Sally Mossman

Taking a Toll on human disease: Toll-like receptor 4 agonists as vaccine adjuvants and monotherapeutic agents

Toll-like receptor (TLR) agonists are being developed for use as vaccine adjuvants and as stand-alone immunomodulators because of their ability to stimulate innate and adaptive immune responses. Among the most thoroughly studied TLR agonists are the lipid A molecules that target the TLR4 complex. One promising candidate, monophosphoryl lipid A, which is a derivative of lipid A from Salmonella minnesota, has proven to be safe and effective as a vaccine adjuvant in > 120,000 human doses. A new class of synthetic lipid A mimetics, the aminoalkyl glucosaminide 4-phosphates (AGPs), have been engineered specifically to target human TLR4 and are showing promise as vaccine adjuvants and as monotherapeutic agents capable of eliciting nonspecific protection against a wide range of infectious pathogens. In this review, the authors provide an update of the preclinical and clinical experiences with the TLR4 agonists, MPL® (Corixa Corporation) adjuvant and the AGPs.

Toll-like receptor 4 agonists as vaccine adjuvants

Publisher Summary Lipopolysaccharide (LPS), the major component of the Gram-negative bacterial cell wall, has long been known as a powerful immunomodulator. Despite its well-known ability to enhance immune responses, LPS is considered too toxic by current standards to be clinically useful because of the induction of excessive amounts of inflammatory cytokines which provoke a sepsis-like syndrome. Finally, it is likely that Toll-like receptors (TLR) agonists and antagonists may enter clinical trials in the next few years as standalone immunomodulators. Intranasal administration of TLR4 agonists may protect the airways against natural infection by viruses for which there are no effective vaccines or antiviral drugs. The transient protection afforded by weekly or biweekly doses of an immunomodulatory nasal spray might prove beneficial for emerging viral infections. The broad protective ability of TLR4 agonists relative to viral and bacterial challenges make them especially well-suited for complex, multifactorial diseases in which exacerbations are most often triggered by upper respiratory viral infection. Indeed, within the immunological epiphany created by the discovery of the TLRs and their respective ligands, a new generation of designer adjuvants, therapeutic and prophylactic vaccines, and immunomodulatory therapies may be close at hand.