April 16, 2012

Can a mutant be a medical breakthrough?

Director, Enteric Vaccine Initiative

In this guest post, Dick Walker—director of the Enteric Vaccine Initiative at PATH’s Vaccine Development Program—writes about how the double-mutant heat-labile toxin is a potential booster for much-needed new vaccines against diarrhea.

The leading bacterial causes of diarrhea are enterotoxigenic Escherichia coli (ETEC) and Shigella, and vaccines against these pathogens could save the lives of up to a half-million children each year. PATH’s enteric vaccine project is working to accelerate the development of several promising vaccine candidates. We are also looking at innovative ways to make these vaccines as effective, practical, and affordable as possible so they can be easily implemented in the developing world.

Adjuvants, ingredients that may enhance the effectiveness of some vaccines, are one important area of focus. PATH is currently involved in research on a highly promising new adjuvant, the double-mutant heat-labile toxin (dmLT), which could open more doors to achieving immunity in the intestine. The dmLT is actually an ETEC antigen (a substance that causes the immune system to produce antibodies against it), so it may offer protection against both diarrhea and intestinal infection when used in conjunction with vaccines that are targeted to mucosal surfaces like the intestine. We aren’t exactly sure why, but children in resource-poor countries often have a lower response rate to mucosal vaccines. A wide range of factors may contribute to this issue, such as the influence of breastfeeding and maternal antibodies, poor nutrition, or increased exposure to intestinal pathogens. An adjuvant like the dmLT may help to bridge this gap in effectiveness.

Dick Walker with children in Cambodia. Promising vaccine technologies can help expand and improve the arsenal of tools to use in the fight against diarrhea among children.

Right now, we’re working with the National Institutes of Health’s (NIH) Division of Microbiology and Infectious Diseases on a Phase 1 clinical trial using oral doses of dmLT (not in conjunction with a vaccine) in healthy adults. We will have complete results later this year, but the preliminary data are quite promising. Meanwhile, we are about to launch our first Phase 1 trial of the dmLT combined with one of our oral ETEC vaccine candidates.

In addition, we plan to start another Phase 1 trial to test the dmLT intradermally (through the skin), and we would also like to study its use sublingually (under the tongue), to see if these alternative delivery routes can achieve an immune response in the intestine. If preclinical studies accurately predict what will be seen in humans, delivering dmLT in these ways could open up a whole range of possibilities for developing more effective and practical vaccines.

This type of innovative research is critical to moving forward the field of vaccines to address diarrheal disease, and support from the NIH and other partners is critical to this effort. As the dmLT and other promising vaccine technologies progress in their development, we know we are getting ever closer to expanding and improving the arsenal of tools to use in the fight against this major killer of children.

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