Alzheimer’s Disease Vaccines Laboratory
The main focus of our laboratory is the development of an effective and safe vaccine against Alzheimer’s Disease (AD), one of the most devastating diseases of the century. Amyloid-beta (Ab) immunotherapy is considered to be a promising approach to reducing the level of Ab in the CNS of AD patients. However, data from the first clinical trial AN1792 indicated that vaccine should be designed not to induce autoreactive cellular responses and to be effective in the majority of the individuals from the risk groups. Therefore, we are focused on the generation of peptide (Petrushina I. et al., 2007 ) or DNA based (Movsesyan N. et al., 2008; Movsesyan N. et al., 2008) epitope vaccines composed of self B cell epitope of Ab peptide and foreign universal T cell epitopes such as synthetic Pan DR epitope PADRE or epitopes from currently approved conventional vaccines. Based on our research the protein AD vaccine was developed and will be tested in clinical trials in the nearest future. On the other hand, together with our collaborators at UCI MIND we generated a DNA-based epitope vaccine composed of 3 copies of self B cell epitope, foreign T cell epitope PADRE and macrophage derived chemokine (MDC) (Movsesyan N. et al., 2008). We demonstrated that immunization of 3xTg-AD mice with DNA epitope vaccine:
- Induced high titers of anti-Ab antibody production without activation of autoreactive T cells
- Reduced soluble and insoluble Ab accumulation in brains of vaccinated mice
- Improved cognitive performance
- Reduced glial activation without inducing hemorrhages
Currently the safety and efficacy of a DNA AD epitope vaccine is being tested in monkeys using the TDS-IM electroporation system in collaboration with ICHOR Medical Systems. DNA vaccines exhibit several significant advantages when compared to recombinant protein or peptide-based vaccines and are very effective in mice. However, they traditionally induce low immune responses in large animals and humans. Therefore, the translation of a DNA vaccine to the clinic may require further enhancement of immunogenicity using different approaches. Currently we are working on the further enhancement of the immunogenicity of our DNA epitope vaccine by:
- Improving the DNA delivery system
- Developing more effective immunization protocols such as the prime/boost regimen
- Combining DNA immunization with an immunostimulant patches (in collaboration with Intercell)
- Incorporating additional foreign Th cell epitopes to target pre-existing memory T cells
Collectively, our published and unpublished results generated with our collaboratorsdemonstrated that a DNA- and protein- based epitope vaccines could be a translatable and effective vaccine strategy for the prevention and treatment of AD.
- Ghochikyan A, Davtyan H, Petrushina I, Hovakimyan A, Movsesyan N, Kiyatkin A, Hannaman D, Evans CF, Cribbs DH, Agadjanyan MG, Refinement of a DNA based Alzheimer’s disease epitope vaccine in rabbits. Vaccine, 2012, in press.
- Davtyan H, Ghochikyan A, Movsesyan N, Ellefsen B, Petrushina I, Cribbs DH, Hannaman D, Evans CF, Agadjanyan MG. Delivery of a DNA vaccine for Alzheimer’s disease by electroporation or gene gun generates potent and similar immune responses. Neurodegenerative Diseases. 2012;10(1-4):261-4.
- Davtyan H, Ghochikyan A, Cadagan R, Zamarin D, Petrushina I, Movsesyan N, Martinez-Sobrido L, Albrecht RA, García-Sastre A, Agadjanyan MG. The immunological potency and therapeutic potential of a prototype dual vaccine against influenza and Alzheimer’s disease. J Transl Med. 2011 Aug 1;9:127.
- Robert R, Lefranc MP, Ghochikyan A, Agadjanyan MG, Cribbs DH, Van Nostrand WE, Wark KL, Dolezal O. Restricted V gene usage and VH/VL pairing of mouse humoral response against the N-terminal immunodominant epitope of the amyloid β peptide. Mol Immunol. 2010 Nov-Dec;48(1-3):59-72.
- Movsesyan N, Davtyan H, Mkrtichyan M, Petrushina I, Tiraturyan T, Ross TM, Agadjanyan MG, Ghochikyan A, Cribbs DH. Low concentrations of anti-Abeta antibodies generated in Tg2576 mice by DNA epitope vaccine fused with 3C3d molecular adjuvant do not affect AD pathology. Hum Gene Ther. 2010, 21(11):1569-1576. Gene Ther. 2010 Feb;17(2):261-71.
