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Review
. 2022 Feb 16;14(2):423.
doi: 10.3390/pharmaceutics14020423.

Recent Advances in the Development of Toll-like Receptor Agonist-Based Vaccine Adjuvants for Infectious Diseases

Jing-Xing Yang  1 , Jen-Chih Tseng  1 , Guann-Yi Yu  2 , Yunping Luo  3 , Chi-Ying F Huang  4 , Yi-Ren Hong  5 , Tsung-Hsien Chuang  1   6   7
Affiliations
Review

Recent Advances in the Development of Toll-like Receptor Agonist-Based Vaccine Adjuvants for Infectious Diseases

Jing-Xing Yang et al. Pharmaceutics. .

Abstract

Vaccines are powerful tools for controlling microbial infections and preventing epidemic diseases. Efficient inactive, subunit, or viral-like particle vaccines usually rely on a safe and potent adjuvant to boost the immune response to the antigen. After a slow start, over the last decade there has been increased developments on adjuvants for human vaccines. The development of adjuvants has paralleled our increased understanding of the molecular mechanisms for the pattern recognition receptor (PRR)-mediated activation of immune responses. Toll-like receptors (TLRs) are a group of PRRs that recognize microbial pathogens to initiate a host's response to infection. Activation of TLRs triggers potent and immediate innate immune responses, which leads to subsequent adaptive immune responses. Therefore, these TLRs are ideal targets for the development of effective adjuvants. To date, TLR agonists such as monophosphoryl lipid A (MPL) and CpG-1018 have been formulated in licensed vaccines for their adjuvant activity, and other TLR agonists are being developed for this purpose. The COVID-19 pandemic has also accelerated clinical research of vaccines containing TLR agonist-based adjuvants. In this paper, we reviewed the agonists for TLR activation and the molecular mechanisms associated with the adjuvants' effects on TLR activation, emphasizing recent advances in the development of TLR agonist-based vaccine adjuvants for infectious diseases.

Keywords: adjuvant; mRNA vaccine; nasal adjuvant; toll-like receptor; vaccine.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A timeline of adjuvant development and vaccine licensing. The year the adjuvant was used in licensed vaccines or emergency use authorized (EUA) vaccines is shown. AS, adjuvant system; MPL, monophosphoryl lipid A; HAV, hepatitis A virus; HBV, hepatitis B virus; HPV, human papillomavirus; WHO, world health organization; OMVs, outer membrane vesicles.
Figure 2
Figure 2
Overview of TLR signaling pathways. TLRs localize to the cell surface and in endosome compartments, where they detect pathogens from microbes. Upon stimulation, TLRs activate two major downstream adaptor proteins, MyD88 and TRIF. Engagement of the signaling adaptor molecules stimulates downstream signaling cascades that involve the production of proinflammatory cytokines and interferons (IFNs). PAMP, pathogen-associated molecular pattern; DAMP, damage-associated molecular pattern; LPS, lipopolysaccharide; MyD88, myeloid differentiation primary response 88; MAL, MyD88 adaptor-like protein; TRIF, TIR domain-containing adaptor-inducing interferon-β; TRAM, TRIF-related adaptor molecule; TRAF, tumor necrosis factor receptor-associated factor; IRAK, interleukin-1 receptor-associated kinase; TBK1, TANK-binding kinase 1; TAB, TAK1-binding protein; TAK1, TGF-β-activated kinase 1; IKK, inhibitor of NF-κB kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; AP-1, activator protein 1; CREB, cAMP-responsive element-binding protein; IFN, interferon; IRF, IFN regulatory factor.
Figure 3
Figure 3
Immune responses elicited by TLR activations. TLR ligands directly activate APCs, such as monocytes/macrophages, DCs, and B cells. The surface expression of maturation markers and costimulatory molecules, including CD80, CD86, and MHC-II are increased in DCs and macrophages. The production of proinflammatory cytokines by activated APCs such as IL-1, IL-12, and type I IFNs promote naïve CD4+ T-cell differentiation to Th1, Th17, and Treg subsets. NK cells and CTLs are also activated, secreting IFN-γ and increasing killing activity, respectively. Moreover, B-cell activation by TLR ligands increases the production of IgM, IL-6, IL-10, and chemokines. Then the B cells differentiate to plasma cells, which increases their antigen-specific IgG production. APC, antigen-presenting cells; DC, dendritic cell; CTL, cytotoxic T lymphocyte; MHC, major histocompatibility complex; TNF, tumor necrosis factor; IL, interleukin.
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