Activation of the endoplasmic reticulum stress sensor IRE1α by the vaccine adjuvant AS03 contributes to its immunostimulatory properties

Givord, Charlotte; Welsby, Iain; Detienne, Sophie; Thomas, Séverine; Assabban, Assiya; Silva, Viviana Lima; Molle, Céline; Gineste, Romain; Vermeersch, Marjorie; Pérez‐Morga, David; Léo, Oberdan; Collignon, Catherine; Didierlaurent, Arnaud M.; Goriely, Stanislas

doi:10.1038/s41541-018-0058-4

Cited by 46 publications

(39 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Adjuvant-mediated innate immune activation via release of endogenous danger signals (danger associated molecular patterns, DAMPs) such as ATP, host DNA or uric acid has been described and likely plays a part in adjuvanticity for all particulate adjuvants 13 . Also the modulation of intracellular compartments and activation of the endoplasmatic reticulum stress sensor and subsequent metabolic changes have been observed for the emulsion adjuvant AS03 14 .…”

Section: Discussionmentioning

confidence: 90%

The droplet size of emulsion adjuvants has significant impact on their potency, due to differences in immune cell-recruitment and -activation

Shah

Taccone²,

Monaci³

et al. 2019

Sci Rep

View full text Add to dashboard Cite

Self-emulsification is routinely used for oral delivery of lipophilic drugs in vivo , with the emulsion forming in vivo . We modified this technique to prepare novel oil-in-water emulsions of varying droplet size and composition on bench to enable adjuvanted vaccine delivery. We used these formulations to show that smaller droplets (20 nm) were much less effective as adjuvants for an influenza vaccine in mice than the emulsion droplet size of commercial influenza vaccine adjuvants (~160 nm). This was unexpected, given the many claims in the literature of the advantages of smaller particulates. We also undertook cell-recruitment mechanistic studies at site of injection and draining lymph nodes to directly address the question of why the smaller droplets were less effective. We discovered that emulsion droplet size and composition have a considerable impact on the ability to recruit immune cells to the injection site. We believe that further work is warranted to more extensively explore the question of whether, the smaller is not ‘better’, is a more common observation for particulate adjuvants.

show abstract

Section: Discussionmentioning

confidence: 90%

The droplet size of emulsion adjuvants has significant impact on their potency, due to differences in immune cell-recruitment and -activation

Shah

Taccone²,

Monaci³

et al. 2019

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Such adjuvant systems are known to augment antigen-specific T cell and antibody responses [57]. In a murine study, the ER stress-related pathway was found to potentially contribute to the adjuvanticity of AS03 in vivo [58]. Furthermore, the expression of the ER stress sensor kinase IRE1α by myeloid cells was involved in adjuvant activity of AS03.…”

Section: Induction Of Humoral Immunitymentioning

confidence: 99%

“…The ER stress-related pathway was required for AS03mediated induction of IL-6, robust Tfh responses, and antigenspecific antibody affinity maturation. IL-6 plays a crucial role in differentiation of Tfh cells as well as in the expression of IL-21 by Tfh cells and in production of antibodies [58].…”

Section: Induction Of Humoral Immunitymentioning

confidence: 99%

Selection of adjuvants for vaccines targeting specific pathogens

Sarkar

Garg

Hurk

2019

Expert Review of Vaccines

View full text Add to dashboard Cite

Introduction: Adjuvants form an integral component in most of the inactivated and subunit vaccine formulations. Careful and proper selection of adjuvants helps in promoting appropriate immune responses against target pathogens at both innate and adaptive levels such that protective immunity can be elicited. Areas covered: Herein, we describe the recent progress in our understanding of the mode of action of adjuvants that are licensed for use in human vaccines or in clinical or pre-clinical stages at both innate and adaptive levels. Different pathogens have distinct characteristics, which require the host to mount an appropriate immune response against them. Adjuvants can be selected to elicit a tailor-made immune response to specific pathogens based on their unique properties. Identification of biomarkers of adjuvanticity for several candidate vaccines using omics-based technologies can unravel the mechanism of action of modern and experimental adjuvants. Expert opinion: Adjuvant technology has been revolutionized over the last two decades. In-depth understanding of the role of adjuvants in activating the innate immune system, combined with systems vaccinology approaches, have led to the development of next-generation, novel adjuvants that can be used in vaccines against challenging pathogens and in specific target populations. ARTICLE HISTORY

show abstract

“…The underlying immunostimulatory mechanisms of various adjuvants have been investigated to develop human vaccines. A squalene-based oil-in-water emulsion, AS03, can induce immunostimulation via activation of IRE1α, an ER stress sensor (32). Glucocorticoids can contribute to immunostimulation on macrophages, which may be correlated to ER stress via the glucocorticoid receptor (33).…”

Section: Discussionmentioning

confidence: 99%

ERdj5 in Innate Immune Cells Is a Crucial Factor for the Mucosal Adjuvanticity of Cholera Toxin

Kim

et al. 2019

Front. Immunol.

View full text Add to dashboard Cite

Cholera toxin (CT) is one of most strong mucosal adjuvants, but it cannot be clinically used owing to its toxicity. The cytosolic A1 subunit of CT (CTA1) is the molecule responsible for its immunostimulatory activity, which increases the concentration of cyclic AMP and causes the induction of pro-inflammatory cytokines in innate immune cells. However, the importance of endoplasmic reticulum (ER) molecules involved in CTA1 retro-translocation to induce immune responses remained to be investigated. ERdj5 is an ER protein which is expected to transfer CTA1 to the Hrd1 complex for the retro-translocation of CTA1. In this study, we investigated the physiological relevance of ERdj5 in immune stimulation by CT. ERdj5-knockout (ERdj5 KO) mice had decreased production of antigen-specific IgG in the serum and IgA in the mucosal secretion after intranasal immunization with Ag and CT. Especially, IgG2c isotypes were specifically reduced in the absence of ERdj5. ERdj5 KO dendritic cells (DCs) failed to full activation with decreased expression of costimulatory molecules, such as MHC class II, CD80, and CD 86. In ERdj5 KO DCs, secretion of pro-inflammatory cytokines, such as IL-1β, TNF-α, and IL-6, was reduced. The cytokine signatures of several helper T cells were reduced in ERdj5 KO mice following intranasal CT immunization. The absence of ERdj5 affects the immunostimulatory properties of CT but does not affect the response to the CTB pentamer, the response to alum, total antibody production, or cytokine release from DCs exposed to CpG. Interestingly, CT enhanced the expression of ER stress proteins in ERdj5 KO innate immune cells. These results suggested that ERdj5 contributed as a decisive factor to the immunostimulatory capacity of CT via CTA1 retro-translocation.

show abstract

Activation of the endoplasmic reticulum stress sensor IRE1α by the vaccine adjuvant AS03 contributes to its immunostimulatory properties

Cited by 46 publications

References 55 publications

The droplet size of emulsion adjuvants has significant impact on their potency, due to differences in immune cell-recruitment and -activation

The droplet size of emulsion adjuvants has significant impact on their potency, due to differences in immune cell-recruitment and -activation

Selection of adjuvants for vaccines targeting specific pathogens

ERdj5 in Innate Immune Cells Is a Crucial Factor for the Mucosal Adjuvanticity of Cholera Toxin

Contact Info

Product

Resources

About