A skin patch vaccine designed to prevent traveler’s diarrhea was shown ineffective in a phase III trial published in Lancet Infectious Diseases.
The patch contained Escherichia coli heat-labile toxin. "Future vaccines against traveler’s diarrhea might need to include several antigens against various diarrheal pathogens, and might need to be able to generate mucosal and higher systemic immunity," concluded the investigators, led by Dr. Ronald Behrens of the Hospital for Tropical Diseases in London.
The subjects, healthy adults around 30 years old, were from Germany and the United Kingdom; 821 got a skin patch that contained 37.5 mcg heat-labile toxin and that they wore on their shoulder for 6 hours; 823 got a placebo patch. Both groups got a second patch on the opposite shoulder 2 weeks later (Lancet Infect. Dis. 2013 [doi:10.1016/S1473-3099(13)70297-4]).
Subjects then traveled to either Mexico or Guatemala for at least a week. They recorded their stool output in a diarrhea diary and provided samples for pathogen identification; 30 (3.7%; 95% confidence interval 2.5-5.2) in the heat-labile toxin-patch group and 46 (5.6%; 95% CI 4.1-7.4) in the placebo group were treated for moderate or severe enterotoxigenic E. coli (ETEC) diarrhea, passing four or more unformed stools in 24 hours.
Vaccine efficacy was 34.6%, (95% CI –2.2-58.9; P = .0621), with no statistical difference in the incidence of ETEC diarrhea between the two groups. "The vaccine did seem to provide a small amount of protection against heat-labile toxin-positive ETEC," but not against other forms of ETEC and diarrhea caused by other pathogens. Using a single antigen vaccine "might not be realistic," the investigators said.
The all-cause diarrhea incidence was 17.1% in the vaccine group and 15.2% in the placebo group. Even "a 100% effective ETEC vaccine would still have had only about 50% vaccine efficacy for moderate-to-severe all-cause diarrhea," they noted.
The vaccine was immunogenic; 84% of the treated subjects, but just 13% of placebo patients, converted to LT-specific serum immunoglobulin G; 41% (vs. 2% in the placebo group) seroconverted to anti-LT IgA, but "serum IgG and IgA titers were not associated with vaccine efficacy, suggesting that such titers cannot be used as a correlate of protection," the investigators said.
The number of ETEC cases was lower than expected, as well, which "might have reduced the precision of our findings," they said.
More than 90% of patients had local reactions to the LT patch, including redness, rash, pruritus, pain, edema, and hyperpigmentation. Vaccine-induced hyperpigmentation persisted at 6-month follow-up in about 20% of study subjects. About 56% of those given placebo had local patch reactions, but none had hyperpigmentation at 6 months.
"The LT component in the patch probably caused this vigorous dermal immune response in nearly all vaccine recipients," said the investigators, who also noted that other ETEC vaccines in development "have not yet shown clinically important benefits."
The study was funded by Intercell USA, makers of the vaccine. One of the 17 investigators is an Intercell employee, and study funding paid part of the other investigators’ salaries. Three investigators reported other financial relationships with Intercell, Salix Pharmaceuticals, or Norgine Pharmaceuticals.