ISCOMATRIX vaccines mediate CD8<sup>+</sup> T‐cell cross‐priming by a MyD88‐dependent signaling pathway

Wilson, Nicholas S.; Yang, Becky; Morelli, Adriana Baz; Koernig, Sandra; Yang, Annie; Loeser, Stefanie; Airey, Denise; Provan, Larissa; Hass, Phil; Braley, Hal; Couto, Suzana; Drane, Debbie; Boyle, Jeff; Belz, Gabrielle T.; Ashkenazi, Avi; Maraskovsky, Eugene

doi:10.1038/icb.2011.71

Cited by 91 publications

(108 citation statements)

References 61 publications

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“…In our study, the induction of a number of cytokines (e.g., IL-6, CCL2, and CCL3) may have been dependent on MPL (8), whereas the induction of IL-1b may have been due to QS-21 because IL-1b induction is associated with the activation of the inflammasome, and the activation of the inflammasome has been observed with QuilA (54). In addition, QS-21 is likely to have played a role in CD8 + T cell induction in the mouse model used in this study, perhaps mediated by a particular population of DCs, as reported recently (35). The contributory roles of MPL and QS-21 in the response are currently under investigation.…”

Section: Discussionmentioning

confidence: 47%

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Enhancement of Adaptive Immunity by the Human Vaccine Adjuvant AS01 Depends on Activated Dendritic Cells

Didierlaurent

Collignon

Bourguignon

et al. 2014

The Journal of Immunology

222

198

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Adjuvant System AS01 is a liposome-based vaccine adjuvant containing 3-O-desacyl-4′-monophosphoryl lipid A and the saponin QS-21. AS01 has been selected for the clinical development of several candidate vaccines including the RTS,S malaria vaccine and the subunit glycoprotein E varicella zoster vaccine (both currently in phase III). Given the known immunostimulatory properties of MPL and QS-21, the objective of this study was to describe the early immune response parameters after immunization with an AS01-adjuvanted vaccine and to identify relationships with the vaccine-specific adaptive immune response. Cytokine production and innate immune cell recruitment occurred rapidly and transiently at the muscle injection site and draining lymph node postinjection, consistent with the rapid drainage of the vaccine components to the draining lymph node. The induction of Ag-specific Ab and T cell responses was dependent on the Ag being injected at the same time or within 24 h after AS01, suggesting that the early events occurring postinjection were required for these elevated adaptive responses. In the draining lymph node, after 24 h, the numbers of activated and Ag-loaded monocytes and MHCIIhigh dendritic cells were higher after the injection of the AS01-adjuvanted vaccine than after Ag alone. However, only MHCIIhigh dendritic cells appeared efficient at and necessary for direct Ag presentation to T cells. These data suggest that the ability of AS01 to improve adaptive immune responses, as has been demonstrated in clinical trials, is linked to a transient stimulation of the innate immune system leading to the generation of high number of efficient Ag-presenting dendritic cells.

show abstract

Section: Discussionmentioning

confidence: 47%

“…CD11c + cell depletion was achieved by injecting DT into animals that had bone marrow transplants from mice transgenic for DTR driven by the CD11c promoter (35). Transgene expression rendered the cells sensitive to the lethal effect of DT.…”

Section: Improved T Cell Response By As01 Is Mediated By Mhcii High Dcsmentioning

confidence: 99%

Enhancement of Adaptive Immunity by the Human Vaccine Adjuvant AS01 Depends on Activated Dendritic Cells

Didierlaurent

Collignon

Bourguignon

et al. 2014

The Journal of Immunology

222

198

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“…Recent studies have demonstrated the ability of IMX to enhance MHC class I cross-presentation and produce long-lasting Ab and T cell immune responses (20)(21)(22)(23)(24). The dependence on the adapter protein MyD88 for cellular immunity to an IMX vaccine remains unresolved (24). Similarly, MyD88 has been implicated in the mechanism of MF59 adjuvanticity in mice (25,26).…”

mentioning

confidence: 99%

“…Ags can be formulated with IMX to produce IMX vaccines (18,19). Recent studies have demonstrated the ability of IMX to enhance MHC class I cross-presentation and produce long-lasting Ab and T cell immune responses (20)(21)(22)(23)(24). The dependence on the adapter protein MyD88 for cellular immunity to an IMX vaccine remains unresolved (24).…”

mentioning

confidence: 99%

Inflammasome-Dependent and -Independent IL-18 Production Mediates Immunity to the ISCOMATRIX Adjuvant

Wilson¹,

Duewell

Yang³

et al. 2014

The Journal of Immunology

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Adjuvants are an essential component of modern vaccines and used for their ability to elicit immunity to coadministered Ags. Many adjuvants in clinical development are particulates, but how they drive innate and adaptive immune responses remains poorly understood. Studies have shown that a number of vaccine adjuvants activate inflammasome pathways in isolated APCs. However, the contribution of inflammasome activation to vaccine-mediated immunity in vivo remains controversial. In this study, we evaluated immune cell responses to the ISCOMATRIX adjuvant (IMX) in mice. Like other particulate vaccine adjuvants, IMX potently activated the NALP-3–ASC–Caspase-1 inflammasome in APCs, leading to IL-1β and IL-18 production. The IL-18R pathway, but not IL-1R, was required for early innate and subsequent cellular immune responses to a model IMX vaccine. APCs directly exposed to IMX underwent an endosome-mediated cell-death response, which we propose initiates inflammatory events locally at the injection site. Importantly, both inflammasome-related and -unrelated pathways contributed to IL-18 dependence in vivo following IMX administration. TNF-α provided a physiological priming signal for inflammasome-dependent IL-18 production by APCs, which correlated with reduced vaccine-mediated immune cell responses in TNF-α– or TNFR-deficient mice. Taken together, our findings highlight an important disconnect between the mechanisms of vaccine adjuvant action in vitro versus in vivo.

