The First Vaccine for Traveler’s Diarrhea May Be Around the Corner

Scandinavian BioPharma is developing a new oral vaccine targeting a major bacterial cause of traveler’s diarrhea.

Photo by Sasun Bughdaryan on Unsplash

What is Traveler’s Diarrhea?

Traveler’s diarrhea (TD) is the most common illness affecting individuals traveling from industrialized nations to regions with lower sanitation and food safety standards. In fact, it is so common that the CDC reports that 30–70% of travelers may be affected, depending on location and season.

Some of the highest-risk destinations are found in Latin America, Africa, South Asia, and Southeast Asia.

TD is generally defined as the passage of three or more unformed stools within 24 hours, accompanied by at least one additional symptom such as abdominal cramps, nausea, vomiting, fever, or fecal urgency.

Although rarely life-threatening in healthy adults, TD can significantly disrupt travel plans and lead to substantial healthcare utilization.

The burden of TD extends beyond individual travelers. Military personnel deployed overseas frequently experience outbreaks that can impair operational readiness and mission effectiveness.

Tourists and business travelers may experience lost productivity and increased medical expenses, while humanitarian aid workers operating in resource-limited settings often face elevated exposure risks.

In endemic regions, diarrheal diseases remain a major cause of childhood morbidity and mortality, contributing to malnutrition, impaired growth, and adverse developmental outcomes.

The Major Cause of TD

A wide range of pathogens can cause TD. Bacterial pathogens account for the majority of cases, around 75–90%, and include enterotoxigenic Escherichia coli (ETEC), enteroaggregative E. coli (EAEC), Campylobacter species, Shigella species, and Salmonella species.

Viral causes include norovirus, rotavirus, adenovirus, and astrovirus. There are also parasitic infections that can cause TD; however, they are not the focus of this piece.

Among these pathogens, ETEC has received particular attention due to its prominent role in both travel-associated and endemic diarrheal disease.

ETEC is widely recognized as one of the leading bacterial causes of traveler’s diarrhea worldwide and is responsible for millions of infections annually. In fact, ETEC is estimated to cause 30–60% of TD cases.

Beyond its impact on travelers, ETEC is a major cause of diarrheal disease among young children living in low- and middle-income countries, where repeated infections contribute to growth stunting, malnutrition, and increased mortality risk.

Microbiology and Pathogenesis of ETEC

Escherichia coli is a Gram-negative, facultatively anaerobic bacterium that normally inhabits the gastrointestinal tract of humans and animals. Most E. coli strains exist as harmless commensals and contribute to intestinal homeostasis. However, several pathotypes have acquired virulence genes through horizontal gene transfer, enabling them to cause gastrointestinal or extraintestinal disease.

Among these pathogenic strains, enterotoxigenic Escherichia coli (ETEC) is distinguished by its ability to colonize the small intestine and produce enterotoxins that induce secretory diarrhea.

Unlike invasive enteric pathogens, ETEC generally remains confined to the intestinal lumen and causes disease through toxin-mediated disruption of normal fluid transport rather than tissue destruction.

ETEC is one of several diarrheagenic E. coli pathotypes, which also include enterohemorrhagic E. coli (EHEC), enteropathogenic E. coli (EPEC), enteroinvasive E. coli (EIEC), and enteroaggregative E. coli (EAEC).

The defining virulence characteristics of ETEC are the expression of colonization factors (CFs) that mediate intestinal adherence and the production of heat-labile (LT) and/or heat-stable (ST) enterotoxins.

Disease begins following ingestion of contaminated food or water. After surviving passage through the acidic gastric environment, ETEC reaches the small intestine, where it establishes colonization through a diverse group of fimbrial and fibrillar adhesins collectively known as colonization factors.

More than 25 colonization factors have been identified, CS6 among the most frequently associated with human disease. These surface structures facilitate attachment to enterocytes and allow the organism to persist within the intestinal environment long enough to deliver enterotoxins, which in turn are the molecules that make us sick.

Development of ETVAX

ETVAX is an oral, inactivated whole-cell vaccine developed to provide broad protection against enterotoxigenic Escherichia coli (ETEC). The vaccine was designed based on decades of research demonstrating that protective immunity against ETEC is primarily directed against colonization factors and enterotoxins.

