MF59 and Pam3CSK4 Boost Adaptive Responses to Influenza Subunit Vaccine through an IFN Type I-Independent Mechanism of Action

Caproni, Elena; Tritto, Elaine; Cortese, Mario; Muzzi, Alessandro; Mosca, Flaviana; Monaci, Elisabetta; Baudner, Barbara C.; Seubert, Anja; Gregorio, Ennio De

doi:10.4049/jimmunol.1101764

Cited by 115 publications

(97 citation statements)

References 34 publications

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“…8). These data are consistent with previously published reports that show an increase in IP-10 and IL-1Ra expression in response to MF59 (Caproni et al, 2012;Mosca et al, 2008;Seubert et al, 2008), as well as increased CRP and IP-10 expression in response to influenza vaccination (Christian et al, 2011;Nakaya et al, 2011;Obermoser et al, 2013). IL-2Ra and sTNFRII remained at baseline levels in the serum, with no difference observed between the adjuvanted and non-adjuvanted animals in response to intramuscular immunisation.…”

Section: Inter-and Intra-assay Variationsupporting

confidence: 82%

Development of a custom pentaplex sandwich immunoassay using Protein-G coupled beads for the Luminex® xMAP® platform

McDonald

Makinde

et al. 2016

Journal of Immunological Methods

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a b s t r a c t a r t i c l e i n f oMultiplex bead-based assays have many advantages over ELISA, particularly for the analyses of large quantities of samples and/or precious samples of limited volume. Although many commercial arrays covering multitudes of biologically significant analytes are available, occasionally the development of custom arrays is necessary. Here, the development of a custom pentaplex sandwich immunoassay using Protein G-coupled beads, for analysis using the Luminex® xMAP® platform, is described. This array was required for the measurement of candidate biomarkers of vaccine safety in small volumes of mouse sera. Optimisation of this assay required a stepwise approach: testing cross-reactivity of the antibody pairs, the development of an in-house serum diluent buffer as well as heat-inactivation of serum samples to prevent interference from matrix effects. We then demonstrate the use of this array to analyse inflammatory mediators in mouse serum after immunisation. The work described here exemplifies how Protein G-coupled beads offer a flexible and robust approach to develop custom multiplex immunoassays, which can be applied to a range of analytes from multiple species. Crown

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Section: Inter-and Intra-assay Variationsupporting

confidence: 82%

Development of a custom pentaplex sandwich immunoassay using Protein-G coupled beads for the Luminex® xMAP® platform

McDonald

Makinde

et al. 2016

Journal of Immunological Methods

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“…Not only an increased cellularity of dLNs but also an enhanced activation of various cell types including B cells, T cells, migratory DCs, NK cells and NKT cells following the adjuvant injection was observed. Similar phenomenon was observed after the use of a TLR agonist such as R848 43 suggesting that RNAdjuvant 44,45 Using a murine model of HPV-16-induced cervical cancer we demonstrated that vaccination with low doses of the previously described HPV-E7-derived peptide containing both, a CTL epitope (E7 [49][50][51][52][53][54][55][56][57] ) and a Th epitope, 24 led to a complete eradication of established tumors in combination with RNAdjuvant V R . Similar results were obtained by Zwaveling and colleagues using E7 peptide combined with CpG.…”

Section: Rnadjuvantmentioning

confidence: 57%

A novel RNA‐based adjuvant combines strong immunostimulatory capacities with a favorable safety profile

Heidenreich

Jasny

Kowalczyk

et al. 2015

Intl Journal of Cancer

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Protein-and peptide-based tumor vaccines depend on strong adjuvants to induce potent immune responses. Here, we demonstrated that a recently developed novel adjuvant based on a non-coding, long-chain RNA molecule, termed RNAdjuvant V R , profoundly increased immunogenicity of both antigen formats. RNAdjuvant V R induced balanced, long-lasting immune responses that resulted in a strong anti-tumor activity. A direct comparison to Poly(I:C) showed superior efficacy of our adjuvant to enhance antigen-specific multifunctional CD81 T-cell responses and mediate anti-tumor responses induced by peptide derived from HPV-16 E7 protein in the syngeneic TC-1 tumor, a murine model of human HPV-induced cervical cancer. Moreover, the adjuvant was able to induce functional memory responses that mediated complete tumor remission. Despite its remarkable immunostimulatory activity, our RNA-based adjuvant exhibited an excellent pre-clinical safety profile. It acted only locally at the injection site where it elicited a transient but strong up-regulation of pro-inflammatory and anti-viral cytokines as well as cytoplasmic RNA sensors without systemic cytokine release. This was followed by the activation of immune cells in the draining lymph nodes. Our data indicate that our RNA-based adjuvant is a safe and potent immunostimulator that may profoundly improve the efficacy of a variety of cancer vaccines.

