Licensed and investigational TLR4 agonists as vaccine adjuvants: structural basis, clinical progress, and future directions

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Next-generation vaccines, including protein subunit and nucleic acid platforms, have advanced but often require adjuvants for optimal immunogenicity.
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Aluminum-containing adjuvants are widely used but primarily enhance humoral immunity and inadequately stimulate cellular immune responses.
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TLR4 agonists are emerging as promising vaccine adjuvants, capable of stimulating both humoral and cellular immune responses.
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Monophosphoryl lipid A (MPL) is the most successful TLR4 agonist, used in clinically licensed adjuvant systems like AS01 and AS04.
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The review aims to provide insights into TLR4 agonists' mechanisms and clinical development to enhance vaccine efficacy.

Frontiers In Immunology

by Jiasheng Zhou, Bo Liu, Qiao Yang, Jingxuan Zhou, Jiahao Zheng, Yujin Chen, Lie Fu, Jianhui Du, Zhegang Zhang, Jiayou Zhang, Changgui Li
July 16, 2026

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