Microcrystalline Tyrosine (MCT®): A Depot Adjuvant in Licensed Allergy Immunotherapy Offers New Opportunities in Malaria

Cabral-Miranda, Gustavo; Heath, M. F.; Gomes, Ariane; Mohsen, Mona O.; Montoya-Diaz, Eduardo; Salman, Ahmed M.; Atcheson, Erwan; Skinner, Murray A.; Krämer, Matthias; Reyes-Sandoval, Arturo; Bachmann, Martin F.

doi:10.3390/vaccines5040032

Cited by 16 publications

(18 citation statements)

References 35 publications

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“…Particularly, MCT facilitated the recruitment of DCs and elicitation of CD8 T cell responses with associated IFN-γ and TNF-α production. These data are in line with studies demonstrating protective efficacy in influenza and malaria mouse models ( 17 – 19 ) and are favorable for long-term clinical tolerance following AIT ( 37 , 38 ). Other important biomarkers for the monitoring of AIT are regulatory T cells and IL-10 ( 34 ).…”

Section: Discussionsupporting

confidence: 86%

Microcrystalline Tyrosine and Aluminum as Adjuvants in Allergen-Specific Immunotherapy Protect from IgE-Mediated Reactivity in Mouse Models and Act Independently of Inflammasome and TLR Signaling

Leuthard

Duda

Freiberger

et al. 2018

The Journal of Immunology

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Allergen immunotherapy (AIT) is the only modality that can modify immune responses to allergen exposure, but therapeutic coverage is low. One strategy to improve AIT safety and efficacy is the use of new or improved adjuvants. This study investigates immune responses produced by microcrystalline tyrosine (MCT)–based vaccines as compared with conventional aluminum hydroxide (alum). Wild-type, immune-signaling–deficient, and TCR-transgenic mice were treated with different Ags (e.g., OVA and cat dander Fel d 1), plus MCT or alum as depot adjuvants. Specific Ab responses in serum were measured by ELISA, whereas cytokine secretion was measured both in culture supernatants by ELISA or by flow cytometry of spleen cells. Upon initiation of AIT in allergic mice, body temperature and further clinical signs were used as indicators for anaphylaxis. Overall, MCT and alum induced comparable B and T cell responses, which were independent of TLR signaling. Alum induced stronger IgE and IL-4 secretion than MCT. MCT and alum induced caspase-dependent IL-1β secretion in human monocytes in vitro, but inflammasome activation had no functional effect on inflammatory and Ab responses measured in vivo. In sensitized mice, AIT with MCT-adjuvanted allergens caused fewer anaphylactic reactions compared with alum-adjuvanted allergens. As depot adjuvants, MCT and alum are comparably effective in strength and mechanism of Ag-specific IgG induction and induction of T cell responses. The biocompatible and biodegradable MCT seems therefore a suitable alternative adjuvant to alum-based vaccines and AIT.

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Section: Discussionsupporting

confidence: 86%

Microcrystalline Tyrosine and Aluminum as Adjuvants in Allergen-Specific Immunotherapy Protect from IgE-Mediated Reactivity in Mouse Models and Act Independently of Inflammasome and TLR Signaling

Leuthard

Duda

Freiberger

et al. 2018

The Journal of Immunology

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“…This is in part due to the biodegradable nature of MCT, while still maintaining depot formation, a crucial part of maintaining a sustained immune response during AIT. Reports of the efficacy of MCT have found it comparable with Alum (47,48). In the currently available allergy vaccine, Pollinex Quattro MCT is the respectively.…”