- Davtyan H, Mkrtichyan M, Movsesyan N, Petrushina I, Mamikonyan G, Cribbs DH, Agadjanyan MG, Ghochikyan A . DNA prime-protein boost increased the titer, avidity and persistence of anti-Abeta antibodies in wild-type mice. Gene Ther. 2010 Feb;17(2):261-71.
- Agadjanyan MG, Cribbs DH. Active and passive Abeta-immunotherapy: preclinical and clinical studies and future directions: part I. CNS Neurol Disord Drug Targets. 2009 Mar;8(1):1-6.
- Ghochikyan A. Rationale for peptide and DNA based epitope vaccines for Alzheimer’s disease immunotherapy. CNS Neurol Disord Drug Targets. 2009 Apr;8(2):128-43.
- Movsesyan N, Mkrtichyan M, Petrushina I, Ross TM, Cribbs DH, Agadjanyan MG, Ghochikyan A. DNA epitope vaccine containing complement component C3d enhances anti-amyloid-beta antibody production and polarizes the immune response towards a Th2 phenotype. J Neuroimmunol. 2008 Dec 15;205(1-2):57-63.
- Petrushina I, Ghochikyan A, Mkrtichyan M, Mamikonyan G, Movsesyan G, Ajdari R, Vasilevko V, Karapetyan A, Lees A, Agadjanyan MG, Cribbs DH. Mannan-Abeta28 conjugate prevents Abeta-plaque deposition, but increases microhemorrhages in the brains of vaccinated Tg2576 (APPsw) mice. J Neuroinflammation. 2008 Sep 29;5:42.
- Movsesyan N, Ghochikyan A, Mkrtichyan M, Petrushina I, Davtyan H, Olkhanud PB, Head E, Biragyn A, Cribbs DH, Agadjanyan MG. Reducing AD-like pathology in 3xTg-AD mouse model by DNA epitope vaccine – a novel immunotherapeutic strategy. PLoS ONE. 2008 May 7;3(5):e2124.
- Mkrtichyan M, Ghochikyan A, Movsesyan N, Karapetyan A, Begoyan G, Yu J, Glenn GM, Ross TM, Agadjanyan MG, Cribbs DH. Immunostimulant adjuvant patch enhances humoral and cellular immune responses to DNA immunization. DNA Cell Biol. 2008 Jan;27(1):19-24.
- Petrushina I, Ghochikyan A, Mktrichyan M, Mamikonyan G, Movsesyan N, Davtyan H, Patel A, Head E, Cribbs DH, Agadjanyan MG. Alzheimer’s disease peptide epitope vaccine reduces insoluble but not soluble/oligomeric Abeta species in amyloid precursor protein transgenic mice. J Neurosci. 2007 Nov 14;27(46):12721-31.
- Mamikonyan G, Necula M, Mkrtichyan M, Ghochikyan A, Petrushina I, Movsesyan N, Mina E, Kiyatkin A, Glabe CG, Cribbs DH, Agadjanyan MG. Anti-A beta 1-11 antibody binds to different beta-amyloid species, inhibits fibril formation, and disaggregates preformed fibrils but not the most toxic oligomers. J Biol Chem. 2007 Aug 3;282(31):22376-86.
- Agadjanyan MG, Ghochikyan A, Petrushina I, Vasilevko V, Movsesyan N, Mkrtichyan M, Saing T, Cribbs DH. Prototype Alzheimer’s disease vaccine using the immunodominant B cell epitope from beta-amyloid and promiscuous T cell epitope pan HLA DR-binding peptide. J Immunol. 2005 Feb 1;174(3):1580-6.
- Ghochikyan A, Vasilevko V, Petrushina I, Movsesyan N, Babikyan D, Tian W, Sadzikava N, Ross TM, Head E, Cribbs DH, Agadjanyan MG. Generation and characterization of the humoral immune response to DNA immunization with a chimeric Beta-amyloid-Interleukin-4 minigene. Eur J Immunol. 2003 Dec;33(12):3232-41.