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OPTIMIZING VACCINE DESIGN FOR ALZHEIMER’S DISEASE: SELECTIVE TARGETING OF COMPUTATIONALLY-DERIVED CONFORMATIONAL B CELL EPITOPES OF SOLUBLE AMYLOID-BETA TOXIC OLIGOMERS
Abstract
Aims
Design an optimal amyloid-beta (Abeta) vaccine to elicit antibodies selective for toxic Abeta oligomers (ABO) without inducing potentially detrimental B or T cell reactivity to normal Abeta.
Methods
A conformational B cell epitope previously determined to elicit antibodies selective and protective against toxic ABO (cyclized HHQK peptide; Gibbs et al, Scientific Reports, 2018), was coupled to KLH as a carrier protein to provide T helper epitopes. Mice received 2 immunizations with the conjugate in 3 different adjuvant formulations (alum, Emulsigen, TriAdj). Serum titers of total IgG, IgG1 and IgG2a antibodies to the peptide epitope were measured by ELISA. T helper type 1 (Th1) and type 2 (Th2) responses to the peptide and to KLH were evaluated by ELISPOT analysis of splenic lymphocytes.
Results
A robust antibody response against the conformational peptide epitope was observed with all 3 adjuvants. Alum gave rise to a predominantly IgG1 response while Emulsigen and TriAdj produced a more comparable IgG1/IgG2a response. ELISPOT analysis showed a lack of Th1 (interferon-gamma) or Th2 (IL-5) cytokine production in response to stimulation with the ABO epitope thereby confirming that the peptide only contains a B cell epitope. T cell help was provided by the carrier and stimulation with KLH induced Th2-biased cytokine production.
Conclusions
A vaccine consisting of an ABO-restricted conformational B cell epitope conjugated to KLH for T cell help successfully induced an antibody response to the B cell epitope without eliciting a potentially inflammatory Abeta-directed T helper response. This vaccine configuration has the potential for optimal safety and efficacy.