Two-pronged immune response offers hope for effective Salmonella vaccine

Posted on Monday 25th January 2010

Research from the University of Birmingham has renewed hope that an effective vaccine could be developed against nontyphoidal strains of Salmonella. The findings suggest that the body's immune system could be primed to tackle even the most resilient of strains.

In developed countries, nontyphoidal Salmonella (NTS) strains are mainly food-borne and usually cause gastroenteritis. In rare cases, they can lead to bacteraemia (bacterial infections of the blood). However, in the developing world, bacteraemia is far more common and serious: fatality rates can be as high as almost one in four among children under two years old and HIV-infected adults.

The work carried out by the University of Birmingham, the University of Malawi College of Medicine and Liverpool School of Tropical Medicine is funded by the Wellcome Trust and GlaxoSmithKline and published today in Proceedings of the National Academy of Sciences.

In previous research led by Dr Calman MacLennan, scientists based at the Malawi-Liverpool-Wellcome Trust Clinical Research Programme (MLW) in Blantyre, Malawi , showed that disease-causing strains of NTS were able to survive outside cells in the blood of children. This survival mechanism enables the bacteria to replicate unchecked, possibly leading to high levels of mortality associated with bacteraemia.

Dr MacLennan and colleagues also identified protective Salmonella-specific antibodies that develop in African children within the first two years of life, the period in which the majority of NTS-related cases of bacteraemia occur. These particular antibodies recognise the bacteria in the blood and then kill the bacteria without the help of immune cells. It is possible that these antibodies develop in response to a relatively mild infection by NTS or similar bacteria. Young children who have yet to encounter these bacteria lack the antibodies and are at greatest risk from infection.

However, the Salmonella bacteria can evade the antibodies by hiding away within phagocytes, another group of cells involved in the body's immune reaction. Phagocytes ordinarily 'eat' invasive bacteria before destroying them, but the Salmonella bacteria have adapted to avoid being destroyed once inside the phagocytes.

In addition, some strains have become resistant to the killing effect of antibodies even when they are outside these cells. If the bacteria are not completely cleared from the body, then it is possible for infection to reoccur if a patient's immune system is compromised, for example through HIV infection.

"Nontyphoidal Salmonella is a very serious problem in Africa and we urgently need a vaccine," says Dr MacLennan. "Our previous work gave some hope that a vaccine could be developed that produces antibodies to protect against fatal Salmonella infections. But unless we can develop a vaccine that completely clears the body of bacteria, including resistant strains, such a vaccine could quickly become redundant."

Today, the researchers from the University of Malawi College of Medicine, Liverpool School of Tropical Medicine and the University of Birmingham, publish a study in the Proceedings of the National Academy of Sciences, which demonstrates a second way that the immune system uses antibodies to kill the bacteria. The results are encouraging for the prospects of developing a vaccine, suggesting that a vaccine against NTS could be more effective than previously thought.

The research, carried out by Miss Esther Gondwe, a Malawian PhD student at MLW in Dr MacLennan’s group, found that the bacteria could be tagged by the antibodies before being 'eaten' by the phagocytes. This made it more likely that the phagocytes would consume them, but would also flag them as unwanted guests, enabling the phagocytes to recognise and destroy them.

This two-pronged approach enables the immune system to kill Salmonella bacteria both within and outside of the blood cells, enabling the body to rid itself of the bacteria including strains that are resistant to killing outside of cells. It further highlights the role that antibodies play in protecting people from Salmonella infection.

"Antibodies clearly play a very important role in protecting people from Salmonella infection," says Dr MacLennan. "This makes even stronger the case for developing a vaccine which can stimulate antibody production. Such a vaccine could potentially save the lives of thousands of African children who would otherwise die."

Dr MacLennan and colleagues will now look for the most effective antibodies for attacking the bacteria in the blood and for activating phagocytes to kill. Finding the best antibodies will be key to developing a much-needed vaccine.

For more information:

Anna Mitchell, University of Birmingham Press Officer, 07920 593946

Notes for editors

1. Gondwe EN et al. Importance of antibody and complement for oxidative burst and killing of invasive nontyphoidal Salmonella by blood cells in Africans. Published online in advance in PNAS; 25 January 2010.

2. The University of Birmingham

The University of Birmingham is a truly vibrant, global community and an internationally-renowned institution. Its work brings people from across the world to Birmingham, including researchers and teachers and more than four thousand international students from nearly 150 different countries.

The University is home to nearly 30,000 students. With more than 7,500 postgraduate students from across the world, Birmingham is one of the most popular universities for postgraduate study in the UK.

The University has a global reputation and is ranked 66th in the world in the latest Times Higher Education–QS World University Rankings.

The University is the eighth largest employer in the Birmingham/Solihull sub-region and plays an integral role in the economic, social and cultural growth of local and regional communities; working closely with businesses and organisations, employing approximately 6,000 staff and providing 10,000 graduates annually.

The University contributes £662 million to the City of Birmingham and £779 million to the West Midlands region, with an annual income of more than £388.6 million.

3. The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending over £600 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing. http://www.wellcome.ac.uk  

4. The Malawi-Liverpool-Wellcome Trust Clinical Research Programme is based at the University of Malawi College of Medicine in Blantyre, Malawi, at its Wellcome Trust-funded research laboratories. These were opened on 22 January 1999, and are adjacent to the Queen Elizabeth Central Hospital. http://www.mlw.medcol.mw  

5. GlaxoSmithKline – one of the world’s leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer. http://www.gsk.com  

6. The Liverpool School of Tropical Medicine has been engaged in the fight against infectious, debilitating and disabling diseases for more than a hundred years and continues that tradition today with a research portfolio in excess of £140 million and a teaching programme attracting students from over 70 countries. http://www.lstmliverpool.ac.uk