Nanoemulsion mucosal adjuvant uniquely activates cytokine production by nasal ciliated epithelium and induces dendritic cell trafficking

Makidon, Paul E.; Belyakov, Igor M.; Blanco, Luz P.; Janczak, Katarzyna; Landers, Jeffrey J.; Bielinska, Anna U.; Groom, Jeffrey V.; Baker, James R.

doi:10.1002/eji.201142346

Cited by 45 publications

(56 citation statements)

References 52 publications

(64 reference statements)

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“…produced protective immunity to a variety of pathogens, including anthrax, vaccinia, HIV, influenza, and hepatitis B surface Ag (32)(33)(34)(35). Recently, we also demonstrated that W 80 5EC NE increases Ag uptake and trafficking by epithelial cells and DCs, resulting in both apoptosis and DC maturation (36,37). These findings suggest that W 80 5EC NE produces unique activation of epithelial cells and DCs on the nasal mucosa.…”

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confidence: 68%

Distinct Pathways of Humoral and Cellular Immunity Induced with the Mucosal Administration of a Nanoemulsion Adjuvant

Bielinska

Makidon

Janczak

et al. 2014

The Journal of Immunology

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Nasal administration of an oil-in-water nanoemulsion (NE) adjuvant W805EC produces potent systemic and mucosal, Th-1– and Th-17–balanced cellular responses. However, its molecular mechanism of action has not been fully characterized and is of particular interest because NE does not contain specific ligands for innate immune receptors. In these studies, we demonstrate that W805EC NE adjuvant activates innate immunity, induces specific gene transcription, and modulates NF-κB activity via TLR2 and TLR4 by a mechanism that appears to be distinct from typical TLR agonists. Nasal immunization with NE-based vaccine showed that the TLR2, TLR4, and MyD88 pathways and IL-12 and IL-12Rβ1 expression are not required for an Ab response, but they are essential for the induction of balanced Th-1 polarization and Th-17 cellular immunity. NE adjuvant induces MHC class II, CD80, and CD86 costimulatory molecule expression and dendritic cell maturation. Further, upon immunization with NE, adjuvant mice deficient in the CD86 receptor had normal Ab responses but significantly reduced Th-1 cellular responses, whereas animals deficient in both CD80 and CD86 or lacking CD40 failed to produce either humoral or cellular immunity. Overall, our data show that intranasal administration of Ag with NE induces TLR2 and TLR4 activation along with a MyD88-independent Ab response and a MyD88-dependent Th-1 and Th-17 cell–mediated immune response. These findings suggest that the unique properties of NE adjuvant may offer novel opportunities for understanding previously unrecognized mechanisms of immune activation important for generating effective mucosal and systemic immune responses.

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confidence: 68%

Distinct Pathways of Humoral and Cellular Immunity Induced with the Mucosal Administration of a Nanoemulsion Adjuvant

Bielinska

Makidon

Janczak

et al. 2014

The Journal of Immunology

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“…Interestingly, NE did not enhance uptake in DCs or macrophages in vitro (not shown), emphasizing the importance of mucoadhesion-facilitated epithelial cell antigen uptake, and supporting our observations on the pivotal role of ciliated epithelial cells in the NE-mediated immune response. 18 …”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that NEs serve as much more than inert vehicles for antigen delivery, and that these formulations are able to activate cytokine production by epithelial cells in the nasal passage, and induce DC trafficking. 18 The simple in vitro screening methods presented here along with our in vivo immunogencity studies provide the first steps to understanding the relationship between the physicochemical properties of emulsion surfactants and adjuvant effectiveness. We demonstrate that NEs with very diverse sets of surface and adhesion properties can be produced by variation of the surfactant combinations.…”

Section: Discussionmentioning

confidence: 99%

Formulation and Characterization of Nanoemulsion Intranasal Adjuvants: Effects of Surfactant Composition on Mucoadhesion and Immunogenicity