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“…Subjects who received three intramuscular doses of this vaccine at 3-week intervals experienced a 50% decrease in viral shedding and a 69% reduction in the rate of genital lesions compared to placebo, which continued for 6 months postvaccination (55). T cell responses have not been reported for this trial, but adjuvants with compositions similar to that of matrix-M2 have been shown in animal models to promote major histocompatibility complex (MHC) class I cross-presentation and the promotion of CTL responses (58). It will be interesting to learn if CD8 T cell responses specific for ICP4 are detectable in these vaccinated individuals.…”

Section: Figmentioning

confidence: 99%

Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir

Hensel¹,

Marshall²,

Dorwart³

et al. 2017

J Virol

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Several prophylactic vaccines targeting herpes simplex virus 2 (HSV-2) have failed in the clinic to demonstrate sustained depression of viral shedding or protection from recurrences. Although these vaccines have generated high titers of neutralizing antibodies (NAbs), their induction of robust CD8 T cells has largely been unreported, even though evidence for the importance of HSV-2 antigen-specific CD8 T cells is mounting in animal models and in translational studies involving subjects with active HSV-2-specific immune responses. We developed a subunit vaccine composed of the NAb targets gD and gB and the novel T cell antigen and tegument protein UL40, and we compared this vaccine to a whole-inactivated-virus vaccine (formaldehyde-inactivated HSV-2 [FI-HSV-2]). We evaluated different formulations in combination with several Th1-inducing Toll-like receptor (TLR) agonists in vivo. In mice, the TLR9 agonist cytosine-phosphate-guanine (CpG) oligodeoxynucleotide formulated in a squalene-based oil-in-water emulsion promoted most robust, functional HSV-2 antigen-specific CD8 T cell responses and high titers of neutralizing antibodies, demonstrating its superiority to vaccines adjuvanted by monophosphoryl lipid A (MPL)-alum. We further established that FI-HSV-2 alone or in combination with adjuvants as well as adjuvanted subunit vaccines were successful in the induction of NAbs and T cell responses in guinea pigs. These immunological responses were coincident with a suppression of vaginal HSV-2 shedding, low lesion scores, and a reduction in latent HSV-2 DNA in dorsal root ganglia to undetectable levels. These data support the further preclinical and clinical development of prophylactic HSV-2 vaccines that contain appropriate antigen and adjuvant components responsible for programming elevated CD8 T cell responses.IMPORTANCE Millions of people worldwide are infected with herpes simplex virus 2 (HSV-2), and to date, an efficacious prophylactic vaccine has not met the rigors of clinical trials. Attempts to develop a vaccine have focused primarily on glycoproteins necessary for HSV-2 entry as target antigens and to which the dominant neutralizing antibody response is directed during natural infection. Individuals with asymptom- Citation Hensel MT, Marshall JD, Dorwart MR, Heeke DS, Rao E, Tummala P, Yu L, Cohen GH, Eisenberg RJ, Sloan DD. 2017. Prophylactic herpes simplex virus 2 (HSV-2) vaccines adjuvanted with stable emulsion and Toll-like receptor 9 agonist induce a robust HSV-2-specific cell-mediated immune response, protect against symptomatic disease, and reduce the latent viral reservoir.

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ISCOMATRIX vaccines mediate CD8⁺ T‐cell cross‐priming by a MyD88‐dependent signaling pathway

Cited by 91 publications

References 61 publications

Enhancement of Adaptive Immunity by the Human Vaccine Adjuvant AS01 Depends on Activated Dendritic Cells

Enhancement of Adaptive Immunity by the Human Vaccine Adjuvant AS01 Depends on Activated Dendritic Cells

Inflammasome-Dependent and -Independent IL-18 Production Mediates Immunity to the ISCOMATRIX Adjuvant

Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir

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ISCOMATRIX vaccines mediate CD8+ T‐cell cross‐priming by a MyD88‐dependent signaling pathway

Cited by 91 publications

References 61 publications

Enhancement of Adaptive Immunity by the Human Vaccine Adjuvant AS01 Depends on Activated Dendritic Cells

Enhancement of Adaptive Immunity by the Human Vaccine Adjuvant AS01 Depends on Activated Dendritic Cells

Inflammasome-Dependent and -Independent IL-18 Production Mediates Immunity to the ISCOMATRIX Adjuvant

Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir

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ISCOMATRIX vaccines mediate CD8⁺ T‐cell cross‐priming by a MyD88‐dependent signaling pathway