Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Allergy ; 79(1): 184-199, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37815010

RESUMO

BACKGROUND: Virus-like particle (VLP) Peanut is a novel immunotherapeutic vaccine candidate for the treatment of peanut allergy. The active pharmaceutical ingredient represents cucumber mosaic VLPs (CuMVTT -VLPs) that are genetically fused with one of the major peanut allergens, Ara h 2 (CuMVTT -Ara h 2). We previously demonstrated the immunogenicity and the protective capacity of VLP Peanut-based immunization in a murine model for peanut allergy. Moreover, a Phase I clinical trial has been initiated using VLP Peanut material manufactured following a GMP-compliant manufacturing process. Key product characterization studies were undertaken here to understand the role and contribution of critical quality attributes that translate as predictive markers of immunogenicity and protective efficacy for clinical vaccine development. METHOD: The role of prokaryotic RNA encapsulated within VLP Peanut on vaccine immunogenicity was assessed by producing a VLP Peanut batch with a reduced RNA content (VLP Peanut low RNA). Immunogenicity and peanut allergen challenge studies were conducted with VLP Peanut low RNA, as well as with VLP Peanut in WT and TLR 7 KO mice. Furthermore, mass spectrometry and SDS-PAGE based methods were used to determine Ara h 2 antigen density on the surface of VLP Peanut particles. This methodology was subsequently applied to investigate the relationship between Ara h 2 antigen density and immunogenicity of VLP Peanut. RESULTS: A TLR 7 dependent formation of Ara h 2 specific high-avidity IgG antibodies, as well as a TLR 7 dependent change in the dominant IgG subclass, was observed following VLP Peanut vaccination, while total allergen-specific IgG remained relatively unaffected. Consistently, a missing TLR 7 signal caused only a weak decrease in allergen tolerability after vaccination. In contrast, a reduced RNA content for VLP Peanut resulted in diminished total Ara h 2 specific IgG responses, followed by a significant impairment in peanut allergen tolerability. The discrepant effect on allergen tolerance caused by an absent TLR 7 signal versus a reduced RNA content is explained by the observation that VLP Peanut-derived RNA not only stimulates TLR 7 but also TLR 3. Additionally, a strong correlation was observed between the number of Ara h 2 antigens displayed on the surface of VLP Peanut particles and the vaccine's immunogenicity and protective capacity. CONCLUSIONS: Our findings demonstrate that prokaryotic RNA encapsulated within VLP Peanut, including antigen density of Ara h 2 on viral particles, are key contributors to the immunogenicity and protective capacity of the vaccine. Thus, antigenicity and RNA content are two critical quality attributes that need to be determined at the stage of manufacturing, providing robust information regarding the immunogenicity and protective capacity of VLP Peanut in the mouse which has translational relevance to the human setting.


Assuntos
Hipersensibilidade a Amendoim , Vacinas de Partículas Semelhantes a Vírus , Humanos , Animais , Camundongos , Hipersensibilidade a Amendoim/prevenção & controle , Receptor 7 Toll-Like , Alérgenos , Arachis , Imunoglobulina G , RNA , Antígenos de Plantas
2.
Allergy ; 78(7): 1980-1996, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-36883475

RESUMO

BACKGROUND: Allergy to peanut is one of the leading causes of anaphylactic reactions among food allergic patients. Immunization against peanut allergy with a safe and protective vaccine holds a promise to induce durable protection against anaphylaxis caused by exposure to peanut. A novel vaccine candidate (VLP Peanut), based on virus-like particles (VLPs), is described here for the treatment of peanut allergy. METHODS AND RESULTS: VLP Peanut consists of two proteins: a capsid subunit derived from Cucumber mosaic virus engineered with a universal T-cell epitope (CuMVTT ) and a CuMVTT subunit fused with peanut allergen Ara h 2 (CuMVTT -Ara h 2), forming mosaic VLPs. Immunizations with VLP Peanut in both naïve and peanut-sensitized mice resulted in a significant anti-Ara h 2 IgG response. Local and systemic protection induced by VLP Peanut were established in mouse models for peanut allergy following prophylactic, therapeutic, and passive immunizations. Inhibition of FcγRIIb function resulted in a loss of protection, confirming the crucial role of the receptor in conferring cross protection against peanut allergens other than Ara h 2. CONCLUSION: VLP Peanut can be delivered to peanut-sensitized mice without triggering allergic reactions, while remaining highly immunogenic and offering protection against all peanut allergens. In addition, vaccination ablates allergic symptoms upon allergen challenge. Moreover, the prophylactic immunization setting conferred the protection against subsequent peanut-induced anaphylaxis, showing the potential for preventive vaccination. This highlights the effectiveness of VLP Peanut as a prospective break-through immunotherapy vaccine candidate toward peanut allergy. VLP Peanut has now entered clinical development with the study PROTECT.


Assuntos
Anafilaxia , Hipersensibilidade a Amendoim , Camundongos , Animais , Hipersensibilidade a Amendoim/prevenção & controle , Estudos Prospectivos , Antígenos de Plantas , Alérgenos , Arachis
3.
Vaccine ; 31(32): 3262-7, 2013 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-23707165

RESUMO

Enteric redmouth disease, caused by Yersinia ruckeri, may result in high mortalities in farmed salmonids. Prophylaxis has been achieved with an immersion vaccine comprised of inactivated serovar 1 biotype 1 (motile) Y. ruckeri cultures. However, there has been a growing number of enteric redmouth outbreaks in vaccinated livestock associated with serovar 1 biotype 2 (non-motile) Y. ruckeri strains which do not produce flagellin. It was the aim of this study to evaluate the protective role of flagellin in enteric redmouth vaccines. Results showed that flagellin in the inactivated whole-cell vaccine were not the main immunoprotective molecule in eliciting a protective immune response towards infection. However, use of non-adjuvanted flagellin as a sub-unit vaccine, both in the native and recombinant form, resulted in a potent non-specific protective function towards challenge with biotype 1 (flagellin-producing) and biotype 2 (flagellin-devoid) Y. ruckeri. This vaccine can also protect rainbow trout against other microbial fish pathogens, for example Aeromonas salmonicida. Thus non-adjuvanted flagellin may have potential as a non-specific vaccine for fish towards bacterial pathogens.


Assuntos
Vacinas Bacterianas/uso terapêutico , Doenças dos Peixes/prevenção & controle , Flagelina/imunologia , Oncorhynchus mykiss/imunologia , Yersiniose/veterinária , Adjuvantes Imunológicos , Aeromonas salmonicida/imunologia , Sequência de Aminoácidos , Animais , Vacinas Bacterianas/imunologia , Proteção Cruzada , Doenças dos Peixes/imunologia , Doenças dos Peixes/microbiologia , Flagelina/administração & dosagem , Imersão , Dados de Sequência Molecular , Oncorhynchus mykiss/microbiologia , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Vacinação/veterinária , Vacinas de Subunidades Antigênicas/administração & dosagem , Vacinas de Subunidades Antigênicas/uso terapêutico , Yersiniose/imunologia , Yersiniose/prevenção & controle , Yersinia ruckeri/classificação
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa