Recent Advances in Toll Like Receptor-Targeting Glycoconjugate Vaccines

Abstract

Many malignant cell surface carbohydrates resulting from abnormal glycosylation patterns of certain diseases can serve as antigens for the development of vaccines against these diseases. However, carbohydrate antigens are usually poorly immunogenic by themselves, thus they need to be covalently coupled with immunologically active carrier molecules to be functional. The most well established and commonly used carriers are proteins. In recent years, the use of toll-like receptor (TLR) ligands to formulate glycoconjugate vaccines has gained significant attention because TLR ligands can serve not only as carrier molecules but also as built-in adjuvants to form fully synthetic and self-adjuvanting conjugate vaccines, which have several advantages over carbohydrate-protein conjugates and formulated mixtures with external adjuvants. This article reviews recent progresses in the development of conjugate vaccines based on TLR ligands. Two major classes of TLR ligands, lipopeptides and lipid A derivatives will be covered with more focus on monophosohoryl lipid A (MPLA) and related analogs, which are TLR4 ligands demonstrated to be able to provoke T cell-dependent, adaptive immune responses. Corresponding conjugate vaccines have shown promising application potentials to multiple diseases including cancer.

The Role of Toll-Like Receptors in Oncotherapy

“…The combination of MPLA and alum, known as AS04, is a vaccine that has been utilized in the treatment of various cancers, including metastatic melanoma prostate cancer, and also for the prevention of cervical cancer 33 . MPLA has been investigated in phase 1 clinical trials in patients with colorectal cancer, and it has been approved as an adjuvant used in Cervarix vaccine, which is a prophylactic treatment for human papilloma virus (HPV)-associated cervical cancer 34 . GLA-SE, GSK1795091, and G100 are also TLR4 agonists that are being tested for the treatment of soft tissue sarcoma, Merkel cell carcinoma, and follicular lymphoma 35 .…”

Application of built-in adjuvants for epitope-based vaccines

“…Synthetic lipopeptides and their analogues play an important role in the study of built-in adjuvants for epitope-based vaccines. However, compared with mature protein carriers for conjugated vaccines, TLR ligands (e.g., lipopeptides and monophosphoryl lipid A derivatives) are still in their early stages as potential vaccine carriers (Li & Guo, 2018). However, since their interaction with TLRs has been thoroughly studied and understood, the prospective development of epitope-based vaccines using TLR ligands as built-in adjuvants is foreseeable.…”

“…At present, one of the major challenges is obtaining a sufficient number of vaccines for clinical research since the structure of these lipopeptides, as well as their synthesis and binding to target antigens is highly complex. Semi-total and aminoalkyl glucosaminide 4-phosphates (AGPs) synthesis are important methods that can be used to solve this problem (Li & Guo, 2018; Persing et al, 2002). AGPs have a less-complex structure that allows for synthesis to be easier, more efficient, and elicit immunostimulatory activity in preclinical studies.…”

Peer Review #3 of "Application of built-in adjuvants for epitope-based vaccines (v0.1)"

“…Synthetic lipopeptides and their analogues play an important role in the study of built-in adjuvants for epitope-based vaccines. However, compared with mature protein carriers for conjugated vaccines, TLR ligands (e.g., lipopeptides and monophosphoryl lipidA (MPLA) derivatives) are still in their early stages as potential vaccine carriers (Li & Guo, 2018).…”