Shaping Modern Vaccines: Adjuvant Systems Using MicroCrystalline Tyrosine (MCT®)

Abstract

The concept of adjuvants or adjuvant systems, used in vaccines, exploit evolutionary relationships associated with how the immune system may initially respond to a foreign antigen or pathogen, thus mimicking natural exposure. This is particularly relevant during the non-specific innate stage of the immune response; as such, the quality of this response may dictate specific adaptive responses and conferred memory/protection to that specific antigen or pathogen. Therefore, adjuvants may optimise this response in the most appropriate way for a specific disease. The most commonly used traditional adjuvants are aluminium salts; however, a biodegradable adjuvant, MCT^®, was developed for application in the niche area of allergy immunotherapy (AIT), also in combination with a TLR-4 adjuvant-Monophosphoryl Lipid A (MPL^®)-producing the first adjuvant system approach for AIT in the clinic. In the last decade, the use and effectiveness of MCT^® across a variety of disease models in the preclinical setting highlight it as a promising platform for adjuvant systems, to help overcome the challenges of modern vaccines. A consequence of bringing together, for the first time, a unified view of MCT^® mode-of-action from multiple experiments and adjuvant systems will help facilitate future rational design of vaccines while shaping their success.

Keywords: MicroCrystalline Tyrosine (MCT®); Monophosphoryl Lipid A (MPL®); adjuvants; allergy; disease; immunization; vaccines; virus-like particles.

Figure 1

Innate and adaptive immunity time course. The non-specific early inflammatory response is characterized by cells of the innate immune system (e.g., Macrophages) which will recognise conserved repetitive features from bacteria or viruses. If recognized as a threat, the adaptive immune responses develops with the activation of lymphocytes.

Figure 2

An overview of the immune response after vaccination with an MCT^® depot. (A) The early innate response is characterized by immediate exudation of neutrophils and eosinophils in vivo. The role of inflammasome/DAMP-associated mechanisms have not been precisely defined. The innate response has recorded an increase in dendritic cells (DCs), observed 24 h post-injection (45). MCT^® is biodegradable/biocompatible with an estimated half-life of 48 h at the injection site (44). As a result, it is cleared within 7 days with a return to a local steady state. The biodegradable depot properties of MCT^® are thought to be key in orchestrating the subsequent adaptive response. (B) The infiltrating antigen presenting cells to the draining lymph node, induce sustained and robust B cell response, via MHC class II antigen presentation (, –44, 54), with sustained IgG antibody titers. The prolonged immune exposure of antigen is thought to further DC uptake and initiate CD4 T helper cell (Tfh) clonal expansion and differentiation (45). Furthermore, immune complexes may form with follicular dendritic cells (FDCs) via Fcγ receptors (Cd16 and CD32) and complement receptors (CD35). (C) The depot properties of MCT^® have been shown to be key in generating a more robust cytotoxic T cell response, thus the priming of T cells combined with optimal antigen delivery, such as when combined with VLPs, are key drivers in orchestrating this arm of the adaptive response (50).

Figure 3

(A) The physical association of MPL^® across the needle-like crystalline structure of 20 mg/ml MCT^® has been characterized using fluorescently labeled LPS (100 µg; Lipopolysaccharide) as a substitute for MPL^® via confocal microscopy. (B) Proposed C–H⋯π interactions between the 2-deoxy-2-aminoglucose on MPL^® and the aromatic ring on L-tyrosine, based on inhibitor studies with Naphthalene (Adapted from Bell et al., 2015).

Figure 4

Confocal microscopy imaging of fluorescent dye AF488 CuMV_TT-p33 nano-vaccine following formulation with the MCT^® (20 mg/ml) adjuvant.