et al. 2013

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Development of effective intranasal vaccines is of great interest due to their potential to induce both mucosal and systemic immunity. Here we produced oil-in-water nanoemulsion (NE) formulations containing various cationic and nonionic surfactants for use as adjuvants for the intranasal delivery of vaccine antigens. NE induced immunogenicity and antigen delivery are believed to be facilitated through initial contact interactions between the NE droplet and mucosal surfaces which promote prolonged residence of the vaccine at the site of application, and thus cellular uptake. However, the details of this mechanism have yet to be fully characterized experimentally. We have studied the physicochemical properties of the NE droplet surfactant components and demonstrate that properties such as charge and polar head group geometry influence the association of the adjuvant with the mucus protein, mucin. Association of NE droplets with mucin in vitro was characterized by various biophysical and imaging methods including dynamic light scattering (DLS), zeta potential (ZP), and surface plasmon resonance (SPR) measurements as well as transmission electron microscopy (TEM). Emulsion surfactant compositions were varied in a systematic manner to evaluate the effects of hydrophobicity and polar group charge/size on the NE-mucin interaction. Several cationic NE formulations were found to facilitate cellular uptake of the model antigen, ovalbumin (OVA), in a nasal epithelial cell line. Furthermore, fluorescent images of tissue sections from mice intranasally immunized with the same NEs containing green fluorescent protein (GFP) antigen demonstrated that these NEs also enhanced mucosal layer penetration and cellular uptake of antigen in vivo. NE-mucin interactions observed through biophysical measurements corresponded with the ability of the NE to enhance cellular uptake. Formulations that enhanced antigen uptake in vitro and in vivo also led to the induction of a more consistent antigen specific immune response in mice immunized with NEs containing OVA, linking NE-facilitated mucosal layer penetration and cellular uptake to enhancement of the immune response. These findings suggest that biophysical measurement of the mucoadhesive properties of emulsion based vaccines constitutes an effective in vitro strategy for selecting NE candidates for further evaluation in vivo as mucosal adjuvants.

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“…9 A recent study indicated that nanoemulsion adjuvants potently and powerfully induce broad mucosal immune responses. 10 However, no nanoemulsion adjuvant has been reported to significantly enhance both the intramuscular systemic and nasal mucosal immune responses.…”

Section: Introductionmentioning

confidence: 99%

Induction of systemic and mucosal immunity against methicillin-resistant Staphylococcus aureus infection by a novel nanoemulsion adjuvant vaccine

Sun¹,

Wei²,

Liu³

et al. 2015

IJN

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The Gram-positive bacterial pathogen methicillin-resistant Staphylococcus aureus (MRSA) can cause infections in the bloodstream, endocardial tissue, respiratory tract, culture-confirmed skin, or soft tissue. There are currently no effective vaccines, and none are expected to become available in the near future. An effective vaccine capable of eliciting both systemic and mucosal immune responses is also urgently needed. Here, we reported a novel oil-in-water nanoemulsion adjuvant vaccine containing an MRSA recombination protein antigen, Cremophor EL-35 ® as a surfactant, and propylene glycol as a co-surfactant. This nanoemulsion vaccine, whose average diameter was 31.34±0.49 nm, demonstrated good protein structure integrity, protein specificity, and good stability at room temperature for 1 year. The intramuscular systemic and nasal mucosal immune responses demonstrated that this nanoemulsion vaccine could improve the specific immune responses of immunoglobulin (Ig)G and related subclasses, such as IgG1, IgG2a, and IgG2b, as well as IgA, in the serum after Balb/c mice intramuscular immunization and C57 mice nasal immunization. Furthermore, this nanoemulsion vaccine also markedly enhanced the interferon-γ and interleukin-17A cytokine cell immune response, improved the survival ratio, and reduced bacterial colonization. Taken together, our results show that this novel nanoemulsion vaccine has great potential and is a robust generator of an effective intramuscular systemic and nasal mucosal immune response without the need for an additional adjuvant. Thus, the present study serves as a sound scientific foundation for future strategies in the development of this novel nanoemulsion adjuvant vaccine to enhance both the intramuscular systemic and nasal mucosal immune responses.

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Nanoemulsion mucosal adjuvant uniquely activates cytokine production by nasal ciliated epithelium and induces dendritic cell trafficking

Cited by 45 publications

References 52 publications

Distinct Pathways of Humoral and Cellular Immunity Induced with the Mucosal Administration of a Nanoemulsion Adjuvant

Distinct Pathways of Humoral and Cellular Immunity Induced with the Mucosal Administration of a Nanoemulsion Adjuvant

Formulation and Characterization of Nanoemulsion Intranasal Adjuvants: Effects of Surfactant Composition on Mucoadhesion and Immunogenicity

Induction of systemic and mucosal immunity against methicillin-resistant Staphylococcus aureus infection by a novel nanoemulsion adjuvant vaccine

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