Pre-clinical and clinical data suggest that the development of a safe and effective A?-immunotherapy for AD requires anti- A? antibodies, while avoiding proinflammatory adjuvants and autoreactive T cells which are believed to be responsible for the adverse events (meningoenchephalitis) that occurred in response to the AN1792 clinical trial in AD patients. Our prototype Peptide epitope Vaccine (PepVac) and DNA epitope Vaccine (DepVac) were designed with three copies of the self-B cell epitope of A?, A?1-11, in tandem with a promiscuous foreign T cell epitope, PADRE, linked to the powerful anti-inflammatory molecular adjuvant, macrophage derived chemokine (CCL22). Our tripartite DepVac approach induced robust anti-A? antibody titers in transgenic mouse models of AD. Unfortunately, the AN1792 clinical trial also suffered from a low number of responders and generally low titers in those that did respond to the AN1792 vaccine. Thus future clinical trials need to address the prevalence of immunosenescence in the elderly to insure both the safety and the success of the vaccine. In order to overcome serious concerns regarding the limited ability of the elderly to mount an effective immune response to active immunization, we propose to take advantage of pre-existing memory CD4+T helper (Th) cells that were generated in response to conventional public health vaccination programs and/or infections with various pathogens. Thus in our new approach we have engineered modified PepVac and DepVac that contain Multiple Th epitopes that are expected to activate memory Th cells, which will then provide Th stimulation of B cells expressing Ig receptors for the A?1-11, B cell epitope. These third generation vaccine candidates have been designated MPepVac and MDepVac to indicate the use Multiple Th epitopes. Thus, the goals of this renewal proposal are: 1) to demonstrate the feasibility of pre-existing memory CD4+Th cells in aged animal models to induce a rapid and robust anti- A? antibody response;2) to examine the safety and efficacy of MDepVac and/or MPepVac in Tg2576 mice and rabbits, which represent an excellent larger animal model compared to rodent to show feasibility to scale up DNA immunization;3) to compare intramuscular versus intradermal DNA immunization using electroporation system that is currently being used in human clinical trials for other vaccine applications. Ultimately we believe that the further refinement our AD DNA- and protein-based epitope vaccine candidates will facilitate translation to human clinical trials in either very early AD, or preferably to preclinical stage individuals identified by validated AD biomarkers.

Public Health Relevance

Alzheimer's Disease is the major cause of dementia in the US and characterized by progressive cognitive decline that impacts memory, language, judgment, orientation to time and place, etc. Pathologically there is an increase in the presence in amyloid plaques, neurofibrillary tangles, dystrophic neurites and a general loss of neurons. In current project we propose to generate safe and effective epitope vaccine that may prevent/reduce development of Alzheimer's disease pathology in pre-symptomatic people diagnosed with early-stage AD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS050895-10
Application #
8465918
Study Section
Special Emphasis Panel (ZRG1-BDCN-Y (04))
Program Officer
Corriveau, Roderick A
Project Start
2004-09-25
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2013
Total Cost
$404,429
Indirect Cost
$44,509
Name
University of California Irvine
Department
Internal Medicine/Medicine
Type
Organized Research Units
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Davtyan, Hayk; Petrushina, Irina; Ghochikyan, Anahit (2014) Immunotherapy for Alzheimer's disease: DNA- and protein-based epitope vaccines. Methods Mol Biol 1143:259-81
Davtyan, Hayk; Ghochikyan, Anahit; Hovakimyan, Armine et al. (2014) Immunostimulant patches containing Escherichia coli LT enhance immune responses to DNA- and recombinant protein-based Alzheimer's disease vaccines. J Neuroimmunol 268:50-7
Davtyan, Hayk; Ghochikyan, Anahit; Petrushina, Irina et al. (2014) The MultiTEP platform-based Alzheimer's disease epitope vaccine activates a broad repertoire of T helper cells in nonhuman primates. Alzheimers Dement 10:271-83
Ghochikyan, Anahit; Petrushina, Irina; Davtyan, Hayk et al. (2014) Immunogenicity of epitope vaccines targeting different B cell antigenic determinants of human *-synuclein: feasibility study. Neurosci Lett 560:86-91
Davtyan, Hayk; Hovakimyan, Armine; Zagorski, Karen et al. (2014) BTX AgilePulse(TM) system is an effective electroporation device for intramuscular and intradermal delivery of DNA vaccine. Curr Gene Ther 14:190-9
Davtyan, Hayk; Ghochikyan, Anahit; Hovakimyan, Armine et al. (2014) A dual vaccine against influenza & Alzheimer's disease failed to enhance anti-?-amyloid antibody responses in mice with pre-existing virus specific memory. J Neuroimmunol 277:77-84
Davtyan, Hayk; Bacon, Andrew; Petrushina, Irina et al. (2014) Immunogenicity of DNA- and recombinant protein-based Alzheimer disease epitope vaccines. Hum Vaccin Immunother 10:1248-55
Ghochikyan, Anahit; Davtyan, Hayk; Petrushina, Irina et al. (2013) Refinement of a DNA based Alzheimer's disease epitope vaccine in rabbits. Hum Vaccin Immunother 9:1002-10
Davtyan, Hayk; Ghochikyan, Anahit; Petrushina, Irina et al. (2013) Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer's disease: prelude to a clinical trial. J Neurosci 33:4923-34
Passos, Giselle F; Medeiros, Rodrigo; Cheng, David et al. (2013) The bradykinin B1 receptor regulates A? deposition and neuroinflammation in Tg-SwDI mice. Am J Pathol 182:1740-9

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