Select the epitope composition of a vaccine designed to achieve maximal targeting of toxic amyloid-beta (Abeta) oligomers.

A large body of evidence indicates that soluble toxic oligomers of Abeta are a primary driver of Alzheimer’s disease (AD).  Through computational modeling, 4 different conformational B cell epitopes of Abeta oligomers were identified.  A novel approach was utilized to select an optimal vaccine composition amongst 15 possible combinations of 1 to 4 epitopes to provide maximal binding to a toxic oligomer-enriched low molecular weight (LMW) fraction of soluble AD brain extract.

All 4 epitopes elicited robust antibody responses.  ELISPOT analysis showed a T cell response to KLH only, and not the oligomer epitopes.  Serum antibodies elicited by the 4 epitopes all showed the desired selective reactivity with oligomers, not monomers nor plaque. Comparison of the SPR binding responses to the LMW fraction of AD brain extract by equivalent amounts of IgG from immune serum of monovalent vaccines vs mixtures of 2, 3 or 4 sera was used to rank vaccine compositions.  Maximal reactivity was observed with immune IgG against a single epitope (peptide 301), the target of PMN310, our clinical-stage monoclonal antibody.  There was no advantage of additional epitopes.

Vaccination with oligomer-restricted conformational B cell epitopes conjugated to KLH produced strong antibody responses with no measurable pro-inflammatory T cell responses against Abeta.  Immunization with epitope 301 alone was sufficient to produce maximal reactivity against brain oligomers.