Developing Vaccines Against E. coli

No one’s in any hurry to talk about diarrhea. But maybe we should be, since as Dr. Weiping Zhang, professor of microbiology at Kansas State University’s College of Veterinary Medicine points out, diarrhea is a leading cause of death in children under 5 years of age. In particular, enterotoxigenic E. coli, or ETEC, causes a significant portion of childhood diarrhea. Dr. Zhang is talking about it because he recently received his third grant in three years to develop a vaccine against E. coli–related diarrhea in both humans and animals.

This five-year, $2.1 million grant from the National Institutes of Health will help Dr. Zhang build on a long history of fighting E. coli, particularly through his research into the molecular pathogenesis of individual enterotoxins produced by enterotoxigenic E. coli. Noting that whole-cell vaccines against E. coli have proven difficult to develop as yet, Dr. Zhang is targeting his research on the prospects of multi-epitope fusion antigens (MEFA).

“MEFA is a new structure-assisted technology to include antigenic elements (epitopes) from multiple virulence factors (antigens or proteins) into a single immunogen to induce broad antibody responses for a vaccine product,” Dr. Zhang explains to Food Quality & Safety. “Conventionally, we mix together a few proteins (representing a few virulence factors) into a vaccine product. However, not every part of a protein induces host immune response (a majority of a protein does not induce antibodies).”

Only surface-exposed and the antigenic parts—also called epitopes—are capable of inducing host responsible, and out of these, only a small number (or even only one) may be critical to inducing host-immune responses.

“By identifying these important parts or pieces of multiple proteins, Dr. Zhang says, “we can use structure biology to construct a single protein to carry the most important parts (epitopes) from multiple proteins for a vaccine product. That not only reduces vaccine product cost, but more importantly leads to a vaccine far more specific and powerful.”

Because the technology is presently in development and entirely new, no MEFA vaccines have yet been produced or licensed. Dr. Zhang points out that his laboratory has published three papers in recent years highlighting the promise of MEFA as a powerful technology for vaccine development.

“More importantly,” he says, “this MEFA technology combining vaccinology and structure biology can be applied in general for vaccine development against different pathogens, and may revolutionize vaccine research and development.”

However, the process of development is an uphill battle. Dr. Zhang underlines that E. coli are immunologically heterogeneous, meaning that, “E. coli strains produce various virulence factors to colonize in host (humans and animals) small intestines. While we prevent one or a few types of E. coli, we cannot prevent all of them. The conventional method is to mix a few live or killed E. coli strains together, but unfortunately this approach is proven not very effective.”

However, there is a great deal more promise in the MEFA method—“The current product is to aim for 80 to 100 percent protection of diarrheagenic enterotoxigenic E. coli strains,” Dr. Zhang underlines.

The process ahead will be arduous enough: Dr. Zhang says that his team is working with funding agencies to produce products according to Good Manufacturing Practices. These will be followed by further pre-clinical studies, then adult human volunteer studies, and finally by field trials.

The battle against E. coli is far from over. However, Dr. Zhang and his team hope they can plan toward a victory big enough to be decisive, not just making immunological history, but saving human—and animal—lives in the process.