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139 A Novel Nanoparticle Approach to Induce Colorectal and Vaginal Mucosal Immunity

Zhu, Qing; Talton, James; Zhang, Guofeng; Cunningham, Tshaka; Kirk, James; Eppler, Bärbel; Klinman, Dennis M; Belyakov, Igor M; Sui, Yongjun; Gagnon, Susan; Mumper, Russell J; Berzofsky, Jay A

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2011 - Volume 56 - Issue - p 56
doi: 10.1097/01.qai.0000397325.18998.79

Vaccine Branch, NCI, NIH, Bethesda, MD; Nanotherapeutics, Inc. Alachua, FL; Lab of Bioengineering and Physical Science, NIBIB, NIH, Bethesda, MD; Lab of Exptl Immunol., NCI, Frederick, MD; and Center for Nanotechnology in Drug Delivery, UNC School of Pharmacy, Chapel Hill, NC.

Many infections, including HIV, are transmitted through mucosal surfaces. Where T cell immunity is needed to protect, we have previously found that local mucosal immunity is most effective. Moreover, intrarectal immunization was the most effective route of several we compared to induce such immunity in the GI mucosa. However, the intrarectal route may not be the most acceptable for human vaccination. We hypothesized that we might mimic intrarectal immunization if we could deliver the vaccine to the colorectal mucosa, and might be able to do so by a more practical oral route of delivery if we could bypass destruction in the stomach and induction of oral tolerance in the small intestine. We have now accomplished this in mice by using a novel construct of pH-dependent microparticles encapsulating nanoparticles that contain the vaccine. The particles are designed to avoid uptake of the microparticles or release of the nanoparticles until they reach the large intestine. This oral vaccine induced a level of T cell immunity in the large intestinal mucosa that rivaled that induced by direct intrarectal delivery, and resulted in comparable protection against intrarectal or intravaginal challenge with a recombinant virus. In contrast, vaccine particles targeted to the small intestine resulted in greater T cell immunity in the small intestine but not in the large intestine, and failed to protect against intrarectal or intravaginal viral challenge. Thus, with these directed particles, we have been able to demonstrate functional compartmentalization of the gut mucosal immune system for T cell immunity, and to develop an orally delivered vaccine capable of providing protection against rectal or vaginal mucosal challenge.

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