WASHINGTON, DC—Diarrheal illnesses are among the most common nonbattle-related illnesses that troops experience when they go overseas, yet there is no vaccine against Enterotoxigenic Escherichia coli (ETEC), a common cause of bacterial diarrhea.
Researchers at the Naval Medical Research Center (NMRC) are hoping to change that, and are moving forward with the development of its ETEC adhesin-based vaccine. “We are pretty excited,” said Capt Stephen Savarino, MD, of the vaccine candidate. Savarino is the NMRC director of the Enteric Diseases Department in the Infectious Diseases Directorate. “We have been working at this for sometime.”
NMRC is now in the process of completing preclinical toxicology testing with its nonprofit partner, PATH, a step required by the FDA before a vaccine candidate is first tested in humans. Clinical researchers anticipate starting their first Phase 1 human clinical trial this summer. If early phase trials show that the vaccine candidate is safe and elicits good immune responses, it will enable further development of a multivalent adhesin-based ETEC vaccine.
Because ETEC has a variety of fimbrial types, it imposes considerable challenges for vaccine developers. NMRC scientists’ identification of conserved components of these adhesive fimbriae promises to simplify the composition of a final vaccine, Savarino said. The approach his team is taking is designed to prevent upwards of 80% or more of ETEC. “Our research is pointed in the direction of making a multivalent vaccine, which would in fact cover upwards of 80% or more of ETEC.”
ETEC is the name given to a group of E coli that produce special toxins which stimulate the lining of the intestines, causing them to secrete excessive fluid, thus producing diarrhea. ETEC pathogens are transmitted by food or water contaminated with animal or human feces.
According to CDC, infection with ETEC is the leading cause of diarrhea among travelers and a major cause of diarrheal disease in underdeveloped nations, especially among children.
For the military, illnesses caused by ETEC infections can be disruptive to military troops. While the military works to ensure that those who are deployed overseas have clean water and uncontaminated food, protecting troops is not always easy. “The problem is that war is a dirty business, even operations other than war can be very dirty,” Savarino said. “If we are sending troops into refugee camps, if we are sending troops into harm’s way in combat situations, it is almost impossible to impose a level of cleanliness that one would expect in parts of the US.”
According to Savarino, studies over the last two decades indicate the monthly attack rate of travelers’ diarrhea across a range of countries and deployment settings has been about 29% per month. Only about one in four or five servicemembers seeks care for their illness. During recent operations, the military has seen attack rates upwards of 60% to 70% per month during initial combat operations, which gradually fell to about 10% to 15% as infrastructure has been established.
In addition, Savarino said that these acute illnesses are associated with long-term sequela and that closer study has shown that, subsequent to a bout of travelers’ diarrhea, the individual is at increased risk for certain diseases.
Savarino attributes the lack of an FDA-approved ETEC vaccine to a combination of the “daunting challenges that this pathogen poses,” and the lack of an adequate market and demand forecast to offset the R&D investment. “This situation has gradually improved in the past three to five years, during which a stronger business case for development of an ETEC vaccine has been articulated and risk has been reduced with more candidates being advanced into the clinical testing pipeline.”
Savarino described the core components of his ETEC adhesin-based vaccine candidate as conserved adhesive domains from the most common hair-like structures (called fimbriae) that promote ETEC attachment to the gut or intestine. Accumulated findings support his team’s hypothesis that such an ‘adhesin-based’ ETEC vaccine will block these microbes at the point when they first come in direct contact with human host cells and prevent attachment and subsequent steps in the disease process. A nontoxic derivative of the important heat-labile enterotoxin (LT) is also included to induce antitoxic immunity, which his team believes will confer additional protective effects.
Early signs in some of the early animal studies as well as a human study show an ability to generate passive protection in humans, Savarino said. “So we are pretty excited about proceeding into the clinic. All the evidence that we have from the animals is indicative that the vaccine should be safe.”
While the military is interested in an ETEC vaccine suitable for military use, it is also hoped that a vaccine would be adaptable in a developing country.
In March of last year, NMRC announced a licensing agreement with Sanofi-Pasteur to further advance preclinical development of its adhesin-based ETEC vaccine technology. Licensing of the technology to Sanofi-Pasteur has the potential to accelerate the developmental time lines such that the vaccine may become available sooner to the war fighter and other populations in need of it.
The military, however, is no stranger to vaccine development or the fact that success and failure are part of the business. Much research must still take place on the vaccine candidate to determine whether it will succeed.
Determining exactly when this ETEC vaccine candidate could potentially be available is difficult, said Savarino. “We have had other vaccines that have failed. Certainly we don’t know how [this] is going to work, otherwise we would not be doing the research. We are hopeful though.”
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