TLR AGONISTS: Are They Good Adjuvants?

TLR4 agonists

Bacterial (LPS) and its derivatives are a commonly used vaccine adjuvants. Monophosphoryl lipid A (MPL) a detoxified component of LPS is derived from Salmonella minnesota, and contains the lipid A moiety that ligates TLR4 (46). Because it is substantially less toxic than LPS, has a history of safety and potently activates human DC, it has been incorporated into several vaccines. It also produces a different pro-inflammatory profile compared to LPS, including the production of type I IFNs, possibly because it may preferentially activate the TRIF vs. MyD88 signaling pathways (47). MPL has been approved for inclusion in a vaccine for Hepatitis B, Fendrix™ (48) and cervical cancer, Cervarix™ (49, 50). Cervarix, a GSK product, is indicated for the prevention of diseases caused by oncogenic human papillomavirus (HPV) types 16 and 18, including cervical cancer, cervical intraepithelial neoplasia (CIN) grade 1 and 2 or worse and adenocarcinoma in situ. Besides MPL, the vaccine contains L1 capsid proteins from HPV and the adjuvant aluminum hydroxide. 100% protection of the vaccine was demonstrated in phase II trials against types 16 and 18 HPV, (51). Over 30,000 women have received this vaccine and it is now approved in both Europe and America. Vaccination offers protection for >6 years, making this vaccine a milestone in the prevention of cancer. A clinical trial to determine whether Cervarix is more effective than Merck's HPV vaccine Gardasil™, which contains L1 capsid proteins and aluminum hydroxyphosphate sulfate, in addition to a yeast protein is under evaluation. MPL is also a component of Glaxo Smith Kline’s vaccine formulations for NSCLC and melanoma in combination with TLR9 agonists (see below). Phase IIB studies showed improved median survival time in patients with stage IIIB NSLC devoid of metastases (52).

 

サーバリックスに含まれるMPLは、TLR４アゴニスト（TLR4に作用する物質）である。