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“…The HI assay was carried out on individual sera taken 2 wk after the second immunization, as described elsewhere (17).…”

Section: Methodsmentioning

confidence: 99%

“…Four mice per group were killed 2 wk after immunization, and spleens were collected to assess the frequency and phenotype of Ag-specific CD4 + /CD44 + T cells induced by vaccination. The assay was performed as described elsewhere (17).…”

Section: Methodsmentioning

confidence: 99%

“…The strong adjuvant effect of MF59 (16,17) has been ascribed to its capability to induce an immunocompetent environment in the muscle, characterized by a rapid and transient influx of a large number of CD11b+ immune cells participating in antigen uptake and transport to draining lymph nodes (18)(19)(20)(21). To clarify the role of ATP in MF59-induced cell recruitment, mice were injected i.m.…”

Section: Significancementioning

confidence: 99%

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The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination

Vono

Taccone

Caccin

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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129

125

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Vaccines are the most effective agents to control infections. In addition to the pathogen antigens, vaccines contain adjuvants that are used to enhance protective immune responses. However, the molecular mechanism of action of most adjuvants is ill-known, and a better understanding of adjuvanticity is needed to develop improved adjuvants based on molecular targets that further enhance vaccine efficacy. This is particularly important for tuberculosis, malaria, AIDS, and other diseases for which protective vaccines do not exist. Release of endogenous danger signals has been linked to adjuvanticity; however, the role of extracellular ATP during vaccination has never been explored. Here, we tested whether ATP release is involved in the immune boosting effect of four common adjuvants: aluminum hydroxide, calcium phosphate, incomplete Freund's adjuvant, and the oil-in-water emulsion MF59. We found that intramuscular injection is always associated with a weak transient release of ATP, which was greatly enhanced by the presence of MF59 but not by all other adjuvants tested. Local injection of apyrase, an ATP-hydrolyzing enzyme, inhibited cell recruitment in the muscle induced by MF59 but not by alum or incomplete Freund's adjuvant. In addition, apyrase strongly inhibited influenza-specific T-cell responses and hemagglutination inhibition titers in response to an MF59-adjuvanted trivalent influenza vaccine. These data demonstrate that a transient ATP release is required for innate and adaptive immune responses induced by MF59 and link extracellular ATP with an enhanced response to vaccination.vaccine adjuvants | danger associated molecular pattern | DAMP | inflammation V accine adjuvants are used to enhance immune responses toward coadministered antigens, thereby improving vaccine potency, immunological memory, or cross-protection (1, 2). Experimental adjuvants range from simple molecules such as calcium phosphate (CaPi) to very complex mixtures such as incomplete Freund's adjuvant (IFA), made of a water-in-oil emulsion, or complete Freund's adjuvant, which also includes killed Mycobacteria (3). However, for human vaccines, adjuvants of highly defined properties that combine efficacy with complete safety are needed; to date, very few compounds have been licensed. Some of the safest and most efficient adjuvants licensed for human use, such as aluminum hydroxide (alum) and the oil-in-water squalene-based emulsion MF59, have been empirically identified, and their mechanism of action is still not fully understood (4, 5). A better understanding of their mechanism of action is needed to develop improved adjuvants that further enhance vaccine efficacy. This is particularly important for diseases for which protective vaccines do not exist (6).An examination of the chemical nature of four major vaccine adjuvants (alum, CaPi, IFA, and MF59) suggested they could interact with the phospholipid bilayer of cell membranes via hydrogen bonding or ionic interactions with the head groups of phospholipids/glycolipids and/or via hydrophobic...

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MF59 and Pam3CSK4 Boost Adaptive Responses to Influenza Subunit Vaccine through an IFN Type I-Independent Mechanism of Action

Cited by 115 publications

References 34 publications

Development of a custom pentaplex sandwich immunoassay using Protein-G coupled beads for the Luminex® xMAP® platform

Development of a custom pentaplex sandwich immunoassay using Protein-G coupled beads for the Luminex® xMAP® platform

A novel RNA‐based adjuvant combines strong immunostimulatory capacities with a favorable safety profile

The adjuvant MF59 induces ATP release from muscle that potentiates response to vaccination

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