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Injectable Excipients as Novel Influenza Vaccine Adjuvants.

ABSTRACT: Influenza outbreaks can be either seasonal or pandemic. Vaccination is an effective strategy to control influenza; however, the efficacy of the currently available inactivated influenza virus vaccines is suboptimal, especially in the elderly. Vaccine efficacy can be improved by the addition of adjuvants, but few adjuvants have been approved for human vaccines. To explore novel, safe, and effective adjuvants for influenza vaccines, here we used a mouse model to screen 46 injectable drug additives approved in Japan. Of these 46 candidates, we identified 20 compounds that enhanced the efficacy of the split influenza HA vaccine against lethal virus challenge. These 20 compounds included 15 novel adjuvant candidates and 5 compounds with previously reported adjuvant effects for other antigens but not for influenza vaccine. Given that these additives are already approved for human use, the hurdle for their clinical use as novel and effective adjuvants for influenza or other vaccines is lower than for other adjuvant candidates whose safety profiles are unknown.

SUBMITTER: Feng H

PROVIDER: S-EPMC6353828 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Injectable Excipients as Novel Influenza Vaccine Adjuvants.

Feng Huapeng H Yamashita Makoto M da Silva Lopes Tiago Jose TJ Watanabe Tokiko T Kawaoka Yoshihiro Y

Frontiers in microbiology 20190124

Influenza outbreaks can be either seasonal or pandemic. Vaccination is an effective strategy to control influenza; however, the efficacy of the currently available inactivated influenza virus vaccines is suboptimal, especially in the elderly. Vaccine efficacy can be improved by the addition of adjuvants, but few adjuvants have been approved for human vaccines. To explore novel, safe, and effective adjuvants for influenza vaccines, here we used a mouse model to screen 46 injectable drug additives ...[more]

PMID: 30733711

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Project description:Vaccine adjuvants enhance and prolong pathogen-specific protective immune responses. Recent reports indicate that host factors-such as aging, pregnancy, and genetic polymorphisms-influence efficacies of vaccines adjuvanted with Toll-like receptor (TLR) or known pattern-recognition receptor (PRR) agonists. Although PRR independent adjuvants (e.g., oil-in-water emulsion and saponin) are emerging, these adjuvants induce some local and systemic reactogenicity. Hence, new TLR and PRR-independent adjuvants that provide greater potency alone or in combination without compromising safety are highly desired. Previous cell-based high-throughput screenings yielded a small molecule 81 [N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide], which enhanced lipopolysaccharide-induced NF-κB and type I interferon signaling in reporter assays. Here compound 81 activated innate immunity in primary human peripheral blood mononuclear cells and murine bone marrow-derived dendritic cells (BMDCs). The innate immune activation by 81 was independent of TLRs and other PRRs and was significantly reduced in mitochondrial antiviral-signaling protein (MAVS)-deficient BMDCs. Compound 81 activities were mediated by mitochondrial dysfunction as mitophagy inducers and a mitochondria specific antioxidant significantly inhibited cytokine induction by 81. Both compound 81 and a derivative obtained via structure-activity relationship studies, 2F52 [N-benzyl-N-(4-chloro-2,5-dimethoxyphenyl)-4-ethoxybenzenesulfonamide] modestly increased mitochondrial reactive oxygen species and induced the aggregation of MAVS. Neither 81 nor 2F52 injected as adjuvants caused local or systemic toxicity in mice at effective concentrations for vaccination. Furthermore, vaccination with inactivated influenza virus adjuvanted with 2F52 demonstrated protective effects in a murine lethal virus challenge study. As an unconventional and safe adjuvant that does not require known PRRs, compound 2F52 could be a useful addition to vaccines.

Dataset Information

Injectable Excipients as Novel Influenza Vaccine Adjuvants.

Publications

Injectable Excipients as Novel Influenza Vaccine Adjuvants.

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