title: Adjuvant-enhanced CD4 T Cell Responses are Critical to Durable Vaccine Immunity.
abstract: Protein-based vaccines offer a safer alternative to live-attenuated or inactivated vaccines but have limited immunogenicity. The identification of adjuvants that augment immunogenicity, specifically in a manner that is durable and antigen-specific, is therefore critical for advanced development. In this study, we use the filovirus virus-like particle (VLP) as a model protein-based vaccine in order to evaluate the impact of four candidate vaccine adjuvants on enhancing long term protection from Ebola virus challenge. Adjuvants tested include poly-ICLC (Hiltonol), MPLA, CpG 2395, and alhydrogel. We compared and contrasted antibody responses, neutralizing antibody responses, effector T cell responses, and T follicular helper (Tfh) cell frequencies with each adjuvant's impact on durable protection. We demonstrate that in this system, the most effective adjuvant elicits a Th1-skewed antibody response and strong CD4 T cell responses, including an increase in Tfh frequency. Using immune-deficient animals and adoptive transfer of serum and cells from vaccinated animals into naïve animals, we further demonstrate that serum and CD4 T cells play a critical role in conferring protection within effective vaccination regimens. These studies inform on the requirements of long term immune protection, which can potentially be used to guide screening of clinical-grade adjuvants for vaccine clinical development.
authors: Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA.
authors: Karen A O
authors: KAO
authors: Martins
authors: Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA.
authors: Christopher L
authors: CL
authors: Cooper
authors: Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA.
authors: Sabrina M
authors: SM
authors: Stronsky
authors: Research Support Division, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA.
authors: Sarah L W
authors: SLW
authors: Norris
authors: Virology Division, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA.
authors: Steven A
authors: SA
authors: Kwilas
authors: Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA.
authors: Jesse T
authors: JT
authors: Steffens
authors: Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA.
authors: Jacqueline G
authors: JG
authors: Benko
authors: Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA.
authors: Sean A
authors: SA
authors: van Tongeren
authors: Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD, USA. Electronic address: sina.bavari.civ@mail.mil.
authors: Sina
authors: S
authors: Bavari
mesh_terms: D000276:Adjuvants, Immunologic; D019264:Adoptive Transfer; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D000914:Antibodies, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D029043:Ebolavirus / Q000276:immunology; D005260:Female; D019142:Hemorrhagic Fever, Ebola / Q000401:mortality / Q000517:prevention & control; D007109:Immunity; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D018655:Lymphocyte Count; D023421:Models, Animal; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014612:Vaccines / Q000008:administration & dosage / Q000276:immunology*; D058425:Vaccines, Virus-Like Particle / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D016207:Cytokines; D007074:Immunoglobulin G; D014612:Vaccines; D058425:Vaccines, Virus-Like Particle
keywords: Adjuvant; BME, beta mercaptoethanol; CD, cluster of differentiation; DSCF, Dwass, Steel, Critchlow-Fligner; Durable protection; ELISA, Enzyme linked immunosorbent assay; ELISPOT, enzyme-linked immunospot assay; Ebola virus; FACS, fluorescence activated cell sorting; FBS, fetal bovine serum; GP, glycoprotein; IACUC, Institutional Animal Care and Use Committee; IM, intramuscular; IP, intraperitoneal; IQR, interquartile range; Immune correlates; LN, lymph node; MPLA, monophosphoryl lipid A; NAb, neutralizing antibody; Ns, not significant; PBS, phosphate buffered saline; PRR, pattern recognition receptor; Pfu, plaque forming unit; PsVNA, pseudovirion neutralization assay; TLR, Toll-like receptor; USAMRIID, United States Army Medical Research Institute of Infectious Diseases; VLP, virus-like particle; Vaccine; ma-EBOV, mouse-adapted Ebola virus