Abstract
Adjuvant CIA09, composed of 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-based cationic liposomes and the toll-like receptor 4 agonist de-O-acylated lipooligosaccharide (dLOS), has been shown to enhance antibody and cellular immune responses to varicella-zoster virus (VZV) glycoprotein E (gE), recombinant tuberculosis vaccine antigen, and inactivated Japanese encephalitis vaccine. In this study, we investigated its modes of action using VZV gE as a model antigen. Liposomes adsorbed gE and cooperatively with dLOS promoted endocytosis-mediated cellular uptake of gE by mouse dendritic cells in vitro. CIA09 increased the stability and cellular uptake of the antigen at the muscle site of injection, and induced immune cell recruitment and cytokine and chemokine production, which led to efficient antigen delivery to draining lymph nodes. Mouse bone marrow-derived dendritic cells, pulsed with CIA09-adjuvanted gE, efficiently presented gE to antigen-specific T cells, inducing Th1-type biased immunity, as shown by high IFN-γ production. The data indicate that liposomes and dLOS cooperate in the adjuvant activity of CIA09 by promoting antigen uptake and delivery to lymph nodes as well as antigen presentation to T cells.
Highlights
Adjuvants are an important component of many vaccines, especially recombinant subunit vaccines
Using varicella-zoster virus (VZV) glycoprotein E (gE) as the model antigen, we investigated the mechanism of action of CIA09 and demonstrate here that liposomes and de-O-acylated lipooligosaccharide (dLOS) cooperatively promote (i) the immunogenicity of VZV gE antigen by increasing the antigen stability, (ii) antigen uptake at the site of injection (SOI), (iii) the recruitment of immune cells, (iv) antigen delivery to the lymph nodes, and v) antigen presentation by antigen-presenting cells (APCs) to T cells
The protective immunity induced by vaccination depends on the interaction of APCs with T cells, which links innate and acquired immunity, and activation of dendritic cells (DCs) is essential for antigen processing and presentation to T cells [46,47]
Summary
Adjuvants are an important component of many vaccines, especially recombinant subunit vaccines. Immunomodulatory adjuvants directly activate immune cells, induce cytokines and chemokines, and recruit immune cells [2,5] They are typically ligands for cellular pattern recognition receptors (PRRs), including toll-like receptors (TLRs), C-type lectin receptors (CLRs), nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), and cytosolic dsDNA sensors (CDSs) [6,7,8,9,10,11]. These ligands mimic pathogen or damage-associated molecular patterns (PAMPs/DAMPs) to recognize PRRs and induce the rapid activation of innate immune responses, leading to adaptive immunity [6,7,8,9,10,11]. Designed adjuvant formulations, containing two or more adjuvants with different, cooperative modes of action, provide high adjuvant activity, optimizing the efficacy of vaccines [12,13]
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