Antibody response and plasma A?1-40 levels in young Microcebus murinus primates immunized with A?1-42 and its derivatives

Trouche, Stéphanie G., Asuni, Ayodeji, Rouland, Sylvie, Wisniewski, Thomas, Frangione, Blas, Verdier, Jean-Michel, Sigurdsson, Einar M. and Mestre-Francés, Nadine (2009) Antibody response and plasma A?1-40 levels in young Microcebus murinus primates immunized with A?1-42 and its derivatives. Vaccine, 27 (7), 957-964. (doi:10.1016/j.vaccine.2008.12.012).

Abstract

We have been developing A? derivative vaccines with the objective to improve the safety of A? targeting immunotherapy. Our A? homologs are designed to have less direct toxicity and to produce a modified immune response compared to A?. In extensive mouse studies, all our vaccines have improved cognition in transgenic mice while eliciting different immune responses and reducing brain amyloid burden to a variable degree. While we are continuing to characterize these vaccines in mice, in preparation for studies in old primates and for human trials we assessed their effect in young lemur primates (n = 25) that with age develop A? plaques and tau aggregates as seen in Alzheimer's disease.

In the primates, all the peptides administered with alum adjuvant elicited a moderate to robust anti-A? IgM response. A?1-42, K6A?1-30 and K6A?1-30[E18E19] resulted in a high anti-A? IgG response, whereas A?1-30[E18E19] produced a weaker more variable IgG titer. Notably, 22 weeks after the 3rd immunization, IgM and IgG levels in derivative-vaccinated primates were similar to preimmune values whereas A?1-42 treated primates maintained a moderate IgG titer. The increase in antibodies that recognized A?1-40 often correlated with increase in A?1-40 in plasma, which suggests that the antibodies were binding to A? in vivo. Interestingly, significant transient weight gain was observed (K6A?1-30-, A?1-30[E18E19]- and A?1-42-treated) or a trend in the same direction (K6A?1-30[E18E19]-treated, adjuvant controls) following the injections. Based on these findings, we have chosen K6A?1-30 for immunizations in old primates as the antibody response to this vaccine was less variable compared to other A? derivatives. Our present findings indicate that most of our A? derivatives elicit a substantial antibody response in primates, and importantly this effect is reversible which enhances the safety profile of our approach.

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