479. An Optimized DNA Vaccine Formulation Protects Against Lethal Ebola Makona Virus Challenge in Non-Human Primates and Elicits Robust Immune Responses
Notice bibliographique
Résumé
The West African Ebola hemorrhagic fever virus outbreak is the most wide-spread occurrence of the virus to-date. Over 28 000 cases have been confirmed, however the actual figures are likely much higher. There are currently no approved vaccines but several clinical trials of viral vector candidates are underway and evidence suggests that the VSV-ZEBOVGP vaccine can prevent further transmission of the virus. However, the considerable drawback of anti-vector immunity still remains to be addressed and reports from human clinical trials observe the presence of adverse events including fever, blistering, and development of arthritis/joint pain which may limit some applications of this vaccine. Therefore, investigating alternative immunization approaches is important. We designed a DNA vaccine formulation expressing 3 synthetic Zaire Ebola virus (EBOV) glycoproteins (GP): 2 designed based on GP sequence alignments (1976-2014) and a 3rd construct matched to a 2014 outbreak strain. Plasmid IL-12 (pIL-12) was also included as an adjuvant to further enhance cellular immune responses. We administered this multivalent GP DNA vaccine formulation in macaques following a DNA-DNA prime-boost immunization regimen. Macaques (n=3 or 4/group) received the multivalent GP DNA formulation + pIL-12 by intramuscular delivery followed by electroporation. We assayed differences in immunogenicity and monitored protection between different doses, regimens (2, 3, 4, and 5 injections), and different spacing intervals between subsequent doses. Both antibody and T cell responses were observed in 83% of animals 2 weeks following the first injection and 100% of animals after the 2nd injection. The macaques were challenged with a lethal dose of the EBOV Guinea-Makona outbreak strain (1000pfu, 7-U virus) and monitored for 28 days following infection. 100% of animals receiving at least 3 injections at 4 week intervals survived lethal challenge. Animals were fully protected against signs of disease and did not exhibit elevated blood chemistry. Interestingly, 50% of animals receiving 2 injections survived lethal challenge. The surviving animals exhibited minimal signs of disease, suggesting that with further optimization complete protection with 2 injections is potentially achievable. In additional optimization studies in mice, single injections were found to be 100% protective and we observed that long-term immune responses 8 months post vaccination were induced. Further studies in NHP are now in progress.
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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 | 0,001 | 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 ».