Protease inhibitor passes oral exam

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Science Translational Medicine  18 Nov 2015:
Vol. 7, Issue 314, pp. 314ec199
DOI: 10.1126/scitranslmed.aad5910

Oral vaccination remains one of the most exciting but challenging frontiers in biomedical engineering. The challenge lies in overcoming the extreme environment of the gastrointestinal (GI) tract, which has evolved to serve as a protective barrier and to break down food, which is formed of the same building blocks as antigens. Achieving a successful orally administered vaccination requires traveling through this unique GI environment, while keeping the antigen intact and immunogenic. Ibañez and colleagues have accomplished this with the identification of a bacterial protease inhibitor from the Gram-negative pathogen Brucella abortus.

The investigators expressed an unlipidated form of the bacterial protease inhibitor Omp19 (U-Omp19) and demonstrated that it blocks the activity of enzymes common in the GI tract, including pepsin, trypsin, α-chymotrypsin, and pancreatic elastase. U-Omp19 maintained its structure across a broad spectrum of pH, from 2 to 8, and temperatures, from 25 to 100 ºC. U-Omp19 induced dendritic cell recruitment to Peyer’s patches and recruited monocytes and CD8+ dendritic cells to mesenteric lymph nodes (MLNs), suggesting its capacity as an adjuvant. Following oral coadministration of U-Omp19 and the model antigen ovalbumin (OVA) to mice, the presence of OVA-specific CD4+ and CD8+ T cells was observed in vivo, and cells isolated from the MLNs of these mice responded significantly to OVA, as evidenced by increased cytokines interferon γ and interleukin-17. Mimicking the oral vaccination process, administration of Shiga and Cholera toxins as well as heat-killed extract from Salmonella typhimurium (HKS) administered with U-Omp19 showed mucosal and systemic immune responses with antibodies detected in feces and in serum. Animals only receiving the toxins or HKS without U-Omp19 had significantly lower levels of antibodies to the respective pathogens. Last, coadministration of U-Omp19 and a recombinant protein from Toxoplasma gondii resulted in significantly decreased brain cyst burden and liver function abnormalities in response to a challenge with oral Toxoplasma cysts.

The U-Omp19 shield was able to protect several different antigens as they traversed the GI tract, allowing for a robust immune response. Protecting precious cargo could pay off in humans, too, but first, further testing with other potential vaccination targets in other animal models will pave the way to translation of this technology.

A. E. Ibañez et al., A bacterial protease inhibitor protects antigens delivered in oral vaccines from digestion while triggering specific mucosal immune responses, J. Control. Release 220, 18–28 (2015). [Full Text]

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