Mutants of the Escherichia coli heat-labile enterotoxin as safe and strong adjuvants for intranasal delivery of vaccines

Peppoloni, Samuele; Ruggiero, Paolo; Contorni, Mario; Morandi, Maurizio; Pizza, Mariagrazia; Rappuoli, Rino; Podda, Audino; Giudice, Giuseppe Del

doi:10.1586/14760584.2.2.285

Cited by 97 publications

(60 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…8,9 Bacteria-derived particles may thus represent attractive alternatives to derivatives of toxins that are currently considered for use as mucosal adjuvants in humans. 10,11 The uptake of antigens through the nasal mucosa may be hampered by luminal drainage, especially when the vaccine is administered in a liquid form. 12 It has been shown, however, that the absorption of medications at this site can be improved by adding a composite thixotropic substance to render the formulation mucoadhesive.…”

Section: Introductionmentioning

confidence: 99%

A Non-Living Nasal Influenza Vaccine Can Induce Major Humoral and Cellular Immune Responses in Humans without the Need for Adjuvants

Samdal¹,

Bakke²,

Oftung³

et al. 2005

Human Vaccines

Self Cite

View full text Add to dashboard Cite

Twenty-eight healthy adult volunteers were immunized intranasally with an inactivated whole-virus influenza vaccine based on the strain A/New Caledonia/20/99 (H1N1), either in saline or mixed with formaldehyde-inactivated Bordetella pertussis as a mucosal adjuvant, or in a thixotropic vehicle with mucoadhesive properties. After four doses, all groups of vaccinees developed significant IgG-and IgA-antibody responses, measured by ELISA, in respectively serum and nasal secretions. None of the volunteers had demonstrable hemagglutination inhibition (HAI) antibodies in serum before being immunized, whereas more than 80% of them reached HAI titers > 40, considered protective, after immunizations. In addition, cellular immune responses, measured as significant increases in CD4 + T-cell proliferation and granzyme B-producing cytotoxic T-cells, were detected against the vaccine strain as well as against heterologous virus strains (H3N2). However, no additive effect on these responses could be demonstrated with use of B. pertussis or the thixotropic substance in the present vaccines. It appeared, actually, that the mucoadhesive vehicle containing the thixotropic substance was less efficient than were the two other formulations. An influenza vaccine made as a simple particulate formulation of inactivated virus, and given repeatedly onto the nasal mucosa, may thus be an attractive alternative to currently available vaccines.

show abstract

Section: Introductionmentioning

confidence: 99%

A Non-Living Nasal Influenza Vaccine Can Induce Major Humoral and Cellular Immune Responses in Humans without the Need for Adjuvants

Samdal¹,

Bakke²,

Oftung³

et al. 2005

Human Vaccines

Self Cite

View full text Add to dashboard Cite

show abstract

“…The induction of cAMP by LT is considered a dominant factor in mediating its adjuvant effects (6,7). However, studies in animal models using the partially active derivative, LTR72, and the enzymatically inactive mutant LTK63, have shown that these molecules retain at least some of the adjuvant properties of LT (8)(9)(10)(11)(12)(13)(14). These findings clearly indicate that the immunomodulatory properties associated with LT are not entirely dependent on ADP-ribosyltransferase activity.…”

mentioning

confidence: 99%

Escherichia coliHeat-Labile Enterotoxin Promotes Protective Th17 Responses against Infection by Driving Innate IL-1 and IL-23 Production

Brereton

Sutton

Ross

et al. 2011

The Journal of Immunology

Self Cite

101

View full text Add to dashboard Cite

Escherichia coli heat-labile enterotoxin (LT) is a powerful mucosal adjuvant; however, it is associated with toxic effects when delivered intranasally, and its mechanism of action is poorly understood. In this article, we demonstrate that LT acts as a highly effective adjuvant when administered parenterally, promoting Ag-specific IL-17, as well as IFN-γ, IL-4, and IL-10 production in response to coadministered Ags. We found that the adjuvant activity of LT was mediated in part by inducing dendritic cell (DC) activation; LT promoted CD80 and CD86 expression by DCs and enhanced IL-1α, IL-1β, and IL-23 production. An LT mutant, LTK63, that lacks enzyme activity was less effective than the wild-type toxin in promoting DC maturation and the development of Ag-specific Th17 cells. LT enhanced IL-23 and IL-1α production from DCs via activation of ERK MAPK and IL-1β secretion through activation of caspase-1 and the NLRP3 inflammasome. These cytokines played a major role in promoting Th17 responses by LT and LTK63. The induction of Th17 cells in vivo in response to LT and LTK63 as adjuvants was significantly reduced in IL-1RI–deficient mice. Finally, using a murine respiratory infection model, we demonstrated that LT can act as a highly effective adjuvant for a pertussis vaccine, promoting Ag-specific Th17 cells and protection against Bordetella pertussis challenge, which was significantly reduced in IL-17–defective mice. Our findings provide clear evidence that LT can promote protective immune responses in part through induction of innate IL-1 and, consequently, Th17 cells.

show abstract

“…Besides stimulating the immune response directed against a coadministered Ag, LT is also highly immunogenic, eliciting strong humoral and cellular responses against itself (9). To circumvent the harmful drawbacks of the native LT toxin, several LT mutants with significantly reduced toxicity have been generated (10). LTK63 is an LT mutant with a serine-to-lysine substitution in position 63 of the A subunit, resulting in the complete loss of enzymatic activity (11).…”

mentioning

confidence: 99%

The Acquired Immune Response to the Mucosal Adjuvant LTK63 Imprints the Mouse Lung with a Protective Signature

Tritto

Muzzi

Pesce

et al. 2007

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

LTK63, a nontoxic mutant of Escherichia coli heat labile enterotoxin (LT), is a potent and safe mucosal adjuvant that has also been shown to confer generic protection to several respiratory pathogens. To understand the mechanisms of action underlying the LTK63 protective effect, we analyzed the molecular and cellular events triggered by its administration in vivo. We show here that LTK63 intrapulmonary administration induced in the mouse lung a specific gene expression signature characterized by the up-regulation of cell cycle genes, several host defense genes, chemokines, chemokine receptors, and immune cell-associated genes. Such a transcriptional profile reflected the activation of alveolar macrophages and the recruitment to the lung of T and B cells and innate immune cells such as granulocytes, NK, and dendritic cells. All of these events were T cell dependent and specific for LTK63 because they were absent in SCID and nude mice. Additionally, we showed that LTK63 induces a potent adaptive immune response against itself directed to the lung. We propose that acquired response to LTK63 is the driving force for the local recruitment of both adaptive and innate immune cells. Our data suggest that LTK63 acts as an airway infection mimic that establishes a generic protective environment limiting respiratory infection by innate immune mechanisms and by improving adaptive responses to invading pathogens.

show abstract

Mutants of the Escherichia coli heat-labile enterotoxin as safe and strong adjuvants for intranasal delivery of vaccines

Cited by 97 publications

References 27 publications

A Non-Living Nasal Influenza Vaccine Can Induce Major Humoral and Cellular Immune Responses in Humans without the Need for Adjuvants

A Non-Living Nasal Influenza Vaccine Can Induce Major Humoral and Cellular Immune Responses in Humans without the Need for Adjuvants

Escherichia coliHeat-Labile Enterotoxin Promotes Protective Th17 Responses against Infection by Driving Innate IL-1 and IL-23 Production

The Acquired Immune Response to the Mucosal Adjuvant LTK63 Imprints the Mouse Lung with a Protective Signature

Contact Info

Product

Resources

About