DNA AB42 VACCINATION LEADS TO HIGH ANTIBODY RESPONSES IN RABBITS AND RHESUS MONKEYS

Abstract

After successful experiments in mouse AD models, active immunization with Aβ42 peptide and passive immunizations with anti-Aβ42 antibodies were started in clinical trials. In humans, active Aβ42 peptide immunization resulted in menigo-encephalitis and inflammation, and the trial was stopped. Passive immunizations had shown some slowing of AD pathology. Active DNA Aβ42 immunizations into the skin elicits a non-inflammatory immune response in mouse models. While in rodents good immune responses had been found for this type of immunization, positive results in larger mammals are missing. We present here results from NZW rabbits and Rhesus macaques after DNA Aβ42 immunization via gene gun delivery into the skin. Sixteen NZW rabbits and six Rhesus macaques were immunized five times with two different doses of a DNA Aβ42 trimer vaccine: Half of the animals in each species received 8 μg DNA per immunization time point (low dose); the other half received 16 μg DNA per immunization (high dose). Antibody responses were analyzed from blood throughout the study. In rabbits, cellular immune responses were determined from spleens after five vaccinations. In monkeys, cellular immune responses were determined with ELISPOT assays from PBMC following the third vaccination, and will be further followed. High antibody responses were found in both species. In the rabbit, 277.1 ± 118.4 μg/ml plasma were measured after 5 immunizations with no significant differences between the dose groups. Antibody levels declined slightly to 246.6 ± 109.5 μg/ml after a resting period of two months. Low levels of IFNγ and IL-17 secreting splenocytes were found in the ELISPOT assays from rabbit splenocytes. Rhesus monkeys reached mean antibody levels of 114.2 ± 41.67 μg/ml plasma after five immunizations. The isotype profile was high on IgG4 antibodies, indicative of a Th2 immune response. After three immunizations, no IL-17 or IFNγ producing cells were found in ELISPOT assays from PBMCs. DNA Aβ42 immunization leads to high antibody titers in large mammals, and is likely to produce high antibody levels and a safe (Th2 biased) immune response in humans as well. supported by NIA/NIH P30AG12300-21, Zale Foundation, Rudman Foundation, AWARE, Presbyterian Village North, Freiberger, and Denker Family Funds