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Papillomavirus-Like Particles Are an Effective Platform for Amyloid- Immunization in Rabbits and Transgenic Mice¹

Eduardo Zamora^2,*, Alessandra Handisurya^2,, Saeed Shafti-Keramat, David Borchelt, Gay Rudow^*, Katherine Conant^*, Christopher Cox, Juan C. Troncoso^3,* and Reinhard Kirnbauer

^* Department of Pathology, Division of Neuropathology, Johns Hopkins University, Baltimore, MD 21205; Laboratory of Viral Oncology, Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Vienna, Austria; Santa Fe Health Alzheimer’s Disease Research Center, Department of Neuroscience, McKnight Brain Institute, University of Florida, Gainesville, FL 32611; and Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205

Immunization with amyloid- (A) prevents the deposition of A in the brain and memory deficits in transgenic mouse models of Alzheimer’s disease (AD), opening the possibility for immunotherapy of AD in humans. Unfortunately, the first human trial of A vaccination was complicated, in a small number of vaccinees, by cell-mediated meningoencephalitis. To develop an A vaccine that lacks the potential to induce autoimmune encephalitis, we have generated papillomavirus-like particles (VLP) that display 1–9 aa of A protein repetitively on the viral capsid surface (A-VLP). This A peptide was chosen because it contains a functional B cell epitope, but lacks known T cell epitopes. Rabbit and mouse vaccinations with A-VLP were well tolerated and induced high-titer autoAb against A, that inhibited effectively assembly of A_1–42 peptides into neurotoxic fibrils in vitro. Following A-VLP immunizations of APP/presenilin 1 transgenic mice, a model for human AD, we observed trends for reduced A deposits in the brain and increased numbers of activated microglia. Furthermore, A-VLP vaccinated mice also showed increased levels of A in plasma, suggesting efflux from the brain into the vascular compartment. These results indicate that the A-VLP vaccine induces an effective humoral immune response to A and may thus form a basis to develop a safe and efficient immunotherapy for human AD.

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