Rational design of a vaccine for Alzheimer’s disease using a computationally‐derived conformational epitope to selectively target toxic amyloid‐beta oligomers
Bibliographic record
Abstract
Abstract Background Amyloid‐beta (Aß) 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 Aß oligomers (AßO), without inducing potentially detrimental B or T cell responses against plaque or normal Aß, we used our Collective Coordinates computational platform to design a vaccine consisting of a conformational epitope of AßO, coupled to keyhole limpet hemocyanin (KLH) as a carrier protein to provide T cell help. Method Mice received 3 immunizations, 4 weeks apart, with vaccine conjugate in alum or QS‐21 as adjuvants. Serum titers of total IgG, IgG1 and IgG2a antibodies to the peptide epitope were measured by ELISA. The selectivity of serum antibodies for toxic AßO versus monomers was evaluated by surface plasmon resonance, and plaque reactivity was assessed by immunohistochemistry on AD brain sections. T helper type 1 (Th1) and type 2 (Th2) responses to the peptide and to KLH were evaluated by ELISPOT analysis of splenic lymphocytes. Result A robust antibody response against the conformational AßO epitope was observed with both adjuvants and remained undiminished out to 6 months after the last immunization. Alum gave rise to a predominantly IgG1 response while QS‐21 produced a more comparable IgG1/IgG2a response. The serum antibodies showed the desired binding profile and reacted with AßO only, not Aß monomers or plaque. ELISPOT analysis showed a lack of Th1 (interferon‐gamma) or Th2 (IL‐5) cytokine production in response to stimulation with the AßO epitope thereby indicating that the peptide only contains a B cell epitope. T cell help was provided by the carrier and, as expected, stimulation with KLH induced Th cytokine production. Conclusion A vaccine consisting of an AßO‐restricted conformational B cell epitope conjugated to KLH produced a strong Aß antibody response with no measurable pro‐inflammatory T cell response against Aß. In addition, the oligomer selectivity of the antibodies focused the response on pathogenic AßO, potentially reducing the risk of ARIA‐E associated with binding to plaque and vascular deposits of Aß.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 source (direct Gemma or distilled Codex), 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".