Abstract
Mast cell activators are a novel class of mucosal vaccine adjuvants. The polymeric compound, Compound 48/80 (C48/80), and cationic peptide, Mastoparan 7 (M7) are mast cell activators that provide adjuvant activity when administered by the nasal route. However, small molecule mast cell activators may be a more cost-efficient adjuvant alternative that is easily synthesized with high purity compared to M7 or C48/80. To identify novel mast cell activating compounds that could be evaluated for mucosal vaccine adjuvant activity, we employed high-throughput screening to assess over 55,000 small molecules for mast cell degranulation activity. Fifteen mast cell activating compounds were down-selected to five compounds based on in vitro immune activation activities including cytokine production and cellular cytotoxicity, synthesis feasibility, and selection for functional diversity. These small molecule mast cell activators were evaluated for in vivo adjuvant activity and induction of protective immunity against West Nile Virus infection in BALB/c mice when combined with West Nile Virus envelope domain III (EDIII) protein in a nasal vaccine. We found that three of the five mast cell activators, ST101036, ST048871, and R529877, evoked high levels of EDIII-specific antibody and conferred comparable levels of protection against WNV challenge. The level of protection provided by these small molecule mast cell activators was comparable to the protection evoked by M7 (67%) but markedly higher than the levels seen with mice immunized with EDIII alone (no adjuvant 33%). Thus, novel small molecule mast cell activators identified by high throughput screening are as efficacious as previously described mast cell activators when used as nasal vaccine adjuvants and represent next-generation mast cell activators for evaluation in mucosal vaccine studies.
Highlights
Mast cells represent a target for a new class of mucosal vaccine adjuvants
Small molecule mast cell activators evaluated for adjuvant activity after nasal immunization were identified by high throughput screening of commercially available compound libraries based on induction of a mast cell degranulation phenotype [23]
Novel small molecule MCAs adjuvant activity is not as effective as that induced by the tolllike receptor 4 (TLR4) ligand MPL, an accepted vaccine adjuvant, for protective immunity in the West Nile virus (WNV) challenge model, we believe the adjuvant activity demonstrated with the small molecules after nasal delivery is significant, especially when we acknowledge that the compounds are at the hit-to-lead phase of drug discovery
Summary
Localized and controlled mast cell activation may be an effective way to induce potent immune responses to coadministered vaccine antigens. Mast cells readily release histamine, prostaglandins, leukotrienes, and cytokines [2, 3] that may enhance innate cell migration to immunological inductive sites, such as the draining lymph node, and initiate a host immune response to co-administered vaccine antigens [4,5,6]. Mast cells synthesize additional inflammatory mediators, such as leukotriene B4, prostaglandin G2, IL-1, IL-3, and IL-10, within hours of activation [7] that may sustain immune responses to increase the potency of vaccine-induced immunity. One special feature of mast cells is the ability to degranulate and re-granulate [2]; providing a constant source of localized inflammation readily available to support adjuvant activity. Mast cells contribute to the adjuvant activity of various adjuvants including surfactin, imiquimod, and CTA1DD/IgG [8,9,10,11] the role of mast cells in the adjuvant activity of some mast cell activators is controversial [12]
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