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.

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.

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.  

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.   

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.