For nearly forty years, every serious attempt at a broadly protective vaccine against enterotoxigenic E. coli and Shigella, two of the leading bacterial causes of diarrheal death in young children, has run into the same wall. These bugs are not one thing. They are dozens. Each strain wears a different coat of surface proteins, the field aimed at the coat, and the next strain walked through.

A team at Washington University’s medical school, working with collaborators at the University of Missouri and the International Centre for Diarrhoeal Disease Research in Dhaka, just published a paper in the Proceedings of the National Academy of Sciences that suggests the field has been aiming at the wrong layer. James Fleckenstein at WashU, Zachary Berndsen at Mizzou, and postdoctoral researcher David Buckley stopped chasing what these bacteria don’t share and went looking for what they do.

What they found, sitting in front of everyone the whole time, are the scissors.

To cause disease, ETEC and Shigella have to get through the layer of mucus that coats the gut wall. They do that by secreting enzymes that chew the mucus protein apart. ETEC carries one called EatA. Shigella and other pathogenic E. coli carry close cousins called Pic and SepA. All three are mucinases, proteases that cleave the gut’s main mucus protein MUC2, and the team showed they share a region structurally conserved enough that an antibody raised against one neutralizes all three in the dish. Buckley and Berndsen’s group then mapped the exact surface patch where those neutralizing antibodies bind. The implication, which the authors are careful to frame as implication rather than proof, is that this patch may be hard for the bacteria to redesign without losing the tool they need to get to the gut wall in the first place. “By identifying key regions of EatA targeted by neutralizing antibodies, we’ve established a foundation for rational vaccine design,” Berndsen said in the WashU announcement.

There is human data behind the bench work, and it points the same direction. Earlier work in the icddr,b cohort in Dhaka showed that children who developed anti-EatA antibodies after a natural ETEC infection were less likely to get sick on subsequent exposures than children who did not, an association rather than a randomized challenge result. The WashU team treats it accordingly. But it is the right shape of evidence for a vaccine target: an immune response that learned to neutralize this enzyme on its own ended up correlated with protection.

The scope of what a working vaccine could change is hard to overstate. ETEC and Shigella together cause hundreds of millions of infections each year and rank among the leading bacterial causes of diarrheal death in children under five, according to the news writeup of the WashU paper summarizing the burden. Diarrheal disease remains one of the top killers of children that age, full stop. Successive WHO and funder consultations have circled back to the same point for two decades: a broadly protective ETEC and Shigella vaccine would be one of the highest-impact tools in global child health, and we still don’t have one. “For something so common and so deadly to young children, it’s striking that we still don’t have a vaccine,” Fleckenstein said.

A few groups are trying to change that, and it helps to know where they sit. The Austrian biotech Eveliqure’s ShigETEC live-attenuated candidate, funded by the European Union’s Horizon 2020 program and licensed for manufacturing to the Serum Institute of India, is running an age-descending Phase 1b clinical trial in Bangladesh through icddr,b. Earlier subunit-vaccine efforts targeting ETEC colonization factors have inched along for years without producing a broadly licensed product. The WashU work doesn’t compete with any of these. It sits one step upstream, naming a target that any of these platforms, or a new one, could carry into the body.

That step upstream is also where the suspense lives. Neutralizing antibodies in a dish are an opening bid, not the answer. Bangladeshi children whose own immune systems made those antibodies were less likely to get sick, but no one has yet built a vaccine that elicits the same response on demand, run it through human challenge, and read out efficacy. The mucosal-vaccine pipeline has eaten more than one promising target. The next data point worth caring about is what Fleckenstein’s group says it is now working on: identifying the antigen format that elicits the right antibody response in humans, then taking it into a Phase 1.

It is worth saying out loud where the money on this discovery came from. The work was funded by two long-running NIAID R01 grants and by the Department of Veterans Affairs, listed in the paper’s funding disclosure. American taxpayers paid for the science. The most advanced clinical program built on a related idea, ShigETEC, is funded by the European Union and will be manufactured in India. That isn’t a scandal in itself, and the ShigETEC consortium is doing serious work. It is, however, the kind of fact a U.S. biomedical strategy worth the name would notice: a target identified on NIH and VA money is most likely to reach the children who need it through a pipeline that begins in Vienna and ends in Pune.

The right way to read this paper, for now, is as a clearer map of a target that has been hiding under the strain-by-strain variability that broke a generation of attempts. What to watch next: the first human immunogenicity data on a mucinase-targeted antigen, the ShigETEC Phase 1b readout out of icddr,b, and whether any U.S. vaccine developer moves to carry the WashU target into a candidate before someone abroad gets there first.

Sources

  1. WashU Medicine – Researchers find a common weakness in major gut pathogens (June 2026)
  2. Buckley, Fleckenstein, Berndsen et al., “Human enterotoxigenic Escherichia coli (ETEC) infections elicit antibodies that broadly neutralize mucinases of pathogenic Escherichia coli and Shigella,” PNAS, June 2026
  3. News-Medical – WashU study identifies shared target for a new diarrhea vaccine (June 17, 2026)
  4. SHIGETECVAX consortium – final project meeting update (EU Horizon 2020 / Eveliqure / Serum Institute of India)