-class expertise, facilities and a skilled delivery workforce to translate discoveries into improved treatments and services;
  • partnering with patients, service users, carers and communities, improving the relevance, quality and impact of our research;
  • attracting, training and supporting the best researchers to tackle complex health and social care challenges;
  • collaborating with other public funders, charities and industry to help shape a cohesive and globally competitive research system;
  • funding applied global health research and training to meet the needs of the poorest people in low- and middle-income countries.

NIHR is funded by the Department of Health and Social Care. Its work in low- and middle-income countries is principally funded through UK Aid from the UK government.

About the University of Oxford
Oxford University has been placed number 1 in the Times Higher Education World University Rankings for the eighth year running, and number 3 in the QS World Rankings 2024. At the heart of this success are the twin-pillars of our ground-breaking research and innovation and our distinctive educational offer.
Oxford is world-famous for research and teaching excellence and home to some of the most talented people from across the globe. Our work helps the lives of millions, solving real-world problems through a huge network of partnerships and collaborations. The breadth and interdisciplinary nature of our research alongside our personalised approach to teaching sparks imaginative and inventive insights and solutions.
Through its research commercialisation arm, Oxford University Innovation, Oxford is the highest university patent filer in the UK and is ranked first in the UK for university spinouts, having created more than 300 new companies since 1988. Over a third of these companies have been created in the past five years. The university is a catalyst for prosperity in Oxfordshire and the United Kingdom, contributing £15.7 billion to the UK economy in 2018/19, and supports more than 28,000 full time jobs.