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Mucosal Vaccination for Influenza Protection Enhanced by Catalytic Immune?Adjuvant

ABSTRACT: Abstract Influenza poses a severe threat to global health. Despite the whole inactivated virus (WIV)?based nasal vaccine being a promising strategy for influenza protection, the mucosal barrier is still a bottleneck of the nasal vaccine. Here, a catalytic mucosal adjuvant strategy for an influenza WIV nasal vaccine based on chitosan (CS) functionalized iron oxide nanozyme (IONzyme) is developed. The results reveal that CS?IONzyme increases antigen adhesion to nasal mucosa by 30?fold compared to H1N1 WIV alone. Next, CS?IONzyme facilitates H1N1 WIV to enhance CCL20?driven submucosal dendritic cell (DC) recruitment and transepithelial dendrite(TED) formation for viral uptake via the toll?like receptor(TLR) 2/4?dependent pathway. Moreover, IONzyme with enhanced peroxidase (POD)?like activity by CS modification catalyzes a reactive oxygen species (ROS)?dependent DC maturation, which further enhances the migration of H1N1 WIV?loaded DCs into the draining lymph nodes for antigen presentation. Finally, CS?IONzyme?based nasal vaccine triggers an 8.9?fold increase of IgA?mucosal adaptive immunity in mice, which provides a 100% protection against influenza, while only a 30% protection by H1N1 WIV alone. This work provides an antiviral alternative for designing nasal vaccines based on IONzyme to combat influenza infection. A CS?IONzyme?based influenza mucosal vaccine with dual targeting of both nasal mucosa and submucosal DCs, leading to a robust immunoprotection against influenza virus is designed. Utilizing an excellent POD?like activity, a catalytic immune?adjuvant CS?IONzyme against the bottleneck of mucosal vaccines is successfully developed by both fully mobilizing submucosal DCs to form TEDs for antigen uptake and strongly activating DC maturation.

SUBMITTER: Qin T

PROVIDER: S-EPMC7509716 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Project description:Abstract Background Oral vaccines delivered as tablets offer several advantages over traditional injection-based vaccines including ease of distribution and administration as well as temperature-stable formulation options. Oral vaccination is also advantageous because it directly induces a strong mucosal response, which is thought to be critical for preventing future infections. Here we present results from a phase II clinical challenge study comparing efficacy of an oral recombinant adenovirus-based vaccine expressing hemagluttinin (HA) from A/California 04/09 to that of a commercial injectable quadrivalent (QIV) influenza vaccine. Methods In this 2016–2017 clinical trial (NCT02918006), subjects were immunized with either oral vaccine, QIV, or placebo and then challenged 90 days post-immunization with wildtype influenza A H1 virus to measure vaccine efficacy and durability. Protection was assessed by measuring changes in HAI titres, microneutralization, and IgA/IgG ASC assays. Additionally, exploratory flow cytometry evaluated quantitative and qualitative aspects of immunogenicity including markers of activation and mucosal homing on B cells. Analysis was performed on days 0 and 7 post-immunization and 0 and 6 days post-viral challenge. Plasmablasts sorted from PBMCs were then isolated for genomic DNA and sequenced for heavy chain receptor sequencing using NGS analysis. Results Of the subjects immunized with Vaxart’s oral tablet vaccine, 48% were protected. QIV, by comparison, protected 38% of immunized individuals. Only 37% of Vaxart subjects developed influenza infection compared with 44% of QIV subjects and 71% of placebo subjects. While both vaccines induced a humoral immune response, FACS analysis and NGS revealed that Vaxart subjects had more activated plasmablasts expressing surface mucosal homing markers and a more diverse B cell population than QIV subjects. Conclusion Vaxart’s oral influenza tablet vaccine protected against influenza infection as well or better than injectable QIV. However, the mechanism of protection appears to be unique to the route of immunization; oral immunization allows for specific homing of influenza specific B cells to sites of infection and produces a more diverse antibody repertoire. Disclosures N. Kolhatkar, Vaxart, Inc.: Employee, Salary. K. Gottlieb, Vaxart, Inc.: Employee, Salary. K. Kasparek, Vaxart, Inc.: Employee, Salary. K. Hodgson, Vaxart, Inc.: Employee, Salary. S. Tucker, Vaxart, Inc: Employee, Salary. D. Liebowitz, Vaxart, Inc.: Employee and Investigator, Salary.

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Mucosal Vaccination for Influenza Protection Enhanced by Catalytic Immune?Adjuvant

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