Rational design of a vaccine for Alzheimer’s disease using computationally-derived conformational B cell epitopes to selectively target toxic amyloid-beta oligomers (S26.004)
Notice bibliographique
Résumé
Objective: Design an optimal amyloid-beta (Abeta) vaccine to elicit a robust and durable antibody response against toxic Abeta oligomers (ABO) without inducing potentially detrimental B or T cell responses against plaque or normal Abeta. Background: Abeta vaccines have the potential to protect against disease but also carry the risk of eliciting proinflammatory T cell responses causing meningoencephalitis, and plaque-reactive antibodies that can increase the risk of brain edema (ARIA-E). To circumvent these issues and induce an antibody response that selectively targets soluble toxic ABO, we designed a vaccine consisting of a computationally-derived conformational B cell epitope of ABO, coupled to KLH as a carrier protein to provide T cell help. Design/Methods: Mice received 3 immunizations, 4 weeks apart, with vaccine conjugate in alum or QS-21 as adjuvants. Serum titers and IgG subtypes of antibodies to the peptide epitope were measured by ELISA. The selectivity of serum antibodies for toxic ABO versus monomers or plaque was assessed by SPR and immunohistochemistry, respectively. T helper responses to the peptide and to KLH were evaluated by ELISPOT analysis of splenic lymphocytes. Results: A robust antibody response against the ABO epitope was observed with both adjuvants and was remarkably maintained unabated out to 6 months after the last immunization. The serum antibodies reacted with ABO only, not monomers or plaque. ELISPOT analysis showed T helper cytokine production in response to stimulation with KLH but not the ABO epitope thereby confirming that the peptide only contains a B cell epitope. Conclusions: A vaccine consisting of an ABO-restricted conformational B cell epitope conjugated to KLH produced a strong Abeta antibody response with no measurable pro-inflammatory T cell response against Abeta. In addition, the oligomer selectivity of the antibodies focused the response on pathogenic ABO, potentially reducing the risk of ARIA-E associated with binding to plaque and vascular deposits of Abeta. Disclosure: Dr. Kaplan has received personal compensation for serving as an employee of ProMIS Neurosciences. Dr. Kaplan has stock in ProMIS Neurosciences. Dr. Kaplan has received intellectual property interests from a discovery or technology relating to health care. The institution of Dr. Napper has received research support from Weston Family Foundation. Ms. Scruten has nothing to disclose. Dr. Gibbs has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Promis Neuroscinces. Ms. Coutts has nothing to disclose. Dr. Cashman has received personal compensation for serving as an employee of ProMIS Neurosciences. Dr. Cashman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Mitsubishi-Tanabe. Dr. Cashman has stock in ProMIS Neurosciences. The institution of Dr. Cashman has received research support from ProMIS Neurosciences. Dr. Cashman has received intellectual property interests from a discovery or technology relating to health care. Dr. Cashman has a non-compensated relationship as a BoD memeber with ALS Society of BC that is relevant to AAN interests or activities.
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 distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
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 tête enseignante, 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 ».