Section: Adjuvants Utilised In Aitmentioning

confidence: 99%

Toll-Like Receptor Agonists as Adjuvants for Allergen Immunotherapy

et al. 2020

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Toll-like receptors (TLRs) are essential components of innate immunity and provide defensive inflammatory responses to invading pathogens. Located within the plasma membranes of cells and also intracellular endosomes, TLRs can detect a range of pathogen associated molecular patterns from bacteria, viruses and fungi. TLR activation on dendritic cells can propagate to an adaptive immune response, making them attractive targets for the development of both prophylactic and therapeutic vaccines. In contrast to conventional adjuvants such as aluminium salts, TLR agonists have a clear immunomodulatory profile that favours anti-allergic T lymphocyte responses. Consequently, the potential use of TLRs as adjuvants in Allergen Immunotherapy (AIT) for allergic rhinitis and asthma remains of great interest. Allergic Rhinitis is a Th2-driven, IgE-mediated disease that occurs in atopic individuals in response to exposure to otherwise harmless aeroallergens such as pollens, house dust mite and animal dander. AIT is indicated in subjects with allergic rhinitis whose symptoms are inadequately controlled by antihistamines and nasal corticosteroids. Unlike anti-allergic drugs, AIT is disease-modifying and may induce long-term disease remission through mechanisms involving upregulation of IgG and IgG4 antibodies, induction of regulatory T and B cells, and immune deviation in favour of Th1 responses that are maintained after treatment discontinuation. This process takes up to three years however, highlighting an unmet need for a more efficacious therapy with faster onset. Agonists targeting different TLRs to treat allergy are at different stages of development. Synthetic TLR4, and TLR9 agonists have progressed to clinical trials, while TLR2, TLR5 and TLR7 agonists been shown to have potent anti-allergic effects in human in vitro experiments and in vivo in animal studies. The anti-allergic properties of TLRs are broadly characterised by a combination of enhanced Th1 deviation, regulatory responses, and induction of blocking antibodies. While promising, a durable effect in larger clinical trials is yet to be observed and further long-term studies and comparative trials with conventional AIT are required before TLR adjuvants can be considered for inclusion in AIT. Here we critically evaluate experimental and clinical studies investigating TLRs and discuss their potential role in the future of AIT.

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“…In addition, alum tends to induce less protective IgG subclasses, such as IgG1 in mice or IgG4 in humans. Hence, if protection is not solely based on pathogen neutralization, but Fc-receptor interactions and complement are also important, alternative adjuvants may be more potent than alum [17,19,20,21,22,23].…”

Section: Introductionmentioning

confidence: 99%

DOPS Adjuvant Confers Enhanced Protection against Malaria for VLP-TRAP Based Vaccines

et al. 2018

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Vaccination remains the most effective and essential prophylactic tool against infectious diseases. Enormous efforts have been made to develop effective vaccines against malaria but successes remain so far limited. Novel adjuvants may offer a significant advantage in the development of malaria vaccines, in particular if combined with inherently immunogenic platforms, such as virus-like particles (VLP). Dioleoyl phosphatidylserine (DOPS), which is expressed on the outer surface of apoptotic cells, represents a novel adjuvant candidate that may confer significant advantage over existing adjuvants, such as alum. In the current study we assessed the potential of DOPS to serve as an adjuvant in the development of a vaccine against malaria either alone or combined with VLP using Plasmodium falciparum thrombospondin-related adhesive protein (TRAP) as a target antigen. TRAP was chemically coupled to VLPs derived from the cucumber mosaic virus fused to a universal T cell epitope of tetanus toxin (CuMVtt). Mice were immunized with TRAP alone or formulated in alum or DOPS and compared to TRAP coupled to CuMVtt formulated in PBS or DOPS. Induced immune responses, in particular T cell responses, were assessed as the major protective effector cell population induced by TRAP. The protective capacity of the various formulations was assessed using a transgenic Plasmodium berghei expressing PfTRAP. All vaccine formulations using adjuvants and/or VLP increased humoral and T cell immunogenicity for PfTRAP compared to the antigen alone. Display on VLPs, in particular if formulated with DOPS, induced the strongest and most protective immune response. Thus, the combination of VLP with DOPS may harness properties of both immunogenic components and optimally enhance induction of protective immune responses.

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Microcrystalline Tyrosine (MCT®): A Depot Adjuvant in Licensed Allergy Immunotherapy Offers New Opportunities in Malaria

Cited by 16 publications

References 35 publications

Microcrystalline Tyrosine and Aluminum as Adjuvants in Allergen-Specific Immunotherapy Protect from IgE-Mediated Reactivity in Mouse Models and Act Independently of Inflammasome and TLR Signaling

Microcrystalline Tyrosine and Aluminum as Adjuvants in Allergen-Specific Immunotherapy Protect from IgE-Mediated Reactivity in Mouse Models and Act Independently of Inflammasome and TLR Signaling

Toll-Like Receptor Agonists as Adjuvants for Allergen Immunotherapy

DOPS Adjuvant Confers Enhanced Protection against Malaria for VLP-TRAP Based Vaccines

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