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Review
. 2011 Jan;239(1):178-96.
doi: 10.1111/j.1600-065X.2010.00978.x.

Use of defined TLR ligands as adjuvants within human vaccines

Malcolm S Duthie  1 , Hillarie Plessner Windish, Christopher B Fox, Steven G Reed
Affiliations
Review

Use of defined TLR ligands as adjuvants within human vaccines

Malcolm S Duthie et al. Immunol Rev. 2011 Jan.

Abstract

Our improved understanding of how innate immune responses can be initiated and how they can shape adaptive B- and T-cell responses is having a significant impact on vaccine development by directing the development of defined adjuvants. Experience with first generation vaccines, as well as rapid advances in developing defined vaccines containing Toll-like receptor ligands (TLRLs), indicate that an expanded number of safe and effective vaccines containing such molecules will be available in the future. In this review, we outline current knowledge regarding TLRs, detailing the different cell types that express TLRs, the various signaling pathways TLRs utilize, and the currently known TLRLs. We then discuss the current status of TLRLs within vaccine development programs, including the importance of appropriate formulation, and how recent developments can be used to better define the mechanisms of action of vaccines. Finally, we introduce the possibility of using TLRLs, either in combination or with non-TLRLs, to synergistically potentiate vaccine-induced responses to provide not only prophylactic, but therapeutic protection against infectious diseases and cancer.

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Figures

Fig. 1
Fig. 1. Vaccine development and implications for TLRL use
Fig. 2
Fig. 2. Examples of the differential expression of PRRs by human cells
Fig. 3
Fig. 3. Differential use of TLRs by human and mouse B cells
B cells from a human donor or from two mouse strains were stimulated with tittered doses of TLR4 (MPL, GLA, LPS) or TLR9 (CpG) ligands, then secretion of IL-10 measured by ELISA.
Fig. 4
Fig. 4. The GLA-SE adjuvant promotes high quality Th1 responses characterized by the generation of antigen-specific pluripotent CD4+ T cells
Mice were immunized by injection of the Mycobacterium tuberculosis fusion antigens in the presence of GLA-SE. Spleens were collected, single cell suspensions prepared and cells cultured with antigen. (A) Cytokines secreted into the culture supernatant were measured by ELISA. (B) Cells were cultured with antigen and BD Golgi STOP (to prevent secretion) overnight, then fixed and stained for flow cytometry. Activated CD4+ T cells were identified based on CD3 and CD4 expression, and further gated as CD44hi. Graphs depict the proportion of activated CD4+ T cells expressing one, two, or the three cytokines (IFN-γ, TNF, and IL-2). Data originally published in (65).
Fig. 5
Fig. 5. Use of various TLRL to generate IFNγ-producing antigen-specific CD4+ T cells
Mice were immunized by subcutaneous injection of the Mycobacterium leprae antigen ML0276 in the presence of CpG, IMQ, or GLA-SE at biweekly intervals, for a total of three immunizations. Spleens were collected 1 month after the third immunization, single cell suspensions prepared, and cells cultured with antigen and BD Golgi STOP (to prevent secretion) overnight, then fixed and stained for flow cytometry to determine the percentage CD3+CD4+CD44hi IFNγ cells. Data were originally published in (63).
Fig. 6
Fig. 6. PRRs use different adapter molecules, allowing the use of agonist combinations to provide synergy in responses
The cellular locations, adapter molecules, and final genes targeted by different PRRs, along with an example of the responses elicited when DCs are stimulated through TLR4 (GLA, MPL), TLR9 (CpG), or both TLR4 and TLR9 are depicted.
Fig. 7
Fig. 7. Impact of infection on vaccines engaging different TLRs
Parasite burden was reduced in the Leishmania major-infected footpads of mice treated with a combination of TLR4 and TLR9 agonists and this corresponded with the ability to prime antigen-experienced CD4+ T cells capable of producing IFN-γ. While single TLRLs could raise these responses in the spleens of uninfected mice, the combination of TLR4 and TLR9 agonists was required to do so in L. major-infected mice. Data originally published in (64).
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References

    1. O’Neill LA, Bryant CE, Doyle SL. Therapeutic targeting of Toll-like receptors for infectious and inflammatory diseases and cancer. Pharmacol Rev. 2009;61:177–197. - PMC - PubMed
    1. Imler JL, Zheng L. Biology of Toll receptors: lessons from insects and mammals. J Leukoc Biol. 2004;75:18–26. - PubMed
    1. O’Neill LA, Bowie AG. The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol. 2007;7:353–364. - PubMed
    1. Gribar SC, Richardson WM, Sodhi CP, Hackam DJ. No longer an innocent bystander: epithelial toll-like receptor signaling in the development of mucosal inflammation. Mol Med. 2008;14:645–659. - PMC - PubMed
    1. Ostuni R, Zanoni I, Granucci F. Deciphering the complexity of Toll-like receptor signaling. Cell Mol Life Sci. 2010;67:4109–4134. - PMC - PubMed

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