Recent advances in the discovery and delivery of vaccine adjuvants

O’Hagan, Derek T.; Valiante, Nicholas M.

doi:10.1038/nrd1176

Cited by 378 publications

(278 citation statements)

References 63 publications

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“…Antigen targeting [1][2][3][4][5] and adjuvancy schemes 6,7 that respectively facilitate delivery of antigen to dendritic cells and elicit their activation have been explored in vaccine development. Here we investigate whether nanoparticles can be used as a vaccine platform by targeting lymph noderesiding dendritic cells via interstitial flow and activating these cells by in situ complement activation.…”

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confidence: 99%

“…Dendritic cells are often matured by 'danger signals' that work through pathways of innate immunity such as activation of Toll-like receptors (TLRs) and inflammatory cytokine receptors. Whereas experimental vaccines using danger signals have shown promise 6,7 , risk of toxicity, physiological transport limitations and economic feasibility remain as potentially limiting issues.…”

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confidence: 99%

“…Next, we designed the nanoparticles to function themselves as an adjuvant, which is necessary to induce dendritic cell maturation and initiate adaptive immunity. Adjuvants are typically danger signals that work by activation of TLRs and inflammatory cytokine receptors; such adjuvants have been widely explored in experimental vaccine formulations 6,7 . For example, molecular danger signals that mimic the effect of the endotoxin lipopolysaccharide (LPS), such as monophosphoryl lipid A, have been explored 7 , as well as the cytokines CD40 ligand and interferon (IFN)-g 1,2,16 .…”

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confidence: 99%

“…Lymphatic delivery is often even prevented by aggregating antigen with alum to produce a depot effect. Adjuvant research is dominated by formulations using TLR activators and inflammatory cytokines as molecular danger signals 6,7 , complement activation having been relatively unexplored. Our results highlight two alternative strategies for vaccination: interstitial-to-lymphatic flow to deliver antigen and adjuvant to lymph node-resident dendritic cells, and in situ complement activation to mature these cells.…”

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Exploiting lymphatic transport and complement activation in nanoparticle vaccines

et al. 2007

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Exploiting lymphatic transport and complement activation in nanoparticle vaccines

et al. 2007

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“…Adjuvants are used in vaccines to provide immunostimulation and facilitate innate immunity and consequently can direct potent adaptive immunity (9). Currently, only Alum and MF59 are approved for widespread human use (10,11) and both fail to evoke a strong CD8 ϩ T cell response.…”

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confidence: 99%

Rapid Clonal Expansion and Prolonged Maintenance of Memory CD8+ T Cells of the Effector (CD44highCD62Llow) and Central (CD44highCD62Lhigh) Phenotype by an Archaeosome Adjuvant Independent of TLR2

Krishnan

Gurnani

Dicaire

et al. 2007

The Journal of Immunology

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Vaccines capable of eliciting long-term T cell immunity are required for combating many diseases. Live vectors can be unsafe whereas subunit vaccines often lack potency. We previously reported induction of CD8+ T cells to Ag entrapped in archaeal glycerolipid vesicles (archaeosomes). In this study, we evaluated the priming, phenotype, and functionality of the CD8+ T cells induced after immunization of mice with OVA-Methanobrevibacter smithii archaeosomes (MS-OVA). A single injection of MS-OVA evoked a profound primary response but the numbers of H-2KbOVA257–264-specific CD8+ T cells declined by 14–21 days, and <1% of primarily central phenotype (CD44highCD62Lhigh) cells persisted. A booster injection of MS-OVA at 3–11 wk promoted massive clonal expansion and a peak effector response of ∼20% splenic/blood OVA257–264-specific CD8+ T cells. Furthermore, contraction was protracted and the memory pool (IL-7Rαhigh) of ∼5% included effector (CD44highCD62Llow) and central (CD44highCD62Lhigh) phenotype cells. Recall response was observed even at >300 days. CFSE-labeled naive OT-1 (OVA257–264 TCR transgenic) cells transferred into MS-OVA-immunized recipients cycled profoundly (>90%) within the first week of immunization indicating potent Ag presentation. Moreover, ∼25% cycling of Ag-specific cells was seen for >50 days, suggesting an Ag depot. In vivo, CD8+ T cells evoked by MS-OVA killed >80% of specific targets, even at day 180. MS-OVA induced responses similar in magnitude to Listeria monocytogenes-OVA, a potent live vector. Furthermore, protective CD8+ T cells were induced in TLR2-deficient mice, suggesting nonengagement of TLR2 by archaeal lipids. Thus, an archaeosome adjuvant vaccine represents an alternative to live vectors for inducing CD8+ T cell memory.

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Mycobacterium tuberculosis low molecular weight T‐cell antigen Mtb8.4 has heme‐binding and fiber‐forming properties

et al. 2022

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Mtb8.4, a secretory T‐cell antigen of Mycobacterium tuberculosis, is important for providing an antigen‐specific immune response. In this study, we showed Mtb8.4 to have both heme‐binding and fibril‐forming properties, using experimental and in silico methods. High absorbance at 410 nm and interaction with hemin‐agarose demonstrated its heme‐binding nature. Titration of Mtb8.4 with heme resulted in 1 : 1 stoichiometry. The heme‐binding pocket in Mtb8.4 was identified by molecular modeling, and binding residues were predicted using molecular docking. The molecular dynamics simulations of apo‐ and heme‐bound Mtb8.4 confirmed that the heme group forms a stable complex. Transmission electron microscopy analyses and dye‐binding assays showed that Mtb8.4 forms fibers. Computational studies predicted that the C‐terminal sequence (93AAQYIGLVESV103) is important for forming fibers. In silico analyses further anticipated the probable epitope (82AMAAQLQAV90) of Mtb8.4. The fiber‐forming properties of Mtb8.4 could be advantageous from a vaccine perspective for aggregate/fibril‐based vaccine delivery or it might influence the epitope presentation of Mtb8.4.

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Recent advances in the discovery and delivery of vaccine adjuvants

Cited by 378 publications

References 63 publications

Exploiting lymphatic transport and complement activation in nanoparticle vaccines

Exploiting lymphatic transport and complement activation in nanoparticle vaccines

Rapid Clonal Expansion and Prolonged Maintenance of Memory CD8+ T Cells of the Effector (CD44highCD62Llow) and Central (CD44highCD62Lhigh) Phenotype by an Archaeosome Adjuvant Independent of TLR2

Mycobacterium tuberculosis low molecular weight T‐cell antigen Mtb8.4 has heme‐binding and fiber‐forming properties

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