Currently, the only adjuvant available for world-wide human use is alum, a poor adjuvant with limited capacity to induce mucosal immunity. Additional adjuvants such as Toll-like receptor (TLR) ligands are being investigated, but these adjuvants are limiting with respect to efficacy and cost. Recently, we described a novel class of potent mucosal adjuvants with broad applicability against a wide range of vaccine antigens (Nature Medicine April 20, 2008). We reported that needle free, nasal administration of vaccine formulations containing small molecule mast cell (MC) activating compounds, evoked high levels of antigen-specific IgG in the serum and IgA along mucosal surfaces in mice. These responses were protective in lethal challenge models, and moreover, did not incur any harmful side effects. Many of these MC activating compounds are small peptide sequences (mast cell activating peptides, MCAP) ~ 14 amino acids in length, which can be readily and economically prepared with high purity. MCAP combined with TLR ligands MPL or CpG provided adjuvant activity that was superior to any adjuvant used alone. We have also determined that dry powder formulations of vaccine antigens maintain potency after room temperature storage and are highly efficacious after nasal immunization, suggesting that they will not require refrigeration during transport while maintaining the ability to induce protective immunity. Therefore the goal of this project is to develop a highly efficacious and safe dry powder vaccine formulation for nasal immunization against West Nile Virus.
The Specific Aims are therefore: 1. Utilize reiterative peptide design to determine the optimal structure of MC activating peptides (MCAP) for maximal adjuvant activity with West Nile Virus antigens in mice. 2. Determine if MC activating peptides combined with TLR ligand adjuvants provides additive or synergistic adjuvant activity able to reduce the antigen dose required for induction of protective WNV immunity. 3. Develop and test WNV dry powder nasal vaccine formulations in rabbits, which share structural features with human nasal passages.
|Choi, Hae Woong; Bowen, Samantha E; Miao, Yuxuan et al. (2016) Loss of Bladder Epithelium Induced by Cytolytic Mast Cell Granules. Immunity 45:1258-1269|
|Choi, Hae Woong; Abraham, Soman N (2015) Mast cell mediator responses and their suppression by pathogenic and commensal microorganisms. Mol Immunol 63:74-9|
|Miao, Yuxuan; Abraham, Soman N (2014) Kidney Î±-intercalated cells and lipocalin 2: defending the urinary tract. J Clin Invest 124:2844-6|
|St John, Ashley L; Abraham, Soman N (2013) Innate immunity and its regulation by mast cells. J Immunol 190:4458-63|
|Staats, Herman F; Kirwan, Shaun M; Choi, Hae Woong et al. (2013) A Mast Cell Degranulation Screening Assay for the Identification of Novel Mast Cell Activating Agents. Medchemcomm 4:|
|Sample, Christopher J; Hudak, Kathryn E; Barefoot, Brice E et al. (2013) A mastoparan-derived peptide has broad-spectrum antiviral activity against enveloped viruses. Peptides 48:96-105|
|Choi, Hae Woong; Brooking-Dixon, Rhea; Neupane, Subham et al. (2013) Salmonella typhimurium impedes innate immunity with a mast-cell-suppressing protein tyrosine phosphatase, SptP. Immunity 39:1108-20|
|Kunder, Christian A; St John, Ashley L; Abraham, Soman N (2011) Mast cell modulation of the vascular and lymphatic endothelium. Blood 118:5383-93|
|Kunder, Christian A; St John, Ashley L; Li, Guojie et al. (2009) Mast cell-derived particles deliver peripheral signals to remote lymph nodes. J Exp Med 206:2455-67|
|Shelburne, Christopher P; Nakano, Hideki; St John, Ashley L et al. (2009) Mast cells augment adaptive immunity by orchestrating dendritic cell trafficking through infected tissues. Cell Host Microbe 6:331-42|