The nasopharyngeal tract is a major portal entry of debilitating and potentially lethal pathogens including Bacillus anthracis and influenza virus. Mucosal vaccines capable of promoting antibody and cytotoxic T cell responses in mucosal tissues, in addition to the general bloodstream, protect more effectively against respiratory pathogens than classical injected vaccines. Therefore, there is a need for safe mucosal adjuvants and vaccine delivery systems. Previous work on this grant focused at defining murine nasal-associated lymphoreticular tissues (NALT) as inductive sites for immune responses targeting the nasopharyngeal tract. We used cholera toxin and developed novel derivatives lacking ADP ribosyl transferase activity to circumvent the reactogenicity of this enterotoxin adjuvant. In addition, we have assessed the action of anthrax toxins on murine NALT. These studies have also included the characterization of antibodies (Abs) to anthrax protective antigens with special emphasis on the potential to protect mucosal tissues. A total of five original Specific Aims were successfully addressed. A major and unexpected finding during the course of our studies was the fact the nasal co-administration of Bacillus anthracis protective antigen together with a mutant of the cAMP-inducing Bacillus anthracis edema factor enhanced mucosal and systemic immunity against these two molecules. Furthermore, we found that the edema toxin (EdTx or protective antigen plus edema factor) derivative enhanced mucosal and systemic immunity to co-administered unrelated antigens such as recombinant Yersinia pestis F1-V antigen. Unlike the ganglioside-binding enterotoxin cholera toxin, neither EdTx nor its derivatives target central nervous system tissues after nasal application. In this renewal grant, we will address the overall hypothesis that sublingual application of EdTx derivatives will induce NALT-based immunity and protect against respiratory pathogens, without the adverse effects often associated with nasal application of enterotoxins.
Specific aim one will establish the adjuvant activity of edema factor derivatives co-administered with protective antigen (PA) via the sublingual route for enhanced immunity to anthrax toxin components.
Specific aim two will characterize protective immunity to respiratory viral infection afforded by sublingual immunization with EdTx derivatives as adjuvant. Studies in specific aim three will identify inductive sites for the generation of secretory IgA (SIgA) Abs and mucosal immunity after sublingual immunization with EdTx-derivatives. Finally, specific aim four will determine molecular signals underlying the induction of SIgA responses by EdTx-derivatives as sublingual adjuvant. This grant will unravel the mechanisms by which EdTx derivatives act as adjuvant for sublingual vaccines and induce NALT-based immunity. We will also validate a new route for mucosal vaccine delivery, as well as new PA-based mucosal adjuvant(s) for the induction of immunity against respiratory pathogens.
Lay abstract Thus far, nasal delivery of vaccines was believed to be the most effective mean to trigger inductive sites of immune responses for the development of optimal immunity against respiratory pathogens. However, enterotoxin adjuvants employed in nasal vaccines could induce severe side effects resulting from their ability to target the central nervous system and sustain inflammatory responses. This grant will explore the efficacy of edema toxin derivatives as adjuvant for sublingual vaccines. Upon completion, we will have validated a new vaccine delivery system, as well as new mucosal adjuvant(s) for the induction of immunity against respiratory pathogens.
|Boyaka, Prosper N (2017) Inducing Mucosal IgA: A Challenge for Vaccine Adjuvants and Delivery Systems. J Immunol 199:9-16|
|Martin, Tara L; Jee, Junbae; Kim, Eunsoo et al. (2017) Sublingual targeting of STING with 3'3'-cGAMP promotes systemic and mucosal immunity against anthrax toxins. Vaccine 35:2511-2519|
|Terrazas, Cesar; Varikuti, Sanjay; Kimble, Jennifer et al. (2016) IL-17A promotes susceptibility during experimental visceral leishmaniasis caused by Leishmania donovani. FASEB J 30:1135-43|
|Nair, Manoj S; Lee, Marianne M; Bonnegarde-Bernard, Astrid et al. (2015) Cry protein crystals: a novel platform for protein delivery. PLoS One 10:e0127669|
|Jee, J; Bonnegarde-Bernard, A; Duverger, A et al. (2015) Neutrophils negatively regulate induction of mucosal IgA responses after sublingual immunization. Mucosal Immunol 8:735-45|
|Bonnegarde-Bernard, A; Jee, J; Fial, M J et al. (2014) IKK? in intestinal epithelial cells regulates allergen-specific IgA and allergic inflammation at distant mucosal sites. Mucosal Immunol 7:257-67|
|Bonnegarde-Bernard, Astrid; Jee, Junbae; Fial, Michael J et al. (2014) Routes of allergic sensitization and myeloid cell IKK? differentially regulate antibody responses and allergic airway inflammation in male and female mice. PLoS One 9:e92307|
|Cormet-Boyaka, Estelle; Jolivette, Kalyn; Bonnegarde-Bernard, Astrid et al. (2012) An NF-?B-independent and Erk1/2-dependent mechanism controls CXCL8/IL-8 responses of airway epithelial cells to cadmium. Toxicol Sci 125:418-29|
|Duverger, Alexandra; Carré, Jeanne-Marie; Jee, Junbae et al. (2010) Contributions of edema factor and protective antigen to the induction of protective immunity by Bacillus anthracis edema toxin as an intranasal adjuvant. J Immunol 185:5943-52|
|Fukuiwa, Tatsuya; Sekine, Shinichi; Kobayashi, Ryoki et al. (2008) A combination of Flt3 ligand cDNA and CpG ODN as nasal adjuvant elicits NALT dendritic cells for prolonged mucosal immunity. Vaccine 26:4849-59|
Showing the most recent 10 out of 63 publications