Nasal Immunization With Small Molecule Mast Cell Activators Enhance Immunity to Co-Administered Subunit Immunogens.

Autor:	Johnson-Weaver BT; Pathology Department, School of Medicine, Duke University, Durham, NC, United States., Choi HW; Pathology Department, School of Medicine, Duke University, Durham, NC, United States., Yang H; Biostatistics and Bioinformatics Department, School of Medicine, Duke University, Durham, NC, United States., Granek JA; Biostatistics and Bioinformatics Department, School of Medicine, Duke University, Durham, NC, United States., Chan C; Biostatistics and Bioinformatics Department, School of Medicine, Duke University, Durham, NC, United States., Abraham SN; Pathology Department, School of Medicine, Duke University, Durham, NC, United States.; Department of Immunology, School of Medicine, Duke University, Durham, NC, United States.; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, United States., Staats HF; Pathology Department, School of Medicine, Duke University, Durham, NC, United States.; Department of Immunology, School of Medicine, Duke University, Durham, NC, United States.; Duke Human Vaccine Institute, Duke University, Durham, NC, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Sep 10; Vol. 12, pp. 730346. Date of Electronic Publication: 2021 Sep 10 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.730346
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Johnson-Weaver, Choi, Yang, Granek, Chan, Abraham and Staats.)
Databáze:	MEDLINE
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