To address the substantial antigenic diversity of ETEC strains, ETVAX incorporates four genetically engineered recombinant E. coli strains that have been inactivated using formaldehyde or phenol while retaining their immunogenic surface antigens.

In addition to colonization factor antigens, ETVAX contains a toxoid component derived from the heat-labile toxin (LT). Because LT is structurally similar to cholera toxin and contributes significantly to ETEC virulence, inclusion of a detoxified LT antigen allows the vaccine to induce protective anti-toxin immune responses without causing disease.

Another interesting thing about this specific vaccine is that, rather than injection, it is administered orally.

Oral administration of ETVAX offers significant benefits for ETEC prevention. Eliminating injections simplifies delivery and increases comfort, which is crucial in low-resource settings with limited medical infrastructure.

Additionally, this route mimics natural exposure by targeting the intestinal mucosa directly. Such immunization effectively stimulates secretory IgA antibodies at the primary site of infection, following the same route as if you were to ingest the bacteria in food or water.

Clinical Trials

Scandinavian BioPharma, the company developing ETVAX, has completed Phase I and Phase II clinical trials evaluating the vaccine’s safety, immunogenicity, and efficacy across multiple populations, including healthy adults, travelers, and children.

Early Phase I studies conducted in Swedish adults showed that ETVAX was well tolerated and induced robust mucosal IgA responses against the vaccine’s colonization factor antigens and LT toxoid component.

Vaccinated participants developed both intestinal antibody-secreting cell responses and long-lasting immunological memory, supporting further clinical development. Subsequent trials in Bangladeshi adults confirmed these findings, demonstrating strong systemic and mucosal immune responses against all major vaccine antigens without significant safety concerns.

A large age-descending Phase I/II trial in Bangladesh further evaluated ETVAX in children aged 24–59 months, 12–23 months, and 6–11 months. The vaccine was safe and well-tolerated across all age groups, with most adverse events being mild and transient.

Importantly, ETVAX generated mucosal IgA responses against multiple colonization factors and LT in a majority of vaccinated children. The inclusion of the dmLT adjuvant enhanced both the breadth and magnitude of immune responses, particularly among infants, a population that is disproportionately affected by ETEC disease.

More recently, a randomized, double-blind, placebo-controlled Phase IIb trial enrolled 4,936 Gambian children between 6 and 18 months of age to evaluate vaccine efficacy against moderate-to-severe ETEC-associated diarrhea.

Serious adverse events occurred in 1.0% of vaccine recipients and 1.3% of placebo recipients, with no events attributed to vaccination.

ETVAX induced significant antibody responses against colonization factors and LT antigens. Although the study did not meet its primary efficacy endpoint, several secondary analyses demonstrated encouraging protective effects.

Vaccine efficacy was estimated at 48.2% against moderate-to-severe ETEC diarrhea regardless of co-infections and increased to 80.6% when enteroparasitic co-infections were excluded.

Among children who began vaccination before nine months of age, efficacy reached 67.8%. The vaccine also reduced all-cause moderate-to-severe diarrhea by 21.4% during the study period.

Where we are now

After decades of incremental progress in enterotoxigenic Escherichia coli (ETEC) vaccine research, ETVAX now stands as the most advanced ETEC vaccine candidate, having completed a Phase IIb field efficacy trial in Gambian infants and young children. This marks the first modern test of an ETEC vaccine under real-world conditions in a high-burden, low-income setting.

On the strength of these findings, investigators and global health partners now regard ETVAX as ready to advance into pivotal Phase III trials for licensure, with the Gambian experience serving as the blueprint for future study design.

Broader ETEC vaccine roadmaps similarly identify ETVAX as the lead candidate most likely to achieve World Health Organization prequalification within the coming years, provided continued investment and successful late-stage development.

Looking ahead, priority activities include optimizing formulation and presentation for use in low-resource settings, confirming efficacy across multiple epidemiological contexts, and generating the evidence required to support global policy recommendations and widespread introduction in the countries that need it most.