595. Nasal Delivery of Adenovirus Expressing the Ebola Glycoprotein Protects Mice Against Ebola Virus in the Presence of Preexisting Immunity to the Vaccine Carrier
Bibliographic record
Abstract
The Ebola hemorrhagic fever virus has drawn increasing interest in the past years due to an augmentation in the number of natural outbreaks and its potential use as a bioterror agent. To date, only vaccine based on Vesicular Stomatitis virus and Adenovirus as the vaccine carrier have successfully protected nonhuman primates against a lethal dose of Ebola virus. Adenovirus vector derived from human adenovirus serotype 5 (AdHu5) has the advantage of having a well document track record following in vivo administration to thousand of individuals in different clinical trials. However, natural exposure to Adenovirus may result in the generation of a potent immunity capable of compromising adenovirus-based vaccine efficacy. 30 to 50% of the human population in North America has levels of serum antibodies that can neutralize relatively high doses of AdHu5. The present study evaluated mucosal vaccination of mice with AdHu5 expressing the Ebola glycoprotein (Ad-EboGP) and the impact of pre-existing immunity to the Adenovirus vector on vaccine efficacy. Intramuscular (I.M.), oral or nasal administration of Ad-EboGP fully protected mice against a lethal challenge with mouse-adapted Ebola virus. However, oral or I.M. vaccination of mice pretreated with pooled human antibodies, mimicking the presence of pre-existing immunity as evidenced by neutralizing antibody (NAB) to AdHu5 in mice sera, resulted in 0 to 10% survival after challenge with mouse-adapted Ebola virus. Interestingly, nasalvaccination with Ad-EboGP was protective even in the presence of preexisting immunity and resulted in 100% survival with no weight loss after challenge with Ebola virus. In untreated mice, T (INF-γ positive CD8 T cells following peptide re-stimulation) and B cell (NAB) responses were detected in all EboGP vaccinated groups although both responses were lower in mice receiving oral or nasal immunization when compared to mice administered I.M.. The presence of pre-existing immunity severely compromised the T and B cell responses in mice vaccinated orally or I.M. but not in mice receiving nasal immunization. Interestingly, PEGylation of the adenovirus vector partially rescued the B cell response but diminished the T cell response after oral vaccination of mice with pre-existing immunity and failed to improve survival. This study highlights the importance of vaccine delivery routes with regards to efficacy in the presence or absence of pre-existing immunity and provides new evidence for successful vaccination with AdHu5 and possibly readministration. James Wilson had equity in Targeted Genetics at the time of the study.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".