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.
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.