title: Toll-like receptor agonist augments virus-like particle-mediated protection from Ebola virus with transient immune activation.
abstract: Identifying safe and effective adjuvants is critical for the advanced development of protein-based vaccines. Pattern recognition receptor (PRR) agonists are increasingly being explored as potential adjuvants, but there is concern that the efficacy of these molecules may be dependent on potentially dangerous levels of non-specific immune activation. The filovirus virus-like particle (VLP) vaccine protects mice, guinea pigs, and nonhuman primates from viral challenge. In this study, we explored the impact of a stabilized dsRNA mimic, polyICLC, on VLP vaccination of C57BL/6 mice and Hartley guinea pigs. We show that at dose levels as low as 100 ng, the adjuvant increased the efficacy of the vaccine in mice. Antigen-specific, polyfunctional CD4 and CD8 T cell responses and antibody responses increased significantly upon inclusion of adjuvant. To determine whether the efficacy of polyICLC correlated with systemic immune activation, we examined serum cytokine levels and cellular activation in the draining lymph node. PolyICLC administration was associated with increases in TNFα, IL6, MCP1, MIP1α, KC, and MIP1β levels in the periphery and with the activation of dendritic cells (DCs), NK cells, and B cells. However, this activation resolved within 24 to 72 hours at efficacious adjuvant dose levels. These studies are the first to examine the polyICLC-induced enhancement of antigen-specific immune responses in the context of non-specific immune activation, and they provide a framework from which to consider adjuvant dose levels.
authors.affiliation: Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Karen A O
authors.initials: KA
authors.lastname: Martins
authors.affiliation: Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Jesse T
authors.initials: JT
authors.lastname: Steffens
authors.affiliation: Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Sean A
authors.initials: SA
authors.lastname: van Tongeren
authors.affiliation: Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Jay B
authors.initials: JB
authors.lastname: Wells
authors.affiliation: Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Alison A
authors.initials: AA
authors.lastname: Bergeron
authors.affiliation: Office of Regulated Studies, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Samuel P
authors.initials: SP
authors.lastname: Dickson
authors.affiliation: Virology Division, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: John M
authors.initials: JM
authors.lastname: Dye
authors.affiliation: Oncovir Inc., Washington, DC, United States of America.
authors.forename: Andres M
authors.initials: AM
authors.lastname: Salazar
authors.affiliation: Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, Maryland, United States of America.
authors.forename: Sina
authors.initials: S
authors.lastname: Bavari
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002266:Carboxymethylcellulose Sodium / Q000031:analogs & derivatives* / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D029043:Ebolavirus / Q000187:drug effects / Q000276:immunology; D006168:Guinea Pigs; D019142:Hemorrhagic Fever, Ebola / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000494:pharmacology*; D011107:Polylysine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051193:Toll-Like Receptors / Q000819:agonists*; D058425:Vaccines, Virus-Like Particle / Q000494:pharmacology*
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D051193:Toll-Like Receptors; D058425:Vaccines, Virus-Like Particle; D011107:Polylysine; C019531:poly ICLC; D002266:Carboxymethylcellulose Sodium; D011070:Poly I-C