Toll-like receptor 4 agonists as vaccine adjuvants

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.