An amyloid beta vaccine that safely drives immunity to a key pathological species in Alzheimer’s disease: pyroglutamate amyloid beta

• Published in: Brain communications Vol. 4; no. 1; p. fcac022
• Main Authors: Vukicevic, M., Fiorini, E., Siegert, S., Carpintero, R., Rincon-Restrepo, M., Lopez-Deber, P., Piot, N., Ayer, M., Rentero, I., Babolin, C., Bravo-Veyrat, S., Giriens, V., Morici, C., Beuzelin, M., Gesbert, A., Rivot, S., Depretti, S., Donati, P., Streffer, J., Pfeifer, A., Kosco-Vilbois, M. H.
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 2022
• Subjects: Original; vaccine; Alzheimer’s disease; pyroglutamate amyloid beta; amyloid beta
• ISSN: 2632-1297; 2632-1297
• DOI: 10.1093/braincomms/fcac022

Abstract Pyroglutamate amyloid beta3–42 (pGlu-Abeta3–42), a highly amyloidogenic and neurotoxic form of Abeta, is N-terminally truncated to form a pyroglutamate and has recently been proposed as a key target for immunotherapy. Optimized ACI-24, a vaccine in development for the treatment and prevention of Alzheimer’s disease, focuses the antibody response on the first 15 N-terminal amino acids of Abeta (Abeta1–15). Importantly, clinical data with an initial version of ACI-24 incorporating Abeta1–15, established the vaccine’s safety and tolerability with evidence of immunogenicity. To explore optimized ACI-24’s capacity to generate antibodies to pGlu-Abeta3–42, pre-clinical studies were carried out. Vaccinating mice and non-human primates demonstrated that optimized ACI-24 was well-tolerated and induced an antibody response against Abeta1–42 as expected, as well as high titres of IgG reactive with pyroGlu-Abeta. Epitope mapping of the polyclonal response confirmed these findings revealing broad coverage of epitopes particularly for Abeta peptides mimicking where cleavage occurs to form pGlu-Abeta3–42. These data are in striking contrast to results obtained with other clinically tested Abeta targeting vaccines which generated restricted and limited antibody diversity. Taken together, our findings demonstrate that optimized ACI-24 vaccination represents a breakthrough to provide a safe immune response with a broader Abeta sequence recognition compared to previously tested vaccines, creating binders to pathogenic forms of Abeta important in pathogenesis including pGlu-Abeta3–42. Vukicevic et al. show that vaccination of mice or non-human primates with the optimized ACI-24 vaccine targeting amyloid beta1–15 (Abeta1–15) as epitope was well-tolerated and importantly induced immunoglobulin G antibodies recognizing not only Abeta1–15 but also the highly neurotoxic pyroglutamate Abeta species. Graphical Abstract Graphical Abstract Video Abstract 10.1093/brain/fcac022_video1 Video Abstract fcac022media1 6298953848001