A structure‐function approach to optimizing TLR4 ligands for human vaccines

Abstract

Adjuvants are combined with vaccine antigens to enhance and modify immune responses, and have historically been primarily crude, undefined entities. Introducing toll-like receptor (TLR) ligands has led to a new generation of adjuvants, with TLR4 ligands being the most extensively used in human vaccines. The TLR4 crystal structures demonstrate extensive contact with their ligands and provide clues as to how they discriminate a broad array of molecules and activate or attenuate innate, as well as adaptive, responses resulting from these interactions. Leveraging this discerning ability, we made subtle chemical alterations to the structure of a synthetic monophosphoryl lipid-A molecule to produce SLA, a designer TLR4 ligand that had a number of desirable adjuvant effects. The SLA molecule stimulated human TLR4 and induced Th1 biasing cytokines and chemokines. On human cells, the activity of SLA plateaued at lower concentrations than the lipid A comparator, and induced cytokine profiles distinct from other known TLR4 agonists, indicating the potential for superior adjuvant performance. SLA was formulated in an oil-in-water emulsion, producing an adjuvant that elicited potent Th1-biased adaptive responses. This was verified using a recombinant Leishmania vaccine antigen, first in mice, then in a clinical study in which the antigen-specific Th1-biased responses observed in mice were recapitulated in humans. These results demonstrated that using structure-based approaches one can predictably design and produce modern adjuvant formulations for safe and effective human vaccines.

Selection of adjuvants for vaccines targeting specific pathogens

“…Subtle chemical alterations to MPLA were made to develop a designer SMIP-based TLR4-agonist known as SLA, which induces TRIF signaling to produce Th1biased cytokines and chemokines like IFN and IP-10, and less IL-1β. SLA in oil-in-water emulsion (SLA-SE) was produced capitalizing on the knowledge that a combination of IFN and caspase-dependent inflammasome signaling leads to powerful adjuvant action [46].…”

A combination of TLR-4 agonist and saponin adjuvants increases antibody diversity and protective efficacy of a recombinant West Nile Virus antigen

“…SLA, a synthetic lipid adjuvant, is a derivative of GLA and has been previously described. 49 QS21 was obtained through in-house purification of Quil A (Brenntag Biosector), or purchased from Desert King (San Diego, CA). QS21 purity was assessed in each lot via a high-performance liquid chromatography-based method established at IDRI and qualified for cGMP release.…”

Better Adjuvants for Better Vaccines: Progress in Adjuvant Delivery Systems, Modifications, and Adjuvant–Antigen Codelivery

“…To obtain a single component of MPL, a chemical synthesis method is used to obtain GLA, an MPL analog that retains the hexa-acyl structure and has better adjuvant effects [81]. Based on molecular simulations and docking of GLA and TLR4/MD2 structures, it was predicted that the truncated acyl side chain could enhance the affinity of these compounds to TLR4, which was later confirmed by the synthesis of side-chain-truncated compound SLA [82]. SLA induces less inflammatory cytokines than GLA and may have better safety.…”