New vaccine concept tackles harmful bacteria in the intestine

The issue of intestinal bacteria is a complex one. On the one hand, we are dependent on the microorganisms because they are the ones that digest the food in our intestine. On the other hand, there are also numerous pathogens present among the bacteria. Some of these pathogens can cause diarrhoea, while with others it depends on the circumstances: they can live unnoticed in the intestine for a long time, but they become dangerous if the immune system is weakened, the intestinal wall is damaged, or they enter the blood via wounds. This can lead to blood poisoning or life-threatening inflammation of organs.

For a long time, scientists have been investigating vaccines against pathogenic microbes in the intestine – particularly those that antibiotics have become ineffective against due to resistance. This is no simple task, however, because the immune system of the intestine works differently from that of the rest of the body and science is yet to fully decipher the intestinal immune system.

An effective combination

Emma Slack, a professor at ETH Zurich and the University of Oxford’s Sir William Dunn School of Pathology, is carrying out research in this area. Together with Médéric Diard, a professor at the Biozentrum of the University of Basel, and an international team of researchers, she has now demonstrated how highly effective oral vaccinations can be formulated against intestinal pathogens: namely, by not only administering the vaccine but also combining it with harmless bacteria that compete with the pathogenic microbes for food and therefore starve them out. The researchers demonstrated this in a study on mice that they have published in the journal Science.

With their combined approach, the researchers were able not only to prevent colonisation with salmonella in the mice but also to effectively tackle already-established E. coli bacteria. In both cases, vaccination or the harmless bacteria alone had a significantly smaller impact.

In order for the rival strains to successfully compete with the pathogenic microbes, it is vital that they grow under conditions that are as similar as possible, i.e. they must live in the same section of intestine, be able to cope with the same acidity and oxygen level, and use the same nutrients.

The researchers chose or produced suitable competitor strains accordingly. Within the framework of the study, they demonstrated in the laboratory that it is possible to produce a highly effective salmonella-competitor strain with the help of genetic engineering. However, this can also be done without genetic engineering if naturally occurring strains are skilfully selected and combined, as the researchers demonstrated with a mixture of three naturally occurring strains of E. coli.

“Like gardening”

“Although we can decimate pathogenic bacteria with a vaccine, we need harmless microorganisms to fill the resulting niche in the intestinal ecosystem in order to achieve long-term success,” explains Slack. “It’s like gardening. If you want to avoid weeds in an area of the garden, you have to plant other plants there after weeding. If you leave the soil empty, the weeds will just grow back.”

As earlier studies have shown, some people’s intestinal flora naturally includes bacterial strains that compete with pathogenic bacteria and therefore keep them in check. In these individuals, vaccinations against intestinal pathogens have already worked well in the past. By administering the competitor strains with the vaccination as part of the new approach, it may be possible to achieve effective protection even in people who don’t have competitor strains of this kind.

Reducing antibiotic use

One major advantage of the new approach is that it displaces pathogenic bacteria without the need for antibiotics. It is also effective against antibiotic-resistant germs, which are becoming an increasing health problem.

With the new approach, pathogenic or even antibiotic-resistant bacteria could be eliminated in patients’ intestines prior to surgical interventions. This would be particularly important in the case of organ transplantations, for example, in which patients have to take immunosuppressant medications. The researchers emphasise that this would pave the way for a reduction in the use of antibiotics.

This approach could also be useful before trips to distant countries where there are bacterial strains circulating that the immune system is not prepared for. “In general, the more successful we are in decimating harmful and antibiotic-resistant strains in the population, the better it is for the health of everyone,” says Slack.

One day, people may be able to swallow a capsule that contains the vaccine and the competitor bacteria, for example. However, further research is needed before this approach can be applied in humans. In the current study, the scientists used model pathogens to demonstrate that it was possible to displace them from the intestine. Now, the big task facing the researchers is to apply their findings to clinically relevant microbial strains – as well as to people.

This research was made possible by financial support from the external page Basel Research Centre for Child Health and the National Centre of Competence in Research (NCCR) external page “Microbiomes” of the Swiss National Science Foundation, as well as a Consolidator Grant from the European Research Council (ERC) to Emma Slack.