Wednesday, June 20, 2007 - 11:30 AM
Cottonwoods (Boise Centre on the Grove)

Lipid A Mimetics for Protection Against Pulmonary Plague

Carolyn Hovde Bohach, Christina L. Airhart, Harold N. Rohde, Claudia F. Deobold, Gregory A. Bohach, and Scott A. Minnich. University of Idaho, Moscow, ID

A hallmark of Yersina pestis infection is a reduced inflammatory response. Synthetic lipid A mimetics were used as therapeutics to stimulate the innate immune response or as vaccine adjuvants with Y. pestis antigens to protect against pneumonic plague. Mice were treated intranasally with nontoxic lipid A mimetics prior to and/or after an intranasal challenge of 10, 100, or 200 LD50 of Y. pestis CO92. Controls were treated with PBS and mice were monitored for time-to-death. In addition, the effect of treatment with lipid A mimetics combined with sub-optimal gentamicin antibiotic therapy was measured. Finally, the efficacy of intranasal vaccination with Y. pestis immunogens, capsular protein Caf1 and/or V-antigen, with a lipid A mimetic as adjuvant were measured. Mice treated with the lipid A mimetics 24h prior to challenge with 10-200 LD50 of Y. pestis had an increased time-to-death or were protected and the effect was pathogen-dose dependant. The lipid A mimetic provided a synergistic effect when combined with a sub-optimal gentamicin treatment with survival rates as high as 85% in mice treated with the lipid A mimetic 24h prior to and 24h after bacterial challenge. The compounds also function effectively as adjuvants. Within 45 days, a single dose vaccination with Caf1 and/or V-antigen provided 80% protection after a 100 LD50 Y. pestis CO92 challenge. 100% protection was rapidly induced (within days) when two doses of vaccine were administered. In conclusion, the modified lipid A compounds stimulated innate immunity in the mouse nasal and respiratory mucosa. These compounds provided protection or delayed time-to-death from Y. pestis challenge, enhanced antibiotic action, and were effective vaccine adjuvants when combined with known protective antigens for pneumonic plague.