Influenza vaccine development: immunogenicity and correlates of protection
Notice bibliographique
Résumé
Influenza viruses cause significant morbidity and mortality worldwide. Vaccines are the best tools available to reduce the disease burden; however, vaccine effectiveness varies significantly between years, target populations and strains. Medicago Inc. has developed a highly efficient platform to produce plant-derived virus-like particle (VLP) vaccines bearing influenza hemagglutinin (HA) that have been shown to elicit strong humoral and CD4+ T cell responses in both pre-clinical and clinical studies. To better understand the immunogenicity of these vaccines, we studied the early interactions of VLPs with antigen-presenting cells (APC) in vitro. We demonstrated that VLPs bind to human monocytoid U-937 cells and monocyte-derived macrophages (MDMs) in a sialic acid-dependent manner. VLP attachment to the cell surface led to internalization, trafficking to acidic cell compartments and fusion of the VLP lipid envelope with endosomal membranes. Incubation of MDMs with VLPs bearing H1 (HA sequence from A/California/07/2009 (H1N1) strain) but not H5 (HA sequence from A/Indonesia/05/2005 (H5N1) induced proliferation of autologous lymphoid cells suggesting antigen processing by MDMs and stimulation of a memory T cell response. Pulse-exposure of MDMs with H1-VLPs resulted in a rapid and massive intracellular accumulation of HA that was driven by clathrin-mediated and clathrin-independent endocytosis as well as macropinocytosis/phagocytosis. The H1-VLPs endosomal distribution pattern suggested that HA delivered by VLP had entered both high-degradative late (supporting major histocompatibility complex (MHC) II-restricted antigen presentation) and low-degradative static early and/or recycling (favoring MHC I-restricted antigen cross-presentation) endosomal pathways. High-resolution tandem mass spectrometry identified a large number of HA-derived peptides associated with MHC I in the H1-VLP-treated MDMs. In addition, many host-derived MHC I peptides were identified in VLP-treated samples. These peptides were mainly processed by matrix metalloproteinases and cathepsins. The host proteins associated with these peptides were primarily involved in pathways modulating inflammation (i.e. stimulation and attenuation), innate and adaptive immunity, clathrin-mediated endocytosis, protein synthesis and endo-lysosomal degradation. Finally, tools we used while studying endosome-lysosome fusion led to the development of a novel serological assay for influenza based on 1,1'-dioctadecyl-3,3,3',3'-tetramethylindodicarbocyanine perchlorate (DiD) fluorescence dequenching. This assay measures 'functional' influenza antibody titers, is free from observer bias and has the potential to be fully automated. In summary, we demonstrated that HA delivery to APCs in a form of plant-derived VLPs facilitates antigen uptake, endosomal processing, presentation and cross-presentation. These observations may help to explain the broad and cross-reactive immune responses generated by VLP vaccines. The new DiD fluorescence dequenching assay we developed may give new insights into the spectrum of antibodies produced in response to influenza infection or vaccination.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,002 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».