Antibiotic multi-resistant (AMR) bacteria, that frequently inhabit the intestinal tract of humans and livestock, are a serious threat, either directly as opportunistic pathogens, or as a reservoir of antibiotic resistance genes. Novel antibiotics are challenging to develop to clinical application and an alternative solution is therefore urgently required.
Our recent work has demonstrated that vaccine-induced intestinal antibodies cannot kill bacteria per se, but they can dramatically decrease their ability of targeted bacteria to compete. Oral vaccination combined with precisely engineered "probiotic" competitors therefore has the potential to eliminate AMR-carrying species from the gut microbiota. Critically, the same antibodies also inhibit horizontal gene transfer, i.e. prevent the spread of antibiotic resistance between gut bacterial strains in the gut. Thus we expect vaccination to simultaneously decrease the frequency of AMR bacteria in the environment, and to slow the spread of remaining AMR genes between bacterial strains/species.
In this project we will test a vaccination/benign competitor protocol for targeted drug-free removal of an individual bacterial strain from the microbiota of mice. Subsequently, we will extend this protocol to domestic pigs, providing a solid framework for subsequent large-scale trials and extension to more diverse bacterial species and hosts.
What is special about the project?
This project brings together three novel concepts, namely inactivated oral vaccines, engineered benign competitor bacteria and our recent understanding of the function of intestinal antibodies. We hope that the elimination of AMR bacteria by these combined techniques will provide a potent alternative to antibiotic usage in livestock rearing and will buy valuable time for the development of next-generation antibiotics. Combining the expertise of mucosal immunologists (ETH Zürich), evolutionary microbiologists (ETH Zürich/Biozentrum Basel), biomathematicians (UPMC, Paris) and veterinarians (Agrovet, Zürich) allows us to develop these technologies in a highly systematic manner.
The first aim of this project was to establish proof-of-principle in mice. For this, we have optimized our inactivated oral vaccine protocol, and have developed a non-cross-reactive niche competitor for Samonella Typhimurium infections in mice. While vaccination alone is highly effective in driving the elimination of Salmonella Typhimurium from the mouse intestine, additional inclusion of a niche competitor that is not bound by vaccine-induced antibodies further increased the protection from invasive Salmonellosis and intestinal inflammation.
We have also begun phase I testing of our vaccines in domestic pigs and have carried out an exploratory study with 4 animals. These pigs consumed oral vaccine weekly between 4 and 16 weeks of age. They actively sought the vaccine and showed perfect health and normal growth as well as excellent organ and gut health at autopsy. We therefore conclude that the vaccines are safe and well tolerated in domestic pigs.
In the next phase of the project, we will quantify vaccine-induced immunity in pigs. Further, we will expand our vaccination and niche-competitor technologies to target multi-drug resistant enterotoxigenic E. coli strains, and will optimize the application strategies to permit clearance of endogenous microbiota strains as well as pathogens arriving from external sources.
Kathrin Moor, Médéric Diard, Mikael E. Sellin, Boas Felmy, Sandra Y. Wotzka, Albulena Toska, Erik Bakkeren, Markus Arnoldini, Florence Bansept, Alma Dal Co, Tom Völler, Andrea Minola, Blanca Fernandez-Rodriguez, Gloria Agatic, Sonia Barbieri, Luca Piccoli, Costanza Casiraghi, Davide Corti, Antonio Lanzavecchia, Roland R. Regoes, Claude Loverdo, Roman Stocker, Douglas R. Brumley*, Wolf-Dietrich Hardt*, Emma Slack*. High-avidity IgA protects the intestine by enchaining growing bacteria. Nature. 2017. 544(7651):498-502;
Médéric Diard, Erik Bakkeren, Jeffrey K. Cornuault, Kathrin Moor, Annika Hausmann, Mikael E. Sellin, Claude Loverdo, Abram Aertsen, Martin Ackermann, Marianne De Paepe, Emma Slack, Wolf- Dietrich Hardt. Inflammation boosts bacteriophage transfer between Salmonella. Science. 2017. Mar 17;355(6330):1211-1215;
Bansept F, Schumann-Moor K, Diard M, Hardt WD, Slack E, Loverdo C. Enchained growth and cluster dislocation: A possible mechanism for microbiota homeostasis. PLoS Comput Biol. 2019 May 3;15(5):e1006986. doi: 10.1371/journal.pcbi.1006986;
Herp S, Brugiroux S, Garzetti D, Ring D, Jochum LM, Beutler M, Eberl C, Hussain S, Walter S, Gerlach RG, Ruscheweyh HJ, Huson D, Sellin ME, Slack E, Hanson B, Loy A, Baines JF, Rausch P, Basic M, Bleich A, Berry D, Stecher B. Mucispirillum schaedleri Antagonizes Salmonella Virulence to Protect Mice against Colitis. Cell Host Microbe. 2019 May 8;25(5):681-694.e8. doi: 10.1016/j.chom.2019.03.004
Persons involved in the project
Dr. Emma Wetter-Slack
, project leader
Verena Lentsch, PhD student
Dr. Claude Loverdo; Collaborator
Prof. Médéric Diard, Collaborator
Dr. Aurore Woller, Postdoctoral researcher
Last update to this project presentation 07.08.2019